Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
humans are infected naturally by 3 species of hookworms ; necator americanus , ancylostoma duodenale , and ancylostoma ceylanicum .
individual people can be infected with 1 species , 2 species , or all 3 species of hookworms [ 1 - 5 ] . although a. ceylanicum is often considered to be a zoonotic pathogen , since it is also found in dogs and cats , its importance as a significant soil - transmitted helminth of humans is increasingly being recognized .
two haplotypes of a. ceylanicum have been identified ; one largely found in humans and another that infects humans , dogs , and cats .
a. ceylanicum is considered to be of emerging importance as a helminth of humans in the asia pacific region .
a fourth hookworm also reported from humans , ancylostoma caninum represents a canine species with zoonotic potential .
this species has mainly been recorded as causing eosinophilic enteritis in people in tropical australia , but never establishes a patent infection and hence humans are regarded as accidental hosts .
human hookworm is common in the solomon islands , with an estimated 192,000 people ( 36% of the population ) infected , but the different species involved are yet to be determined [ 9 - 11 ] .
the report to the rockefeller hookworm campaign in 1928 described only n. americanus as being present on these islands .
the only previous report of a. ceylanicum from the solomon islands was a 5-year - old boy who imported the species in 1938 from the shortland island group of the solomon islands to australia .
the solomon islands is a small pacific nation to the north east of australia , with a predominantly melanesian population .
the regional assistance mission to solomon islands ( ramsi ) occurred between 2003 and 2013 , at the request of the solomon island s government , to assist in stabilizing internal troubles occurring within the nation .
ramsi consisted of 2,200 police and soldiers from many pacific island nations and was led by australia .
this case report describes the finding of a. ceylanicum in an australian soldier who developed symptomatic disease after returning from a deployment in solomon islands with ramsi .
the patient was a 26-year - old male living in townsville , north queensland , australia who presented in march 2004 with central poorly defined abdominal pain of 4 weeks duration and increased frequency of defecation .
a peripheral eosinophilia had been noted on blood tests in february prior to symptom development , and in march , when eosinophils were 6.2010/l whilst red blood cell indices were normal ( hemoglobin 146 g / l , mcv 93 fl , hematocrit 0.44 , red cell count 4.710/l ) .
the patient had served with ramsi in the solomon islands from late july to early december 2003 .
his duties involved travel to various remote areas and provided multiple opportunities to become infected with hookworms .
routine treatment with albendazole had been given by the australian defense force on return to townsville in december , 2 months prior to development of symptoms .
initially , in march 2004 no parasite eggs were detected in feces by formalin - ethyl acetate concentration , but infective larvae of hookworms were found on harada - mori culture .
infective larvae were sheathed , had inconspicuous buccal spears , the intestine was narrower than the esophageal bulb , and inconspicuous transverse striations were noted on the sheath in the tail region .
the infective larvae , measured after preservation in hot formalin , had the following dimensions , meansd ( range ) : length 657.19.6 m ( 633 - 669 m ) , width 21.40.9 m ( 20.2 - 22.2 m ) , esophagus 156.73.5 m ( 151 - 162 m ) , tail 77.93.8 m ( 69 - 81 m ) , length of sheath 763.78.6 m ( 779 - 746 m ) ; esophagus / length 23.80.5% , and tail / length 11.90.6% . due to the failure of single dose post - deployment albendazole therapy to eradicate this infection , the patient was treated with 100 mg of mebendazole twice daily for 3 days .
twelve adult hookworms ( 6 females and 6 males ) were recovered by dissection of stools passed during the 48 hr immediately following treatment . the en face view revealed a robust ventral cutting plate bilaterally with a prominent point on the dorsal end and less obvious point on the ventral end ( fig .
the width of the bursa in lateral view was greater than its length , and the mediolateral and posteriolateral bursal rays were parallel ( fig .
the morphology of the adult hookworms was consistent with a. ceylanicum with key features being : the large ventral cutting plates terminating at the dorsal end in a large single tooth ; and in the male the parallel mediolateral and posteriolateral bursal rays .
although the morphology and dimensions of the infective larvae are more consistent with a. ceylanicum than n. americanus , differentiating them from infective larvae of a. duodenale is unreliable .
although molecular taxonomy is valuable in identifying hookworm species , it was not available in this case and , as the specimen was subsequently accidentally disposed of , molecular taxonomic studies can not be performed now . however , the morphological features were sufficient to identify this species as a. ceylanicum .
this represents only the second report of human a. ceylanicum infection having been acquired in this nation , with the first being made almost 80 years ago .
this finding not only expands the known range of human a. ceylanicum infection but also raises the question of whether a. ceylanicum is in fact a common cause of human hookworm infection in some regions of the solomon islands , as it has recently been described as being in many parts of asia . the only previous reported description of hookworm species in the country was almost 80 years ago and was anecdotal , not providing descriptions of number of people tested or how the species identifications were arrived at .
a. ceylanicum infection has recently been reported from two people in western australia . prior to this , a. ceylanicum had been reported from dogs and cats in northern australia , including those from townsville .
hence , the infection could have been acquired in north queensland or while deployed with ramsi .
the likelihood of infection with ancylostoma from humans in the solomon islands is high , but negligible in north queensland since human feces are disposed of safely .
however , since a. ceylanicum is present in dogs and cats in north queensland , there is a possibility of a zoonotic australian source even though this infection has not been seen in humans in this region .
many ramsi personnel were infected with hookworms during their mission to the solomon islands , and an isolated case of a. ceylanicum infection had been reported from this area early in the 20th century .
this adds to the likelihood that the case presented here was acquired in the solomon islands and not elsewhere .
the clinical symptoms displayed by our patient were consistent with the phase of hookworm infection during which the host attempts to eliminate the parasite using an allergic response , manifesting morphologically as eosinophilic enteritis . for n. americanus
this response begins about 10 days after infection and persists for up to a month .
a. caninum and a. duodenale have a more complicated life cycle in which some infective larvae can enter a state of hypobiosis ( arrested development ) and can orchestrate entry to the intestine to coincide with the wet season and physiological events [ 23 - 26 ] . whether a. ceylanicum has
the failure of a routine post - deployment albendazole treatment to eliminate the infection in our patient supports a hypothesis that the current infection was due to hypobiotic larvae activated after the anthelmintic was given .
acute enteritis has been described previously in soldiers with a. ceylanicum acquired in west papua ( formerly dutch new guinea )   and in a traveller returning from myanmar to france .
treatment with albendazole in the latter patient cleared the gut infection but symptoms and parasites recurred after 3 months adding evidence for hypobiosis in a. ceylanicum .
our patient was treated after diagnosis with mebendazole due to its far greater tissue penetration and therefore greater capacity to kill hypobiotic larvae in the tissue .
the key points from this case report are : a. ceylanicum should be considered as a cause of acute eosinophilic enteritis in returned travellers , workers , or defense force personnel who have lived or visited tropical and subtropical countries ; laboratory confirmation may require persistence to make the diagnosis of hookworms and will require special tests ( morphology of adults after treatment ; molecular taxonomy on stools or infective larvae ) to identify the species ; and human infection with a. ceylanicum is probably endemic in the solomon islands and further study of the prevalence of different hookworm species present in this country is warranted .

Answer:
a 26-year - old male member of the australian defense force presented with a history of central abdominal pain of 4 weeks duration and peripheral eosinophilia consistent with eosinophilic enteritis .
 acute hookworm disease was diagnosed as the cause .
 adult worms recovered from feces after therapy with albendazole were morphologically consistent with ancylostoma ceylanicum .
 as the patient had been deployed with the regional assistance mission to solomon islands for 6 months prior to this presentation , it is very likely that the a. ceylanicum was acquired in solomon islands .
 until now , it has been assumed that any ancylostoma spp . recovered from humans in solomon islands
 is a. duodenale .
 however , this case demonstrates that human hookworm infection acquired in the solomon islands could be caused by a. ceylanicum .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
cytomegalovirus ( cmv ) colitis is common among immunocompromised patients who are more prone to opportunistic infections .
after the infection of cmv is detected by histology or serology , antiviral treatment is usually chosen initially . since cmv disease
can not be diagnosed on clinical symptoms alone , diagnosis and treatment are sometimes delayed . here
, we report a case of a hemorrhagic cmv colitis that occurred in an immunocompromised patient after a colectomy due to colon cancer and was successfully treated with ganciclovir .
an 85-year - old woman underwent esophagogastroduodenoscopy and colonoscopy for investigation of anemia . a laterally spreading tumor of the granular type , 85 mm in diameter ,
although magnifying image - enhanced colonoscopy suggested a tubulovillous adenoma , surgical resection , not endoscopic mucosal resection , was chosen because of the size of the tumor . however , as she had a medical history including breast cancer , myocardial infarction , general edema due to chronic renal failure ( oral administration of prednisolone 5 mg / day ) , diverticulosis of sigmoid colon , and bilateral ureteral stent placement due to retroperitoneal fibrosis , she did not want to take medical treatment anymore but to monitor her own condition for a while .
after 3 months , she finally agreed to have surgery and was admitted to our hospital .
the patient underwent ileocecal resection followed by stapled functional end - to - end anastomosis ( fig .
the postoperative course was favorable ; dietary intake and oral drug administration were started on postoperative day 4 and both flatus and stool passed .
however , she had sudden abdominal pain and heavy bloody discharge on postoperative day 11 .
although conservative treatment , including blood transfusion therapy for anemia , was performed initially , there was no improvement after a week .
in addition to the endoscopic findings , the patent 's immunocompromised state suggested possible cmv colitis . because cmv antigen was confirmed in peripheral blood samples , intravenous antiviral treatment was started from the postoperative day 23 ( ganciclovir , 150 mg / day ) .
after 4 days of the treatment , bloody discharge stopped , and at 8 days , improvement of abdominal pain was observed .
the antiviral treatment was continued for 2 weeks until the serological confirmation of negative cmv antigen .
after improvement of the colitis - related symptoms , the patient was discharged from our hospital .
cmv infection often develops a latent infection with no signs or symptoms after acute infection .
although most people are exposed to cmv in their lifetime , typically only the patients with weakened immune systems , such as aids , malignancy , organ transplant or bone marrow transplant , and steroid or immunosuppressive treatments , become ill by reactivating cmv and present with cmv pneumonia , gastroenteritis , retinitis , and encephalitis .
cmv disease is often diagnosed by pathologic and serologic confirmation because clinical symptoms are not specific .
furthermore , colonoscopic findings of cmv colitis mimic many conditions , including pseudomembranous colitis , ischemic colitis , ulcerative colitis and crohn 's disease . in our case , as we initially considered the bleeding from the diverticulum or anastomosis , conservative treatment was chosen .
after one week of conservative therapy , there was no sign of improvement in bloody discharge ; therefore , we decided to perform colonoscopy .
we were hesitant to perform colonoscopy due to our patient having had a colectomy . according to the meta - analysis of cmv colitis in immunocompetent hosts , the highest mortality rates were associated with immune modulating conditions that include 16 patients . of those analyzed ,
5 patients ( 31.3% ) received colectomy as initial treatment and 8 patients ( 50% ) and 6 patients ( 37.5% ) had coexisting renal failure and diabetes mellitus , respectively . in our case
, as the patient was given steroids due to chronic renal failure and the colonoscopy revealed the longitudinal ulcer at the anastomosis , we were able to suspect cmv colitis and confirmed the diagnosis serologically .
because endoscopic biopsy was not performed , cmv infection was not evaluated histologically . of note
, we performed immunohistochemistry of cmv protein using resected colon cancer specimen , though cmv - positive stain was not detected .
this result seems to relate with the fact that cmv is not associated with carcinogenesis and reactivation of latent cmv infection causes cmv colitis [ 5 , 6 ] .
the first choice of treatment of cmv infection is antiviral therapy [ 7 , 8 ] .
systemic antiviral treatment has provided significant advances and has resulted in dramatically improved outcomes [ 7 , 8 ] .
treatment time usually ranges from 1 to 4 weeks , depending on the treatment effect such as improvement of the symptoms and/or confirmation of the negative cmv antigen . in our case , despite the necessity of reducing the dose of ganciclovir due to renal failure , the patient showed good response to systemic therapy and did not require further treatment . fortunately , as she did not show uncontrollable heavy bleeding or symptoms of bowel perforation , surgical resection was not needed .
the case we mentioned above can potentially occur in immunocompromised patients . with recent progress in medicine
, the number of high - risk patients who undergo surgery is increasing ; therefore , the reactivation of latent cmv infection in immunocompromised patients should be actively considered for the differential diagnosis , leading to timely diagnosis and appropriate treatment .

Answer:
we report a case of hemorrhagic cytomegalovirus ( cmv ) colitis , occurring in a postoperative patient due to a weakened immune system .
 an 85-year - old woman with a medical history , including chronic renal failure treated with oral administration of prednisolone , underwent colectomy due to an ascending colon cancer . while the postoperative course was favorable , she exhibited acute severe abdominal pain and massive bloody discharge after 11 days of surgery .
 her colonoscopic examination showed multiple longitudinal ulcers on the anastomosis .
 in addition to these endoscopic findings , her past medical history helped suggest cmv colitis . because serological testing revealed positive cmv antigen , she was finally given a diagnosis of cmv colitis and received intravenous ganciclovir for the initial treatment .
 hemorrhagic cmv colitis after colectomy is an important postoperative complication ; we therefore present our case with diagnosis and treatment experience .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
intraspinal juxtafacet cysts ( commonly , synovial or ganglion cyst ) can be an uncommon cause of lower and radicular pain , neurogenic claudication , and cauda equina syndrome2,9,10,13 ) .
spinal synovial cysts generally arise from a degenerated facet joint and often presenting as a gradual onset of back pain and potentially , chronic progressive radiculopathy
is a much less common occurrence , and patients may present with acute onset of symptoms3,13 ) .
we describe a case in which hemorrhage into a right l2 - 3 facet synovial cyst caused acute back pain and radiculopathy and required surgical excision .
a 72-year - old - woman with a past history of hypertension presented to the clinic with acute back pain radiating to the anterior surface of the right thigh and leg .
the right straight - leg - raise test elicited pain in the leg at 30 which was exacerbated further by ankle dorsiflexion .
magnetic resonance imaging ( mri ) revealed the presence of a cystic formation in the right l2-l3 facet joint with arthritis compressing the l3 right root and the dural sac ( fig .
, the mri displayed a hyperintense abnormality on t1-weighted images and hypointense on t2-weighted images consistent with hemorrhage .
the posterior elements from l1 to l3 were exposed and right l2-l3 laminectomy and facetectomy were performed .
a brownish mass was found in continuity with the right l2-l3 facet joint adherent to the dural sac .
the extradural hematoma was visualized and evacuated , effectively decompressing the right 2 nerve root and sacral sac .
microscopically , there was a synovial cyst with synovial cell lining , neovascularization , hemosiderin microdeposits , and blood ( fig .
one month after the operation , the patient had no symptoms in her lower back and leg .
spinal synovial cyst can be defined as a soft tissue mass located extradurally along the medial border of a degenerated facet joint , especially l4 - 5 level1,4,8,11,12 ) .
these cysts are filled with clear or xanthochromic fluid and have a synovial - like epithelial lining with a demonstrable connection to a joint capsule3,11 ) .
if the synovial cell lining and the communication with a joint capsule are absent , the cyst is classified as ganglion11 ) .
intraspinal synovial cysts are rare but have been documented with increasing frequency because of the improvement of neuroradiological imagings4 ) .
an mri is considered a good modality for diagnosis . on mri , cysts appear as well - circumscribed , epidural mass lesions that are hypo- and hyper - intense on t1 and t2 weighted images , respectfully . bleeding into a synovial cyst may cause a sudden expansion of the cyst leading to compression of the epidural space result in root compression symptoms .
hemorrhage into a synovial cyst results in an acute increase in pain and radicular symptoms , including neurological deficits12 ) .
hemorrhagic presentation can be caused by anticoagulation treatment , trauma , disc herniation , vascular anomaly , and neoangiogenesis in the cyst4 ) .
in addition , high vascularization of the cyst can cause hemorrhage in spite of minor trauma or just spinal instability .
synovial cyst hemorrhagic events in some cases can occur despite the absence of trauma or coagulopathy13 ) . as a result ,
other yet to be determined risk factors for synovial cyst hemorrhage occurrence exist prompting the need for more studies .
non - hemorrhagic synovial cysts are occasionally treated by percutaneous aspiration with successful resolution of symptom6 ) .
the injection of corticosteroid agents into the facet joint may be an treatment option . despite conservative treatment , recurrence of cyst with symptoms
the natural history of spinal synovial cysts is unknown , but spontaneous remissions of a synovial cyst on follow up imaging with improved symptoms have been reported5 )
however , pain can be treated with steroid injections and bed rest in substantial number of patients .
we report of a case in which hemorrhage into a right l2 - 3 facet synovial cyst causing an acute back pain and radiculopathy .
treatment by resection of the cyst and evacuation of the hematoma led to complete neurological recovery .
synovial cysts of the lumbar spine are an uncommon cause of back and radicular pain .
rarely , these cysts can go through hemorrhagic transformation by trauma , anti - coagulopathic state , or for unknown reasons .
hemorrhage into a cyst is an uncommon occurrence that can lead to acute symptom . in most cases , surgery is the treatment of choice for symptomatic hemorrhagic synovial cysts .
surgery involving the evacuation of the hematoma and/or cyst can result in complete resolution of acute symptoms and neurologic deficit .

Answer:
synovial cysts of the lumbar spine are an uncommon cause of back and radicular pain .
 these cysts most frequently present as back pain , followed by chronic progressive radiculopathy or gradual onset of symptoms secondary to spinal canal compromise .
 although less common , they can also present with acute spinal cord or root compression symptoms .
 we report of a case in which hemorrhaging into a right l2 - 3 facet synovial cyst caused an acute onset of back pain and radiculopathy , requiring surgical excision .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
we report a case of a patient who presented with a complex open 3c gustilo  anderson fracture who subsequently developed flap failure , failed internal fixation complicated with osteomyelitis of the talus .
they vary in severity from minor metatarsal / phalangeal fractures to complicated midfoot and hindfoot injuries .
open fractures are poorly reported since they are rare and usually treated in specialist trauma centres .
reported amputation rates in open midfoot fractures are 30% highlighting their severity , coexisting soft tissue compromise , infection and difficulty covering midfoot injuries with flaps . with the midfoot playing a key role in foot function ,
soft tissue defects of the foot pose further challenges given the specially adapted architecture to facilitate tendon gliding .
a 55-year - old woman presented with an open 3c gustilo  anderson fracture . her  medical history included rheumatoid arthritis , osteoarthritis , ischaemic heart disease , diabetes mellitus and asthma .
soft tissues were closed using a free flap from the left thigh and a flap from the right lower limb .
bony injury was treated with open reduction internal fixation with screw fixation of the first and third metatarsals into the talus with restoration of the medial and middle columns achieved using cannulated screws .
additional stability was achieved by plate fixation of the medial and lateral columns ( fig .
( c and d ) radiographs illustrating open reduction internal fixation ( orif ) ( screw fixation of the first and third metatarsals into the talus ) .
the orif using cannulated screws allowed restoration of the medial and middle columns of the foot .
( c and d ) radiographs illustrating open reduction internal fixation ( orif ) ( screw fixation of the first and third metatarsals into the talus ) .
the orif using cannulated screws allowed restoration of the medial and middle columns of the foot .
four months since the initial presentation , she was readmitted due to foot dorsal flap edge failure for which vacuum - assisted closure was unsuccessful ( fig .
figure 2:flap failure on dorsal aspect of foot when patient presented after failed vacuum - assisted closure treatment .
flap failure on dorsal aspect of foot when patient presented after failed vacuum - assisted closure treatment .
primary limb shortening with a talectomy was conducted to reduce the soft tissue deficit and remove infected and necrotic bone , tibiocalcaneal arthrodesis for joint stability using external fixation , and dead space was treated with calcium sulphate mixed with vancomycin and systemic intravenous and oral antibiotics for osteomyelitis postoperatively ( figs 3 and 4 ) .
the wound was closed after the external fixator was applied . wound swabs and bone samples revealed enterococcus faecalis and e. raffinosus and diphtheroids .
the patient was treated with intravenous teicoplanin and meropenem with oral stepdown to linezolid and ciprofloxacin .

( b  d ) radiographs showing external fixation in situ .
 figure 4:external fixation used to facilitate tibiocalcaneal arthrodesis post talectomy .
eight months since the initial presentation , the patient was taken to the theatre where a large defect in the anterior dorsum of the foot , and the external fixator was adjusted in the foot to allow for exploration and debridement .
the abductor hallucis was identified and the tendon divided distally and mobilized and rotated to fill in the soft tissue medial defect .
calcium sulphate with vancomycin and gentamycin was inserted into the bony defect , and external fixation frame was adjusted back to its original position .
the wound was closed using the abductor hallucis and skin graft from the right lateral leg .
postoperatively the patient was put on intravenous teicoplanin and meropenem with oral stepdown to linezolid and ciprofloxacin . on discharge once the infection was controlled the patient s crp was 6.0 , white cell count 7.9 and neutrophils 4.0 .
after having the external fixation for 8 months in total , it was removed when fusion was deemed adequate on computed tomography imaging ( fig .
she was instructed to weight bear while in a plaster of paris cast for 14 days and then a moon boot for 14 days .
two months after this , the patient was mobilizing without issues and was doing well . at 12 months
, the patient stated that she is able to mobilize with any mild residual pain controlled with analgesia .

( a ) anterior  posterior view ; ( b ) lateral view . computed tomography scans illustrating tibiocalcaneal fusion 1 year postoperatively .
midfoot injuries with talar infections can often lead to below - knee amputation with the main goals of treatment being to successfully treat the infection and maintain a functional foot . in adults ,
most work focuses predominantly on internal fixation techniques or a combination of internal and external fixation .
most reports of arthrodesis following talectomy are for patients with charcot deformities rather than traumatic injuries with osteomyelitis . to successfully treat patients with infected midfoot injuries ,
calcium sulphate with antibiotics was used intraoperatively in the fusion site with some evidence supporting its use in deep foot infections . following this ,
a long course of intravenous antibiotics was used according to the sensitivities of the microorganisms growing in the region .
external fixation facilitates soft tissue healing , allows earlier weight bearing , closer monitoring of surgical incision sites and postoperative adjustments .
fabian and colleagues   concluded that tibiocalcaneal fusion in seven charcot joint patients using external fixation alone was unlikely to lead to fusion but the fibrous healing was sufficient .
agarwala s group and dennison s group report full fusion in all of their patients undergoing arthrodesis using external fixation [ 8 , 9 ] .
our results are in concordance with work of agarwala and dennison et al . in that external fixation
there is a need for randomized controlled trials to investigate the most appropriate fixation technique for tibiocalcaneal arthrodesis . in conclusion , we report a good outcome treating an open 3c gustilo  anderson fracture complicated by osteomyelitis , necrosis and inadequate soft tissue coverage .
our management involved a single - staged talectomy to remove the infected bone and tackle the inadequate soft tissue coverage , external fixation for tibiocalcaneal arthrodesis to achieve joint stability and a combination of bone graft antibiotics and a course of intravenous and oral antibiotics postoperatively to deal with the underlying osteomyelitis .

Answer:
foot fractures vary in severity with complex midfoot fractures having poor morbidity rates and high amputation rates .
 complex midfoot fractures are rarely reported since they are uncommon and only treated in specialist centres .
 given the important role of the midfoot in foot function , reconstruction is preferable .
 soft tissue management on the dorsal aspect of the foot poses further challenges to reconstructive surgeons .
 we report a case of a 55-year - old woman who sustained an open 3c  gustilo
 anderson fracture that was initially treated with open reduction internal fixation and free flap .
 she subsequently developed flap and internal fixation failure with osteomyelitis of the talus .
 we report a good outcome using primary limb shortening with a talectomy , tibiocalcaneal arthrodesis using external fixation and a combination of vancomycin - loaded calcium sulphate and intravenous antibiotics in our patient .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
aneurysmal bone cysts ( abcs ) are rare entities which cause expansile and destructive bone lesions characterized by reactive proliferation of connective tissue1,5 ) .
they are benign lesions and can occur in any part of the skeleton and the spine can be affected up to 30% of the cases .
abcs can cause symptoms such as back and/or dorsal pain , neurological deficitis , and pathological fractures .
although abcs mostly occur in the distal part of femur and/or proximal part of the tibia , some cases have been reported in pelvis and posterior elements2,4,5 ) .
abcs can occur rarely in the sacrum and this location has some difficulties in treatment because of the relations with the sacral nerves .
togetherness of abc and fibrous dysplasia , giant cell tumors and/or osteoblastomas are defined as secondary abc by some authors and this association was seen aproximately in 20 - 30% of cases .
diagnosis can be verified by ct scans and mri . in this paper , authors reported two rare cases with thoracic and sacral aneurysmal bone cysts .
a 14-year - old male admitted to neurosurgery department with suffering of being unable to walk for 15 days .
thoracic mri images and ct scans demonstrated a mass which causes mass effect on spinal cord ( fig .
2 day he was mobilised and his neurological examination was enough for walking with arm holder on postoperative 7 day .
on the 5 months control of the patient there were no suffering and no instable images on x - ray and mr images ( fig .
an 8-year - old male pateint admitted to us with right hip and back pain . in his history , he had fallen down from 2 meters .
spinal mri revealed abc on the right side of the 3 sacral vertebra with an enlargement of 2419mm(fig .
the second case is under control and no surgical treatment is suggested because of the patient 's age and observing no neurological deficits at the patient .
a 14-year - old male admitted to neurosurgery department with suffering of being unable to walk for 15 days .
thoracic mri images and ct scans demonstrated a mass which causes mass effect on spinal cord ( fig .
2 day he was mobilised and his neurological examination was enough for walking with arm holder on postoperative 7 day .
on the 5 months control of the patient there were no suffering and no instable images on x - ray and mr images ( fig .
an 8-year - old male pateint admitted to us with right hip and back pain . in his history , he had fallen down from 2 meters .
spinal mri revealed abc on the right side of the 3 sacral vertebra with an enlargement of 2419mm(fig .
the second case is under control and no surgical treatment is suggested because of the patient 's age and observing no neurological deficits at the patient .
known as a non - neoplastic expansile bone lesion , abc has a consistance of blood - filled spaces separated by connective tissue septa containing bone and osteoclastic giant cells .
discussions about thoracic and sacral aneurysmal bone cysts are limited and only a few cases have been reported3,7 ) .
papagelapoulos et al described 44 pelvis abcs and 12 of them were in the sacrum6 ) .
it is well known that total extirpation of sabc is so difficult and surgical results in treatment of sabc are excellent .
these clinical findings include leg weakness and numbness , bowl or bladder dysfunctions . in our cases
up to 60 - 70% of abc cases that occured in spine present with neurological deficits .
the clinical aspects are pain due to the destruction and neurological deficits due to the fractures and compression . in our case
the diagnostic problems are because of the expeditious growth of abc and its expansive destruction of bone .
the diagnosis becomes more complicated if there is an extra - osseous and soft - tissue tumour mass .
it also helps to evaluate the fluidfluid level , which is characteristic for abc on mr images1 ) .
our first case was evaluated as a pathological fracture , and the patient underwent urgent surgery because of the compression on spinal cannal .
but the second case was so typical for abc on the radiological examinations as if in the literature .
the primary option for treatment is surgery . enneking classified 3 surgical types : 1-intralesional ( curettage and bone grafting ) , 2-marginal ( en bloc ) resection , 3-wide resection ( segmental resection)3,4,5,6,7 ) .
the most important factors in preoperative planning are the location and the growing pattern of the abc . if abc is growing superficially and besides if it is not involving the one - third of the bone , in this case it will be more advantageous .
this is really a good intervention for abc and local recurrences occur less com- monly . besides this
, if the abc is so large and located in pelvis or spine extraperitoneal excision and bone grafting could be more difficult and risky .
in similar cases like this , curettage and bone grafting remain a choiceable surgical technique .
low - dose radiotheraphy can be performed after curettage and bone grafting as an other option for treatment5 ) .
age , location , size and number of mitotic figures have been suggested for recurrence treatment of abc is difficult and histological examination should be done to prevent overlooked of an underlying more aggressive neoplasm .

Answer:
aneurysmal bone cysts are rare entities which causes expansile and destructive bone lesions characterized by reactive proliferation of connective tissue .
 they usually grow rapidly with hypervascularity . in clinical practice
 they can be easily misdiagnosed due to the rare occurance and having no such typical findings as radiologically .
 most cases have uncommon pain symptoms , but rarely , if fractures occur , neurological findings can be seen and the surgical treatment , if needed , could be difficult .
 we will discuss our evaluations to two cases that we experienced in our clinic in this report .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Ni(II), Cu(II), and Zn(II) Diethyldithiocarbamate Complexes Show Various Activities Against the Proteasome in Breast Cancer Cells

Paper sections:

Since FDA approval of cisplatin 30 years ago, thousands of coordination compounds have been synthesized and screened. However, cisplatin and its analogues (carboplatin and oxali-platin), ranked among "alkylating agents", are the only metal-based anticancer drugs in common use.1 Because many metal-based compounds are effective in vitro,2 it is a great challenge to find an in vivo active metal drug sufficiently safe for clinical use. One of the promising strategies to accelerate drug discovery and development research seems to be in finding new uses for old drugs. Once approved, these drugs can quickly enter phase II clinical trials and save a lot of time and money.3-5

Along that line, it deserves attention that an old anti-alcoholic drug disulfiram (tetraethylthiuram disulfide), in combination with zinc gluconate, has been reported to reduce hepatic metastases and produce clinical remission in a patient with ocular melanoma.6 Furthermore, disulfiram mixed with copper was found to selectively destroy melanoma cells in vitro.7 The antimelanoma activity of disulfiram was suggested to be attributed to diethyldithiocarbamate (EtDTCa) complex with copper because disulfiram can be converted to EtDTC in the body.8 Also, few other metal-dithiocarbamate complexes were shown to be effective against many types of cancer cells in vitro and in vivo.9-13 However, the involved molecular mechanism has not been completely defined.

The proteasome inhibition is a new and viable strategy in cancer therapy with the first-in-class approved drug bortezomib (dipeptide boronic acid analogue) as a successfule example.14 A giant protease responsible for degradation of about 90% cellular proteins, the proteasome is usually targeted at its proteolytically active β-rings (Figure 1). However, there is an increasing demand for new approaches to inhibit the proteasome, e.g., by targeting its so-called 19S particle (Figure 1).15 This component of the proteasome is responsible for recognizing ubiquitinated target proteins and their further processing (cleavage of ubiquitin chain) before the degradation.16 The deubiq-uitinating activity of 19S particle is dependent on a metal-loisopeptidase with a coordinated zinc ion,17,18 and this structural motif in 19S particle (JAB1/MPN/Mov34 domain or JAMM domain) has been suggested as a perspective target for anticancer drugs.19

In our current work, we show that synthetic and well-characterized complexes of three metals (Cu, Zn, and Ni) with EtDTC have different abilities to inhibit purified 20S proteasome (without 19S particles containing JAMM domain) and cellular 26S proteasome (with JAMM domain-containing 19S particles).

Regarding the metals, we selected zinc and copper as their EtDTC complexes were reported to suppress cancer growth in vivo, while nickel was used to create stable complexes with a coordination sphere similar to that of Cu(II) and Zn(II).

These complexes were prepared as described previously,20 and their molecular structures were confirmed using X-ray single-crystal diffraction (for details, see Supporting Information).

In view of the fact that disulfiram was reported to be able to inhibit the proteasome activity in MDA-MB-231 breast cancer xenografts with elevated copper levels, we decided to test the complexes in this highly malignant and metastatic cell line (experimental procedures are summarized in Supporting Information).21 We determined: (a) toxicity of synthetic compounds, (b) cellular morphological changes after treatment, (c) activity of the proteasome in the treated cells, and finally, (d) ability of the three complexes to inhibit purified 20S proteasome.

We found that Ni(II) complex was quite inactive to MDA-MB-231 cells in all the experiments. In a sharp contrast, both Zn(EtDTC)2 (the putative active compound in disulfiram/zinc gluconate treatment of metastatic melanoma) and Cu(EtDTC)2 were toxic to these breast cancer cells, associated with inhibition of cellular 26S proteasome (Table 1). When a purified 20S proteasome was used, both Zn(EtDTC)2 and Cu(EtDTC)2 showed much less inhibitory activity than against cellular 26S proteasome (Table 1).

Our previous work with different ligands (including dithio-carbamates) and their metal complexes suggested that the proteasome-inhibitory effects were strictly attributed to the complexes with specific metals. Ligands alone were active only against the tumor cells grown in copper-enriched medium, which increased the level of cellular copper available for reacting with the ligand within the cells,22 or against the tumors in vivo (that have elevated copper levels as well).23

The stability of dithiocarbamate complexes with metals within the cells has not been directly proved yet, although some of these complexes, such as Cu(EtDTC)2, seem to be stable in brain tissue.24 However, the putative (in)activity of our currently reported compounds toward the proteasome could be explained by their molecular structures. Until now, almost nothing is known about interactions between metal complexes and JAMM domain (except for, e.g., JAMM domain protein inhibition by zinc acetate25). In recent years, we have published a number of metal complexes that inhibit the proteasome, specifically its chymotrypsin-like (CT-like) activity, and induce apoptosis in human cancer cells.10,13,22,23 On the basis of the published work on metal complexes, the proteasome and JAMM domain, we have recently suggested that dithiocarbamate complexes with metals could inhibit JAMM domain proteins.26 Here, in the light of new data generated with these three metal complexes against the purified and cellular proteasome, we are proposing that inhibition of JAMM domain in the 19S particle of the proteasome is responsible for the effect of the tested metal complexes observed in the breast cancer cells. Following arguments support our hypothesis.

The JAMM domain is very similar to the metal-binding domain of carboxypeptidase A because both of them comprise glutamine and two histidines, a water molecule and glutamine, or aspartate in nearly the same arrangement. Carboxypeptidase A was shown to be efficiently inhibited by Zn(OH)Cl, creating a binuclear complex with the zinc from the protein by displacing the water molecule27 (Figure 2).

To bridge the JAMM zinc by dative bond, the diethyldithio-carbamate ligand requires rich electronic density on the sulfur atom (Figure 2, the sulfur in pink). Recently, electronic densities on atoms and bonds within Ni(EtDTC)2, Cu(EtDTC)2, and Zn(EtDTC)2 were analyzed. The greatest σ-repulsion (that moves electronic densities from the bond to the atoms) was found between Zn and S, while the lowest σ-repulsion was found between Ni and S.28 Therefore, a sulfur atom within a zinc complex has higher electronic density compared to the sulfur atoms in copper and nickel complexes. Moreover, Zn(EtDTC)2 and Cu(EtDTC)2 are, in solid phase, actually dimers (for figures, see Supporting Information) with sulfur atom bridging two metals; the bond length of the Zn-S(bridge) is shorter than that of the Cu-S(bridge) (2.391 vs 2.779 Å), suggesting the larger electronic density on the sulfur atom within Zn(EtDTC)2 compared to the one within the Cu(EtDTC)2 complex. Nickel complex, however, is not able to create dimers (according to our data).

From this point of view, Zn(EtDTC)2 should be most active against the JAMM domain of the 26S proteasome, Cu(EtDTC)2 activity would be less potent against the JAMM domain, and nickel complex would not be active at all. However, this needs to be confirmed by showing direct interactions between the JAMM domain and diethyldithiocarbamate complexes and consequent inhibition of JAMM activity.

We have also recently reported29 that another group of dithio-carbamate complexes with copper and zinc, Cu(PyDTC)2 and Zn(PyDTC)2 (Py = pyrrolidinedithiocarbamate), could inhibit CT-like activity of cellular 26S but not purified 20S proteasome. It is possible that the overall effect of metal-dithiocarbamates within the cell is a result of their different effects on CT-like activity located on 20S catalytic core and deubiquitinating activity located on the 19S particle (e.g., JAMM domain) within the 26S proteasome. Further electronic density analysis of different dithiocarbamate complexes would help in answering this question.

Moreover, the hypothesis that metal complexes might inhibit JAMM domain could also, in some way, explain several previously observed effects of dithiocarbamate complexes, including blockage of ATF/CREB DNA binding6 and inhibition of H4 histone acetylation30 that requires ATF/CREB DNA binding.31 According to our hypothesis, JAMM domain acts as a deubiquitinase that coordinates histone acetylation and deu-biquitination32 and by targeting this deubiquitinase, dithiocar-bamate complexes would be able to regulate acetylation and biological activity of H4 and other players.

Answer: A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) was prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
biopsies from the ampulla of vater are usually essential to diagnose premalignant and malignant lesions in asymptomatic or symptomatic patients .
acute pancreatitis is an extremely unusual complication following non - thermal biopsy of the ampulla without attempted cannulation .
we present this case because of its rarity and the accompanying intense clinical manifestations without further severe consequences .
a 51-year - old man underwent two gastroscopies over the prior 2 years with the indication of intermittent dyspepsia . on the last endoscopy ,
the ampulla of vater was described as bulging ; biopsies were performed and histological examinations revealed mild chronic , nonspecific , inflammatory mucosal lesions of the ampulla and duodenum , with regional architectural disturbances , epithelial hyperplasia , accompanying mild nuclear stratification , and atypia , not fulfilling the diagnostic criteria for epithelial dysplasia .
the patient was referred to our clinic with persistent , intermittent epigastric discomfort and pain , and we therefore scheduled a repeat examination in order to exclude an ampullary tumor .
the extensive work - up after this episode did not reveal any aggravating factors for the embolism . in view of the results of the endoscopy
, we advised the patient to discontinue acenocoumarol and changed to low molecular weight heparin ( enoxaparin 40 mg / day ) .
the patient was heterozygous for sickle cell disease ( hemoglobin electrophoresis : hbs , 29.5% ; hbf , 0.6% ; hba2 , 3.6% ) .
a side - viewing scope ( olympus tjf-145 video duodenoscope ; olympus , tokyo , japan ) was used with the patient under conscious sedation ( midazolam 2 mg , propofol 60 mg ) .
eight biopsies were obtained from the area around the ampulla with a reusable oval - cup forceps ( olympus fb-26n-1 ; olympus ) . no excessive bleeding
one hour after the meal , the patient experienced an acute , severe ( eight out of 10 ) , persistent abdominal pain with recurrent , unrelieved vomiting .
he contacted his family doctor but refused hospital admission and was monitored on an outpatient basis . on the second day , the patient reported less vomiting , but the pain was still intense and he additionally became febrile to 38.5c .
he was advised to stop solid food intake and only take regular oral hydration . on day 3 , the symptoms improved with no vomiting , milder abdominal pain , and a temperature less than 37.8c .
serum and urine amylase levels were 845 u / l ( normal < 100 ) and 8,500 u / l ( normal < 460 ) , respectively .
kidney and liver tests showed normal results except for a slight elevation of the alanine aminotransferase level .
blood triglyceride level was 110 mg / dl ( normal < 150 ) and the calcium level was 9.2 mg / dl ( normal 8.5 to 10.2 ) .
a second abdominal ultrasound was unremarkable , while contrast - enhanced abdominal computed tomography ( ct ) revealed mild enlargement of the pancreatic head and stranding of the surrounding retroperitoneal fat ( fig .
eight tissue samples , with an approximate diameter of 1 to 3 mm each , were analyzed .
histological examinations revealed mild inflammatory mucosal lesions of the ampulla and duodenum , with regional gastric metaplasia , regional epithelial hyperplasia , and mild nuclear stratification , which did not meet the diagnostic criteria for epithelial dysplasia .
the majority of periampullary neoplasms are malignant , whereas benign neoplasms account for less than 10% of the cases . among benign lesions , adenomas are the most common , with a potential for malignant transformation .
although biopsies are essential in the diagnosis and follow - up of these lesions , the histological distinction between normal and pathological features of the ampullary mucosa is often difficult to make on endoscopically obtained samples .
acute pancreatitis is a well - recognized complication of endoscopic retrograde cholangiopancreatography , but is extremely rare after biopsy of the ampulla of vater without a previous attempt at cannulation .
however , an asymptomatic increase in amylase concentration has been reported in up to 30% of cases . in the case we present ,
the diagnosis of acute pancreatitis was based on symptomatology in combination with the increase in serum and urine amylase levels , as well as the ct findings . to our knowledge
, there are only three reported cases associating acute pancreatitis with endoscopic biopsies from the ampulla of vater .
the first case was reported in a patient with gardner syndrome , who developed acute progressive periumbilical pain radiating laterally to the back 4 hours after endoscopy , with temperature increasing up to 39.2oc on the following day , high serum amylase levels , and a ct scan that showed pancreatic enlargement and diffuse stranding of the peripancreatic fat .
another case of severe acute pancreatitis was attributed to endoscopic biopsies of the minor papilla in a patient with pancreas divisum and liver metastases due to colon cancer .
the third was also a case of severe pancreatitis with formation of a large pancreatic walled - off necrosis that was managed with ultrasonography - guided drainage .
in all the aforementioned cases , abdominal pain was the presenting symptom and occurred 4 hours after sampling of the papilla .
the clinical profile and course of our patient was similar to the case with gardner syndrome , with intense symptoms but still not a severe form of pancreatitis .
our patient was indeed on heparin up to 24 hours before the procedure , which in combination with the biopsy process could have led to the development of a small hematoma .
patients with sickle cell trait , especially african - americans , are more prone to manifest deep vein thrombosis and pulmonary embolism , although this remains a matter of debate .
vaso - occlusive phenomena have been described in patients with sickle cell trait ( splenic infarction or sequestration , hyphema , etc . ) .
the occurrence of a thrombotic event would have led to ischemic pancreatitis , which is also a very rare condition and is usually associated with a major circulatory event such as hemorrhagic shock .
mucosal edema due to biopsies is the most plausible mechanism for pancreatitis in our case .
we tried to direct the biopsies to the area around the orifice , but due to edema and bleeding after taking the first samples , it is sometimes very difficult to ensure that one or more biopsies are not directed towards the orifice .
this same mechanism is also proposed by ishida et al .   and morales and hixson , who reported cases of acute pancreatitis following endoscopic biopsy of the ampulla .
ishida et al .   additionally mentioned that the rise in the pancreatic duct pressure must have been low and of short duration , as no dilation of the pancreatic duct was observed . despite the clear chronological association between sampling of the ampulla and acute pancreatitis in our patient
no use of nonsteroidal anti - inflammatory drugs , paracetamol , proton pump inhibitors , antibiotics , or other commonly used medications were reported .
propofol has rarely been associated with pancreatitis if large doses are given in patients with coexistent hypertriglyceridemia .
when we reviewed both the patient s older and recent blood tests , no evidence of pathological values for lipids and/or calcium was found . to our knowledge
, there is no association of flumazenil with pancreatitis , whereas midazolam - induced pancreatitis reports has been scarcely reported and is not well - documented .
finally , it is worth mentioning that our patient recalled having substantial epigastric discomfort that lasted for 24 hours after a previous upper endoscopy when biopsies from the ampulla had been taken .
one can assume that mild forms of pancreatitis may occur more often than is actually reported in the literature . in conclusion , we present a case of acute pancreatitis following biopsy of the ampulla .
the case is significant for certain characteristics that have not been described in similar cases .
our patient s symptomatology was severe and not in parallel with the trivial laboratory and radiological pathology , and most importantly , with the excellent outcome .
the patient s medical history entails features of unknown importance for the pathogenesis of pancreatitis ( sickle - cell trait , previous use of anticoagulants , and repeat sampling ) , but these features may have contributed to the advent of pancreatitis ; therefore , this case may be worth reporting for future reference . finally , although pancreatitis after sampling of the ampulla is a rare complication , endoscopists should take it into consideration before the procedure and inform patients accordingly .

Answer:
a 51-year - old man underwent diagnostic work - up for an abnormal - appearing ampulla of vater .
 three hours after biopsy of the ampulla , the patient presented with intense symptoms suggesting acute pancreatitis , which was later confirmed with laboratory and radiographic examinations .
 other causes were excluded and the acute pancreatitis was considered a procedural complication .
 this is a rarely reported complication that must be taken into consideration when biopsies are performed in the ampulla of vater .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
for instance , in 1999 , john chapin s laboratory at hahnemann university in philadelphia and my own laboratory at duke university collaborated in the first experimental demonstrations of a brain - machine interface in animals . in these experiments
, rats learned to use the combined electrical activity of a handful of cortical neurons to move a robotic arm in order to obtain a water reward . around the same time ,
niels birbaumer at the university of tbingen in germany reported how completely paralyzed patients learned to use brain - derived signals ( recorded though a classic method known as electroencephalography , or eeg ) to write messages on a computer screen . even in its initial version ,
this brain - computer interface was the only way for these locked - in patients to communicate with the external world .
it was an early indication of bmis significant potential as new rehabilitation tools . in subsequent years
, further animal experiments with bmis indicated that monkeys could learn to employ the combined electrical activity of hundreds of their cortical neurons to move multiple degree - of - freedom robotic arms , entire humanoid robots , and even avatar limbs and bodies without the need for any overt movement of their own bodies .
soon , initial clinical studies also reported that patients could rely on bmis to control the movements of computer cursors and robotic arms .
as the bmi field rose to the forefront of modern neuroscience , the possibility of establishing a bidirectional dialogue between brains and artificial devices was also realized . in 2011 , through a technique called cortical electrical microstimulation , my laboratory was able to deliver simple  tactile messages  directly into the brains of monkeys .
every time one of our monkeys used its brain activity to move a virtual hand to scan the surface of a virtual sphere , a simple electrical wave , proportional to the virtual texture of the touched object , was immediately delivered to the animal s primary somatosensory cortex , an area known to be fundamental for the definition of one s tactile perceptions .
after a few weeks of training , by taking advantage of this direct and continuous inflow of tactile information into their brains , a pair of monkeys became capable of discriminating the fine texture of the virtual objects by using their virtual hands , as if they were using their own biological fingertips .
we called this new paradigm a brain - machine - brain interface ( bmbi , figure 1 ) .
in 2009 , as a direct result of this auspicious first decade of bmi research , the duke university center for neuroengineering and the edmond and lily safra international institute of neuroscience of natal ( els - iinn , in brazil ) jointly created a nonprofit research consortium called the walk again project . by the end of 2012 , the walk again project received a grant from the brazilian government to assemble a large international research team of roboticists , neuroscientists , engineers , and computer scientists .
this international team joined with a brazilian multidisciplinary rehabilitation team , composed of physicians , psychologists , and physical therapists , to take on a very ambitious project : designing and implementing the first bipedal robotic exoskeleton whose movements could be controlled directly by human - brain activity .
the central goal of the first phase of project was to allow paraplegic patients suffering from severe spinal - cord lesions to use their eeg activity to control the exoskeleton s leg movements ( figure 2 ) and , in so doing , regain lower - limb mobility .
in addition to restoring basic locomotion behaviors , the exoskeleton would be the first in its class to provide continuous sensory feedback to the user in the form of artificial tactile and proprioceptive signals . in december 2013 , a group of eight patients suffering from complete and incomplete spinal - cord lesions started the training process required for achieving proficiency in controlling a brain - controlled robotic exoskeleton .
four months later , all eight were capable of commanding the exoskeleton with their brain activity alone , and all had regained the sensation of walking in a laboratory setting .
the feeling of walking again was even more realistic in these patients because of the addition of two innovative technologies in the design of our exoskeleton .
the first was a new type of artificial tactile sensor known as artificial skin , developed by gordon cheng at the technical university munich .
these sensors were distributed across key locations of the exo s legs and feet to detect the device s movements and contact with the ground .
the second was an ingenious haptic display , created by hannes bleuler s laboratory at the cole polytechnique fdrale de lausanne ( epfl ) in switzerland , that allowed the tactile feedback signals generated by the arrays of the artificial sensors to be delivered to the skin of a patient s forearms .
for the haptic display to work properly , patients had to wear a special shirt containing a linear array of small vibromechanical elements in the distal half of each sleeve while walking with the brain - controlled exoskeleton .
to celebrate a major first step toward the development of a new generation of neuroprosthetic devices , one of our patients , juliano pinto , who is paralyzed from the mid - chest down , was invited to help our team demonstrate our exoskeleton s enormous potential before the opening match of the 2014 fifa world cup in brazil on june 12 .
for the first time in history , a human subject showed that a brain - controlled exoskeleton could be used to initiate the kicking of a soccer ball .
the demonstration was witnessed by 70,000 fans at the itaquero stadium and an estimated 1 billion people watching on tv .
seconds after executing this historic kick , juliano reported to us that he clearly felt his leg moving in the air during the moment at which the exo s foot made contact with the surface of the ball . according to juliano s perception , it was his own body , not the exo , that executed the kick .
the effort and complexity required to pull off that world cup demonstration well exemplifies the current state of the art of bmis . over the last 15 years ,
and although the case has been made that bmis offer concrete hope for the future development of a variety of new neurorehabilitation tools , we are still a few years away from being able to produce neuroprosthetic devices that patients can routinely use outside well - controlled laboratory conditions . certainly ,
at this point , we are very far from the braincaps imagined by science - fiction writers like clarke .
despite the uncertainty , recent experiments combining bmis with cortical electrical microstimulation effectively open the doors for more daring adventures .
indeed , i could almost bet that clarke himself would have enjoyed the opportunity to be present when miguel pais - vieira , a portuguese postdoctoral fellow in my lab , demonstrated the operation of the first brain - to - brain interface designed to link two animals brains directly ( figure 3 ) .
first proposed in my 2011 book beyond boundaries : the new neuroscience of connecting brains with machines  and how it will change our lives , our brain - to - brain interface ( btbi ) paradigm , reported in 2013 , allowed a pair of rats to transmit and receive rudimentary mental sensorimotor messages . in one of the published experiments , the first rat of the pair , known as the encoder ,
was trained to use its facial whiskers to determine the diameter of a computer - controlled aperture placed inside a behavioral box . from trial to trial , the aperture could assume two distinct diameters , classified as narrow ( x mm ) or wide ( y mm ) .
the encoder s job was to use its facial whiskers to correctly judge the aperture s diameter and then indicate its value by placing its snout in one of two holes located in a nearby chamber .
if the encoder nose - poked in the hole corresponding to the correct aperture diameter , it received a water reward .
as the encoder used its facial hair to evaluate the opening s diameter , electrical activity recorded from neurons located in its somatosensory cortex was combined and transmitted , via cortical electrical microstimulation , to the brain of a second rat , the decoder , located in a different behavioral box .
the decoder had no access to an aperture , so its facial whiskers were useless in solving the task and getting water . yet to receive such a reward , the decoder also had to indicate , by nose poking , the diameter of the aperture touched by the encoder . to do that , the decoder had to rely solely on the simple neural message being transmitted to its brain by electrical microstimulation .
after a bit of training , decoder rats became capable of using our brain - to - brain interface to successfully perform this task way above chance level .
this indicated that the brain of a decoder rat could make sense of the messages broadcasted by its associated encoder rat .
interestingly , since the encoder received an extra reward allotment every time a decoder was able to correctly indicate the aperture s diameter , encoder rats adapted their behavior and cortical activity to make it easier for their counterpart to complete the task , particularly after the latter committed a series of trial errors .
that further suggested to us that these rat dyads had established a new form of communication , despite the fact that neither animal was aware of its counterpart s existence . as an extra proof of the effectiveness of this btbi
, we repeated these tactile - discrimination experiments by using an encoder rat placed in a laboratory in the els - iinn , in natal , brazil , while the decoder rat performed its trick in my lab at duke university , in the u.s . despite the distance and
the use of an average internet connection , the brain - to - brain interface worked as well as it did when the two animals were in the same laboratory . in a final test of our btbi , decoder rats used neuronal signals provided by the motor cortex of encoder rats to choose which of two levers to press , without ever seeing the visual cues that instructed the encoders to make the same decision in the first place .
in other words , the brain - to - brain connection between the encoder and decoder rats allowed the latter to correctly make a motor decision based on visual cues experienced only by its encoder partner . during the past year , two other laboratories published studies involving brain - to - brain architectures .
moreover , a press release from a group at the university of washington indicated that the group had established a functional link between human subjects brains by combining two noninvasive techniques : eeg to record brain activity in the first subject ( encoder ) and transcranial magnetic stimulation ( tms ) to deliver an eeg - triggered signal to the second subject s ( decoder s ) brain . since the group has not yet published a full scientific report , it is difficult to evaluate what was really achieved .
if anything , the limited description ( and video clip ) provided in the press release did not fully support the claim that a true functional communication between human brains occurred .
this is because , essentially , the encoder s eeg activity was simply used to trigger a magnetic stimulus in the decoder s motor cortex .
as expected , every time this magnetic stimulation was delivered , the decoder subject produced an involuntary body movement . yet
as such , i do not see how two brains shared a true message in this paradigm . on the other hand ,
the potential methodology for doing so was unveiled , and that was certainly enough to cause a significant media and public response .
we are currently investigating what kinds of social behaviors and global patterns of neuronal activity emerge when groups of animal brains are allowed to collaborate directly , through the employment of different types of brain - to - brain interfaces .
the central task of each of these animal brainets is to optimize the combination of neuronal activity , sampled from multiple brains simultaneously , into a supranervous system that is responsible for attaining a common behavioral goal , such as identifying a complex tactile pattern or moving an elaborate virtual limb .
the results of these studies , which are currently under review for publication , mostly focus on how btbis can enhance social interactions between animals and whether brainets could operate as a new type of computational architecture , like some sort of non - turing biological computer .
in addition , these experimental paradigms allow one to study whether , in a still - distant future , artificial interfaces like these may be used to functionally reconnect brain areas where communication may have been disrupted by brain damage , such as that produced by strokes or other neurological disorders . right now
however , seeking such a path has become a hallmark of our laboratory during the past decade . during this period ,
we have successfully translated similarly abstract basic - science ideas into potential new therapies for untreatable epilepsy , parkinson s disease , and disabling paralysis .
all of these therapies are currently undergoing clinical testing worldwide . as exciting as these animal research projects are , none of them come close to competing with the fictional wonders of clarke s braincaps .
, nobody would ever consider it ethically or medically acceptable to implant nanotubes or other types of electrodes in healthy human subjects for the purpose of testing a btbi , as suggested by clarke .
but even if , years or decades from now , better noninvasive technology enables us to record large - scale brain activity in real - time , at the millisecond scale , and then another efficient , noninvasive method might be used to deliver brain - derived messages to another human brain , it is highly unlikely that such a btbi would lead to the emergence of a fluid and efficient form of human communication , as long as we rely on digital computers to mediate this task . nor
do i believe that there will be a day in which braincap - like technologies will allow us to upload vast and complex information packets  like a new language or a large amount of scientific knowledge , as clarke describes in his book  into our brains , or to download all our memories or personal experiences into some sort of digital storage media .
apart from tasks such as motor control for which bmis can become very useful , mimicking higher - order brain functions , such as knowledge acquisition , memory storage , performance of cognitive tasks , and even consciousness , may be beyond the reach of binary logic , the basis from which all digital computers operate , no matter how simple or elaborate .
an interesting corollary of this view is that we need not worry about the forecast that , in the near future , a  really smart  digital computer / machine will supplant human nature or intelligence . in all likelihood
, this day will never come because , in a more - than - convenient arrangement , our most intimate neural riddles seem to have been properly copyright - protected by the very evolutionary history that generated our brains , as well as the very complex emergent properties that make it tick .
as such , neither evolution nor neurobiological complexity can be effectively simulated by digital computers and their limited logic . in the end
, this may not be so bad . like commander poole , as much as i would love to take advantage of a brand - new braincap  minus the nanotubes  to learn a few new intellectual tricks in a hurry , from the perspective of someone living in the early 21st century ( not the 31st ) , it is very difficult to imagine that any of us at this juncture in our history would , in good faith , feel comfortable in surrendering our final frontier of individual privacy , knowing that there is a chance , no matter how insignificant it may be , that an uninvited snoop may , nevertheless , want to take a peek .

Answer:
editor s note : every memory that we have , act that we perform , and feeling that we experience creates brainstorms  interactions of millions of cells that produce electrical signals .
 neuroscientists are now able to record those signals , extract the kind of motor commands that the brain is about to produce , and communicate the commands to machines that can understand them and facilitate movement in the human body .
 research in this area has the potential to help paraplegics and others suffering from spinal - cord injuries to control machines with their thoughts and to bolster their ability to get around .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
when patients present with acute occlusion of either the internal carotid artery ( ica ) or the proximal middle cerebral artery ( mca ) within the therapeutic time window for restoration of cerebral blood flow , rapid recanalization using intravenous / intra - arterial ( ia ) thrombolysis and ia mechanical embolectomy is the goal of acute stroke management.11 ) however , if the patient presents beyond the therapeutic time window , life - threatening brain swelling and herniation , known as malignant mca infarction , can manifest within one week after the onset of stroke symptoms , along with a further decrease of consciousness and pupillary dilatation , necessitating early application of a decompressive hemicraniectomy for achievement of a better clinical outcome.24 ) the present article reviews the pathophysiology , historical background in previous studies , operative timing , surgical technique and clinical outcomes of decompressive hemicraniectomy for malignant mca infarction involving the mca territory with or without anterior cerebral artery and posterior cerebral artery territories .
acute occlusion of either the ica or the proximal mca and insufficient collateral blood flow result in cerebral infarction of the mca territory and associated severe brain edema .
cytotoxic edema results from failure of sodium - potassium adenosine triphosphatase in brain cell membranes and is followed by vasogenic edema in association with disruption of the blood - brain barrier .
the space - occupying lesion inside the cranial vault increases the intracranial pressure , thereby reducing the cerebral perfusion pressure and cerebral blood flow .
in particular , a space - occupying lesion in a unilateral hemisphere causes pressure gradients between the supratentorial and infratentorial compartments and between the bilateral supratentorial compartments .
the transtentorial uncal herniation and the resultant displacement of the subthalamic - upper brainstem structures will impair the consciousness of the patient .
thus , the aim of decompressive surgery is external herniation of the swollen infarcted brain for relief of brainstem compression and to reduce intracranial pressure .
the original purpose of decompressive hemicraniectomy was to help patients survive in cases of acute large hemispheric infarction.25 ) various case reports , retrospective studies and trials have suggested that this surgical treatment lowers mortality without increasing the incidence of severely disabled survivors.8)13)15)23)27)29 ) three european randomized , controlled clinical trials were conducted between 2001 and 2007.10)12)32 ) however , the decimal ( decompressive craniectomy in malignant middle cerebral artery infarction ) trial in france and destiny ( decompressive surgery for the treatment of malignant infarction of the middle cerebral artery ) trial in germany were stopped due to slow recruitment of cases and significant difference in mortality between groups.12)32 ) notwithstanding , the hamlet ( hemicraniectomy after middle cerebral artery infarction with life - threatening edema trial ) study , conducted in the netherlands , was completed and published in 2009.10 ) thirty two patients were randomly assigned to undergo surgical decompression and another 32 patients received the best medical treatment over a five - year period . according to the results , the use of hemicraniectomy resulted in a reduction in the number of case fatalities and poor outcomes ( modified rankin scale score 5 ) for patients with large hemispheric infarction who were treated within 48 hours of stroke onset .
the clinical outcome for patients is considered to show improvement with early surgical decompression before or immediately after any neurological deterioration related to brain swelling.10)22)26)28)31)33)36 ) this clinical deterioration includes pupil asymmetry , an altered consciousness level and aggravated hemiplegia.6 ) patients commonly manifest such neurological deterioration within one week after the onset of stroke symptoms . in particular , one third of patients show deterioration within 24 hours , while another third show deterioration 24 - 48 hours after symptom onset.24 ) to date , many clinical and radiological data defining early predictors of malignant hemispheric infarction have been reported.6)7)9)14)16)18)20)30)34 ) malignant edema after acute infarction can be predicted based on the volume of the infarcted brain tissue , however , extension of the initial infarct territory , delayed spontaneous recanalization of the occluded vessel , hemorrhagic transformation of the infarcted brain and the fluid volume state of the patient can all make the prediction difficult .
thus , the predictors lack a sufficient predictive value with regard to selection of candidates for a decompressive hemicraniectomy prior to neurological deterioration . in addition , in order to ensure timely decompressive surgery , all patients with acute large hemispheric infarction should be observed in an intensive care unit or stroke unit setting .
thus , determination of strict cutoff criteria with a high specificity and positive predictive value for malignant infarction is needed.21 ) the predictive value of the infarct volume assessed by early ct scan after stroke onset has not been found to be satisfactory , as follows : ( 1 ) hypodensity covering > 50% of mca territory within five hours after symptom onset was predictive of a malignant course with a sensitivity of 61% and specificity of 94%;34 ) ( 2 ) hypodensity covering > 50% of mca territory within 12 hours was predictive with a sensitivity of 64% and specificity of 66%;17 ) ( 3 ) hypodensity covering > 50% and 67% of mca territory within 18 hours was predictive with a sensitivity of 58% and 45% , respectively and specificity of 94% and 100% , respectively.7 ) one useful predictor is the initial infarct volume assessed using diffusion - weighted magnetic resonance ( mr ) imaging > 145 cm within 14 hours after acute mca occlusion , which achieved a sensitivity of 100% and a specificity of 94% in the study by oppenheim et al.20 ) the cutoff criteria for lesion volume and associated midline brain shift for prediction of malignant edema should differ according to the timing after stroke onset.4)21 ) gerriets et al . reported a midline shift  2.5 , 3.5 , 4.0 and 5.0 mm in transcranial color - coded duplex sonography as a predictor of malignant edema after 16 , 24 , 32 and 40 hours , respectively , after stroke onset with a specificity of 100% and positive predictive value of 100%.4 ) meanwhile , assessment of the final infarct volume can be performed using perfusion ct or perfusion mr images on admission , however , such perfusion parameters are still not optimal.3)30 ) in the mr perfusion study reported by thomalla et al .
, perfusion lesion volume > 162 ml on a time - to - peak ( ttp ) map with a ttp delay threshold of > 4 seconds was found to predict malignant infarction with a sensitivity of 83% and specificity of 75%.30 )
conceptually , decompressive craniectomy procedures include both internal and external decompression . in the case of external decompression , the frontal , temporal and parietal bones overlying the infarcted hemisphere
are removed , allowing for external herniation of the swollen infarcted brain . with the patient in a state of general anesthesia , a skin incision
is started just above the zygomatic arch 0.5 cm anterior to the tragus and then carried superiorly and posteriorly over the ear and around the parietal bone to the contralateral frontal midpupillary line .
the hemicraniectomy then involves the removal of a large fronto - temporo - parietal bone flap , as large as possible .
the bone flap is made anteriorly in order to avoid violation of the frontal sinus , except in the case of a huge frontal sinus .
the medial limit is 2 cm from the midline , in order to minimize venous bleeding on the dura .
the posterior limit of the bone flap is approximately 5 - 6 cm posterior to the external auditory canal , thereby covering the mca territory posteriorly and allowing for a neutral head position without compressing the brain .
inferiorly , the temporal squama is removed to the level of the zygomatic arch . following a stellate - shaped dural incision ,
it is commonly recommended that the infarcted brain tissue not be removed due to the presence of a salvageable penumbra area or viable tissue.10)12)32 ) however , the internal decompression ( removal of the infracted brain tissue and/or an anterior temporal lobectomy ) can be performed for patients with whole hemispheric infarction.19 ) expansive duraplasty is then performed using a large flap of pericranial tissue or an artificial dura substitute .
the dimensions of the expansive duraplasty should be extended in order to accommodate the subsequent aggravation of the brain edema .
multiple dural tenting sutures , bipolar coagulation of bleeding points on the dural surface , application of commercial hemostatic materials and placement of a closed suction drain in the epidural / subgaleal space are all used .
finally , the temporalis muscle and skin flap are reapproximated and sutured layer by layer .
however , the temporalis muscle and fascia can be resected in order to maximize external herniation of the swollen brain .
removal of the temporalis muscle does not cause problems with chewing , as the grinding phase of the closure stroke only requires one - third of the maximal bite force and only leads to a minimal decrease in the maximal bite force.1)5 ) resection of the temporalis muscle and fascia provides a two - fold volume expansion on average when compared with the conventional technique on postoperative day 3 ( fig .
1).22 ) technical obstacles to obtaining the best external decompression are an insufficient craniectomy size , epidural / subgaleal hematoma , thick and swollen temporalis muscle , tough and inelastic temporalis fascia and tight scalp.2)22)35 ) making hemicraniectomy as large as possible , meticulous hemostasis and resection of the temporalis muscle and fascia will all maximize external herniation of the infarcted brain .
cranioplasty is then performed using the autogenous bone flap two to three months after the craniectomy .
after decompressive surgery for malignant mca infarction , clinical outcomes at 6 - 12 months after stroke onset have been reported .
for the criteria determining favorable and unfavorable outcomes , a dichotomization of the mrs score between 0 - 3 and 4 to death or between 0 - 4 and 5 to death has been used ; however , an mrs score of 0 - 3 is most appropriate for a favorable outcome as it includes independent functional outcomes . in the hamlet study ,
the patients were randomly assigned to undergo surgical decompression or to receive the best medical treatment within four days of stroke onset.10 ) the decompressive - surgery group had a lower incidence of mortality ( 22% versus 59% ) and mrs 5 - 6 ( 41% versus 59% ) than the group that received the best medical treatment . however , the incidence of patients with mrs of 0 - 3 did not differ between the two groups ( 25% versus 25% ) .
results of a pooled analysis of the three european randomized controlled trials indicated a better clinical outcome than that of the hamlet study.31 ) performance of decompressive surgery within 48 hours of stroke onset resulted in reduced mortality and an increase in the number of patients who had a favorable functional outcome .
in addition , more patients in the decompressive - surgery group had mrs 0 - 3 ( 43% versus 21% ) and mrs 0 - 4 ( 75% versus 24% ) compared with those in the control group who received the best medical treatment . in analysis of the three predefined subgroups of the decimal trial , in the decompressive - surgery group , younger age showed correlation with a favorable outcome and there was a trend toward a worse outcome in patients with higher infarct volumes.32 ) however , no significant difference in the clinical outcome with mrs scores was observed between surviving patients with dominant and non - dominant hemisphere infarction .
in patients with malignant hemispheric infarction , decompressive surgery can reduce the number of cases of fatality and increase the number of favorable outcomes .
in particular , if a decompressive hemicraniectomy is performed early , before irreversible cerebral herniation , using appropriate surgical techniques , favorable outcomes with functional independence can be achieved in a high proportion of patients .

Answer:
in spite of the best medical treatment , large hemispheric infarction , resulting from acute occlusion of either the internal carotid or the proximal middle cerebral artery with insufficient collateral blood flow is associated with a high case fatality rate of approximately 60% .
 thus , a decompressive hemicraniectomy is considered a life - saving procedure for this devastating disease .
 findings of three recent randomized , controlled clinical trials and their meta - analysis showed that early surgical decompression not only reduced the number of case fatalities but also increased the incidence of favorable outcomes .
 the authors review the pathophysiology , historical background in previous studies , operative timing , surgical technique and clinical outcomes of surgical decompression for malignant hemispheric infarction .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
to the surprise and deep disappointment of all involved in the treatment of lung cancer , several large trials did not demonstrate any benefit of tyrosine kinase inhibitors ( tkis ) as an addition to chemotherapy [ 13 ] .
basic and clinical research then focused on mutations of the gene for epidermal growth factor receptor ( egfr ) as a predictive factor for response to monotherapy with tkis and to development of new compounds with broader and/or irreversible inhibition .   the biological basis for the negative experience with combined treatment
gefitinib and erlotinib met all three standard criteria for inclusion in a combination with chemotherapy : activity as monotherapy , different mechanism of action , and different toxicity .
why , then , did the combination not work ? as explained in a recent editorial
, we believe that the cells of tumors sensitive to tkis are pushed into the g-0 phase of the cell cycle and therefore become resistant to cytotoxic drugs
. if antagonism between the two classes of drugs is really the biological basis for the aforementioned negative experience , then an optimal combination of tkis and chemotherapy should be in an intermittent , rather than a continuous schedule .
this brief report presents a single - institution experience on intermittent chemotherapy and tki in a small series of patients with advanced adenocarcinoma of the lung .
our hypothesis was that intermittent treatment would lead to superior time to progression , when compared to experience with chemotherapy alone .
if confirmed , such a result would be a solid basis for a randomised clinical trial .
patients eligible for the trial were chemonave with microscopically confirmed adenocarcinoma of the lung , had stage iii b ( wet ) or iv according to uicc - tnm classification ( 6th edition ) , had smoking history of less than 10 packs in years , had an ecog performance status 0 or 1 , and had adequate parameters of hematological , liver , and renal function to receive cisplatin - based chemotherapy . in the absence of neurological symptoms , patients with brain metastases were eligible and were treated with brain irradiation only in case of intracranial progression .
all patients had their diagnosis confirmed by biopsy or cytology . at the time when the trial was initiated , testing for egfr mutations was not available .
within three weeks prior to treatment , the precise extent of the disease was determined by chest x - ray and ct scanning of the chest , upper abdomen , and brain . since 2008 ,
pet - ct scanning has been available and included in the initial diagnostics and in followup .
the treatment started with four cycles of intermittent chemotherapy and erlotinib according to the following schedule : day 1 : gemcitabine 1250  mg / m in 30-minute infusion , day 2 : cisplatin 75  mg / m , with appropriate hydration and antiemetics , day 4 : gemcitabine 1250  mg / m in 30-minute infusion , days 515 : erlotinib 150  mg daily p.o .
the number of cycles depended on tolerance to cisplatin - based chemotherapy and was determined individually . immediately after the last cycle
, patients continued with erlotinib 150  mg / m daily continuously until progression or unacceptable toxicity .
definition of complete response ( cr ) , partial response ( pr ) , stable disease ( sd ) , and progression followed the recist criteria .
the first evaluation of response was done during the third cycle of intermittent therapy , with confirmation of response during the fifth cycle .
control radiological examinations were repeated every 2 months for chest x - ray , every 4 months for ct , and at 6 and 12 months for pet - ct ( only patients who had this examination during their initial diagnostics ) . in october 2010 , all biopsy samples were reviewed , and specimens with more than 10% of tumour tissue were analyzed .
genomic dna was extracted from formalin - fixed , paraffin - embedded tissue sections using qiaamp dna ffpe tissue kit ( qiagen , hilden , germany ) according to the manufacturer 's instructions .
quantification of extracted dna was done on qubit fluorometer ( invitrogen , carlsbad , usa ) . to detect egfr gene - activating mutations , we used therascreen egfr29 mutation kit ( dxs diagnostics , qiagen , manchester , uk ) .
all realtime pcr reactions were performed in a 25  l final volume on abi 7500 instrument ( applied biosystems , carlsbad , usa ) .
after standard chemotherapy for metastatic nonsmall cell carcinoma , the expected ttp is 5 months .
the size of this single - arm nonrandomised trial of intermittent therapy was based on the assumption of 9 months as the median time to progression ( ttp ) .
to obtain such a result with a confidence interval of 612 months , we planned to recruit 40 patients .
the investigators strictly followed recommendations of the helsinki declaration ( 1964 , with later amendments ) and of the european council convention on protection of human rights in bio - medicine , as accepted in oviedo in 1997 .
the protocol was approved by the institutional review board ( institute of oncology , ljubljana ) and by the national committee for medical ethics , ministry of health , republic of slovenia .
one patient was later found to have metastatic carcinoma of the pancreas rather than primary lung cancer and was excluded from all further analyses .   with 12 patients each ,
twelve patients were never - smokers , and most were in good general condition ( ps 0 - 1 for 21 patients ) . with the exception of a single patient with  wet
bone metastases were the most common site of metastatic disease , followed by pleura / pericardium , contralateral lung metastases , and liver .
two or more sites of metastatic disease were documented in 4 and 12 patients , respectively ( table 1 ) .
three patients had only cytological diagnosis , and an additional 3 had biopsy samples too small to allow for analysis of egfr mutations in tumor cells .
of the 18 adequate samples , 8 were positive for egfr gene - activating mutations .
the actual number of cycles of intermittent therapy was from 1 to 6 cycles ( median : 4 cycles ) . due to early progression ,
7 patients were still on maintenance treatment with erlotinib , and an additional patient stopped treatment with erlotinib after 12 months in pet - ct confirmed complete remission ( figures 1 and 2 ) . for the remaining patients , median total duration of treatment was 10 months . during the initial phase ,
side effects of maintenance with erlotinib were skin toxicity ( grade 3 : 1  pt ; grade 2 : 11  pts ) and diarrhea ( grade 2 in 1  pt ) .
all patients are evaluable for response , and no patient has been lost to followup . for the whole group of 24 patients , complete remission ( cr ) was seen in 5 pts ; partial remission ( pr ) in 9  pts ( response rate 58% ) , minimal response or stable disease ( sd ) in 8  pts , and progression in 2  pts . a clear and statistically significant ( p <
.05 ) correlation was seen between the presence of activating egfr mutations and response . among the 8 patients who were positive for egfr gene - activating mutations , 4 complete and
no cr and only 2 pr were seen among the 10 patients negative for mutations ( table 2 ) .
for the whole group , median time to progression ( ttp ) was 13.4 months , and median overall survival ( os ) was 23 months .
median ttp and os for this group was 21.5 months and 24.2 months , respectively .
for patients without egfr mutations , ttp was 5 months , and os was 7 months ( table 2 and figures 3 and 4 ) .
this clinical trial was launched at a time when routine testing for egfr gene - activating mutations was not yet available .
selection of patients for a combination of chemotherapy and erlotinib was made on the basis of classical histopathology ( adenocarcinoma ) and smoking status .
since testing for egfr gene mutations is now available , it is clear that patients with activating mutations are those who really benefit from tkis . in addition ,
standard first - line treatment for patients with activating egfr mutations is now monotherapy with a tki [ 6 , 7 ] .
since continuing a trial with the same selection criteria and without considering the status of egfr gene activating mutations was not justified , the research group made a decision to close the trial and analyse the experience . in order to get a longer interval for intermittent erlotinib , gemcitabine was given on days 1 and 4 of the cycle . when compared to the standard day 1 and day 8 schedule
, this minor modification in timing of cytotoxic drugs did not have any adverse effect on the tolerance to treatment .
clearly , other platin - based schedules which apply chemotherapy on a 3-weekly basis ( such as pemetrexed - cisplatin or paclitaxel - carboplatin ) can offer an even longer interval for tkis and might be considered for future trials of intermittent treatment .
two other groups recently reported promising experience with intermittent chemotherapy and tkis . in a trial from the usa ,
two schedules of intermittent treatment were tested . in combination with pemetrexed ( 500  mg / m on day 1 ) , erlotinib
was given either as a pulse application in a high dose ( range : 800 to 1400  mg ) given on days 2 , 9 and 16 , or in lower doses ( 150250  mg daily ) on days 2 to 16 .
while tolerance to this treatment was good , the small number and heterogeneity of patients recruited into this trial do not allow for any clear conclusion regarding the effectiveness of intermittent treatment . of more importance
this study from asia compared gemcitabine and either cisplatin or carboplatin to a schedule with addition of intermittent application of erlotinib ( 150  mg on days 14 to 28 of the cycle ) and reported significantly superior ttp with the intermittent schedule .
their experience is most valuable but may not be of direct relevance for the rest of the world , due to the well - known differences in sensitivity of lung cancer to tkis between asian and caucasian patients .   despite its small size ,
our trial can offer valuable experience for further research on optimisation of treatment with combinations of chemotherapy and tkis .
looking at the whole series of patients , we can conclude that intermittent chemotherapy and erlotinib is a treatment of very low toxicity .
it is also clear that the efficacy of treatment is closely related to the presence or absence of egfr gene - activating mutations .
the most important finding is the excellent response rate with a substantial proportion of complete responses and prolonged ttp and os for patients positive for egfr gene - activating mutations . for many years , the maximal expectation of a patient with metastatic nonsmall cell lung cancer was a partial remission of relatively short duration in the range of 5 to 9 months . with intermittent treatment ,
while the number of patients in our trial is small and any definitive conclusion would be premature , we nevertheless believe that further research of intermittent therapy for patients positive for egfr gene - activating mutations is warranted . a randomised trial comparing first - line tki as monotherapy to the intermittent schedule should clarify the real value of this new approach .

Answer:
background . intermittent application of chemotherapy and tyrosine kinase inhibitors may avoid antagonism between the two classes of drugs .
 this hypothesis was tested in a phase ii clinical trial .
 patients and methods .
 eligible patients were nonsmokers or light smokers , chemo - nave , with metastatic adenocarcinoma of the lung .
 treatment : 4 to 6 cycles of gemcitabine 1250  mg / m2 on days 1 and 4 , cisplatin 75  mg / m2 on day 2 , and erlotnib 150 mg daily on days 515 , followed by erlotinib as maintenance . results .
 24 patients entered the trial .
 four pts had grade 3 toxicity .
 complete remission ( cr ) and partial remission ( pr ) were seen in 5  pts and 9  pts , respectively ( response rate 58% ) .
 median time to progression ( ttp ) was 13.4 months and median overall survival ( os ) was 23 months . when compared to patients with negative or unknown status of egfr mutations ,
 8 patients with egfr gene activating mutations had significantly superior experience : 4 cr and 4 pr , with median ttp 21.5 months and os 24.2 months ( p < .05 ) . conclusions .
 intermittent schedule with gemcitabine , cisplatin and erlotinib has mild toxicity . for patients who are positive for egfr gene activating mutations
 , this treatment offers excellent response rate , time to progression and survival .