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:
the number of patients undergoing chemotherapy grows year by year . despite their efficacy in controlling the cancer , chemotherapy drugs are not inert , and they cause damage to the human body
regarding nail involvement , diverse clinical features can be observed , according to the structure affected and the severity of the damage caused .
the most common chemotherapeutic agents implicated in nail changes are cyclophosphamide , doxorubicin and hydroxyurea [ 2 , 3 ] . in the majority of cases ,
the effects are fully reversible after a few months once the causative agent has been withdrawn [ 2 , 4 ] .
a 25-year - old male patient was admitted to the hospital 's hematology ward with the diagnosis of acute lymphocytic leukemia .
the hyper - cvad regimen delivers a combination of drugs in 2 cycles ( cyclophosphamide , vincristine , doxorubicin and dexamethasone in cycle a , methotrexate and cytarabine in cycle b ) , split into smaller doses and administered at more frequent intervals in order to minimize side effects . during hospitalization , a dermatology assessment was requested .
the dermatological examination showed nail injury characterized by transverse , brown - gray hyperpigmentation affecting the proximal half of the nail plate , with a brown band delimiting the healthy nail plate on all fingers ( fig . 1 , fig
chromonychia induced by chemotherapeutic agents has different forms , the most common being melanonychia [ 2 , 4 , 5 ] . the dark pigmentation in nails can be diffuse , transverse or longitudinal and can coexist with skin and mucosal pigmentation [ 2 , 4 , 6 ] .
it has been suggested that chemotherapy drug regimens influence the incidence of changes that may result from toxicity in the nail matrix , nail bed , periungual tissue and digits vessels [ 2 , 6 ] .
although several chemotherapeutic agents can cause these changes , those most associated with these side effects are cyclophosphamide , doxorubicin and hydroxyurea [ 2 , 3 ] .
cyclophosphamide is an alkylating agent whose main target is the cell cycle ; thus , tissues with high proliferation rates are more susceptible .
alkylating agents form cross - links with dna filaments and prevent dna replication , therefore entailing cytotoxicity .
cyclophosphamide can cause nail changes such as diffuse , black pigmentation , longitudinal striae ranging in color from slate gray to black , and diffuse , dark gray pigmentation located proximally , with overlying transverse , black bands [ 2 , 4 ] .
this drug - induced nail pigmentation starts from the proximal edge of the nail and proceeds towards the distal edge . upon withdrawal of the drug
it takes approximately 46 months [ 2 , 3 ] . in 60% of patients ,
cyclophosphamide is also associated with pigmentation of the oral mucosa and tongue , which also regresses upon withdrawal of the drug [ 2 , 4 ] .
its side effects include skin and nail hyperpigmentation , alopecia , skin rash , pruritus , photosensitivity , urticaria , acral erythema and palmoplantar erythrodysesthesia .
nail changes such as transverse , dark brown bands alternating with white stripes [ 2 , 7 ] and dark brown diffuse pigmentation bands 45 mm wide , which affect two - thirds of the distal portion of the nail , also occur [ 2 , 5 ] .
additionally , doxorubicin can cause subungual keratosis , onycholysis and thickening of the nail plate .
hydroxyurea causes an immediate inhibition of dna synthesis by acting as an inhibitor of ribonucleotide reductase , without interfering in the synthesis of ribonucleic acid or protein .
this pigmentation has a diffuse , dark brown color which may appear as single or double transverse bands [ 2 , 4 ] .
ungual hyperpigmentation induced by chemotherapy is not uncommon , although its occurrence is underestimated and seldom reported , especially in patients with dark skin phototypes , such as our patient , in this case , the drugs most probably implicated are doxorubicin and cyclophosphamide because they produce ungual alterations very similar to the ones seen in our patient ; his chemotherapeutic scheme included both of them .

Answer:
chemotherapy drugs can affect the skin and its appendages .
 several clinical presentations can be observed , depending on the affected structure .
 the most common dermatological side effect is chromonychia .
 the main causative agents are : ( 1 ) cyclophosphamide , which can provoke a diffuse , black pigmentation , longitudinal striae and dark grey pigmentation located proximally on the nails ; ( 2 ) doxorubicin , which promotes dark brown bands alternating with white striae and dark brown pigmentation in transverse bands , and ( 3 ) hydroxyurea , which produces a distal , diffuse , dark brown pigmentation . in the majority of cases ,
 the effects are reversible after the suspension of the causative agent for a few months .
 we report a patient who developed chromonychia while undergoing treatment with cyclophosphamide , vincristine , doxorubicin , dexamethasone , methotrexate and cytarabine for acute lymphocytic leukemia .


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:
they may be the first manifestation of metastatic spread of an internal malignancy or herald cancer recurrence long after treatment of a primary tumor .
breast cancer , colorectal cancer , and melanoma frequently metastasize to the skin in women . in men ; melanoma , lung cancer , and colorectal cancer are the most common sources of cutaneous metastases .
however , such patterns may differ geographically as a study in taiwan found internal malignancies metastasize to the skin with different frequencies and at rates differing from primarily caucasian populations .
an extensive literature review was conducted using pubmed from may 26 , 2011-july 16 , 2013 relating cutaneous metastases .
articles chosen for reference were queried with the following prompts :  cutaneous metastases  ,  clinical presentation  ,  histological features  , and
further searches included  treatment  and  management  options for  metastatic breast  ,  metastatic colorectal  ,  metastatic melanoma  ,  metastatic lung  , and  hematologic cancers  .
we review the literature on clinical presentation , diagnosis , and advances in the management .
cutaneous metastases may be asymptomatic or be associated with pain and tenderness [ figure 1a ] .
they frequently present as a rapidly growing painless dermal or subcutaneous nodules with intact overlying epidermis [ figures 1b  d ] , but can also mimic an inflammatory dermatosis .
metastases may also present as macules , infiltrated or indurated plaques , discoid lesions , tumor nodules with telangiectasias , bullous or papulosquamous lesions , scarred plaques , or pigmented tumors . while there is no single diagnostic characteristic which predominates ; a few patterns have been recognized .
( a ) gingival metastases from a primary chondrosarcoma.(b ) firm nodule at the base of the ear from a primary lung cancer .
( c ) two subcutaneous firm nodules in the clavicular fossa from metastatic lung cancer .
( d ) isolated firm nodular lesion from metastatic colon cancer metastases originating from breast cancer tend to appear in the anterior chest wall , either from direct extension of underlying tumor or by lymphatic spread [ figures 2a and 3a ] .
extensive cutaneous involvement of metastatic breast cancer can simulate cellulitis ( carcinoma erysipeloides ) or a breast - plate of armor ( " en cuirasse " pattern ) .
interestingly , a subset of breast cancer patients has superior prognosis , even among breast cancer patients with stage iv disease .
( a ) cellulitis - like appearance of metastatic breast cancer.(b ) plaque - like area with multiple nodules from a primary breast cancer .
( c ) massive recurrence of breast cancer on the chest wall and abdomen of the  en cuirasse  type .
( d ) breast cancer , metastatic to the thoracic spine with extension to the skin , and lceration secondary to radiation therapy ( a ) cellulitic - type appearance with multiple nodules in metastatic breast cancer of the shoulder and upper back .
a cam 5.2 stain reveals perinuclear staining ( original magnification , 400).(c ) metastatic squamous cell carcinoma of the skin reveals neoplastic cells in the dermis ( cytokeratin 5/6 stain ; original magnification , 100 ) .
a her2/neu stain is positive and decorates the neoplastic cells in the dermis indicating possible metastasis from breast carcinoma ( original magnification , 200 ) while most cancers present as solitary nodules , melanoma and carcinomas with an unknown primary frequently present as multiple nodules .
locoregional melanocytic metastases may be explained by angiotropism , an extravascular migratory phenotype , and an important marker and prognostic factor of metastasis in melanoma .
the face and scalp are most commonly affected by metastases , suggesting that blood vessels and patterns of innervation may influence the spread of metastases .
these patterns can also been associated with cancers of gastric , pulmonary , prostatic , ovarian , laryngeal , palatine - tonsillar , pancreatic , colorectal , parotid , thyroid , or uterine origin and may suggest local treatments that work for melanoma may also work for other metastatic cutaneous malignancies .
although metastases may be comprised of cells which are more undifferentiated than the primary tumor , careful examination usually reveals important clues .
for example , melanoma is associated with pigment in at least some of the neoplastic cells in most cases .
squamous cell carcinoma is associated with keratin pearl formation , and adenocarcinomas usually exhibit gland formation .
thyroid cancer may exhibit colloid bodies , colon cancer may be associated with mucinous cells , and other tumors may exhibit telltale clues as to their origin . when confronted with a possible metastasis ,
comparison with the histologic appearance of any prior malignant neoplasms is usually one of the first steps that may help identify the source .
additionally , studies have indicated the majority of metastatic cancers to the skin are adenocarcinomas .
when tumors are poorly differentiated or anaplastic , screening immunohistochemical studies can be very helpful .
when neoplastic cells stain with cytokeratin markers such as ae1/ae3 and cam 5.2 , a carcinoma is likely [ figure 3b ] .
staining with cd45/leukocyte common antigen ( lca ) indicates that neoplastic cells are of lymphoid origin , while s-100 , melan - a , mart-1 , hmb-45 , and sox-10 decorate most melanomas .
more detailed immunohistochemical studies [ table 2 ] can be performed when screening studies and clinical correlation have not been fruitful in identifying a tumor of origin .
although advances in immunohistochemistry are very promising , there is still much work that needs to be done to characterize metastases .
a recent letter to the editor highlights the pitfalls that can occur when differentiating primary cutaneous apocrine carcinoma from a metastasis .
although cytokeratin 5/6 is associated with cutaneous apocrine carcinoma , this staining pattern has also been noted with metastatic squamous cell carcinoma [ figure 3c ] .
similarly , cytokeratin 7 usually stains metastases diffusely , but is associated with only focal staining in primary adnexal carcinoma , but this pattern is not absolute .
mammaglobin is of interest as it is associated with more widespread staining of metastases than primary apocrine carcinoma , but the results are still preliminary .
cyclooxygenase 2 is associated with tumors of the mid - gut ( ileum and appendix ) , gut , colorectal adenocarcinoma as well as gastroesophageal adenocarcinoma .
staining of adenocarcinoma of the lung and endometrioid adenocarcinoma can also occur , highlighting the fact that all immunochemical marker studies must be interpreted in the context of other findings .
when an epithelial carcinoma is identified , cytokeratin 7 and 20 stains can provide important useful characterization of tumors .
additional testing can include thyroid transcription factor-1 ( ttf-1 ) and other markers as needed . when clinical appearance , clinical history , and the histologic findings on biopsy are all taken into account
unfortunately , there are still many cases that elude precise diagnosis regarding whether a tumor is primary or metastatic .
recent reports have proposed a diagnostic algorithm for metastatic tumors of unknown primary . until better methods are developed
we recommend excising metastases when surgically feasible and when this will result in a significant decrease in total tumor burden , improve quality of life , or result in increased functionality .
novel treatments have had a profound effect on prolonging the survival and improving quality of life with metastatic cancer .
oftentimes , treatment of the primary cancer with a successful regimen will cause cutaneous lesions to lessen .
interestingly , the abscopal response represents an unusual response to radiation therapy in which radiation of a tumor causes untreated distant skin lesions to dissipate without recurrence .
the pathophysiology and mechanism of the abscopal effect have not been well - defined , but one study used monoclonal antibodies to analyze infiltrating lymphocytes and suggested that the abscopal effect was caused by activated cellular immunity .
the abscopal response has been reported with treatment of melanoma , merkel cell carcinoma , hematologic , and solid tumors .
the study of effective local treatments for melanoma may serve as a model for other malignancies that disseminate via lymphatics and the blood stream to the skin . for melanomas ,
we typically excise isolated metastases with a 1 cm margin of normal skin , understanding that there are no evidence based studies looking at the utility of margins for metastatic disease . in areas of high cosmetic importance or when therapy is limited to palliation
, we sometimes perform excisions with very limited margins . therapy for patients with widespread cutaneous and subcutaneous metastases of advanced melanoma that are nonresectable is limited to other types of palliative therapy .
options include radiotherapy , systemic chemotherapy , polychemotherapy , isolated limb perfusion , interferon alpha injections , cryotherapy , laser ablation , or radiofrequency ablation .
electrochemotherapy is a novel therapeutic option based on enhanced drug delivery into cancer cells using externally applied electrical fields that increase cell membrane permeability . using targeted electric pulses on tumor - specific areas , cytotoxicity of cisplatin
increased 80 times and bleomycin 8,000 times with a large reduction in systemic side effects .
a study comparing tumor nodules treated with electrochemotherapy with cisplatin versus cisplatin alone found at a 124-week follow - up , 77% of control rate of tumor nodules treated with electrochemotherapy was observed compared to 19% for those treated with cisplatin only .
electrochemotherapy is well - tolerated by patients , highly effective with low doses of cisplatin or bleomycin , has a short duration of treatment sessions , insignificant side effects , and is more cost - effective than isolated limb perfusion , radiotherapy , interferon - alpha , and hyperthermia associated with radiotherapy and chemotherapy .
oncogene - targeted therapy for metastatic melanoma using vemurafenib ( plx4032 ) for melanoma associated with a mutation of the braf gene v600 mutation results in complete or partial tumor regression in the majority of patients with an estimated median progression - free survival of more than 7 months .
side effects include arthralgia , rash , nausea , photosensitivity , fatigue , cutaneous squamous - cell carcinoma , pruritus , and palmoplantar dysesthesia .
imiquimod 5% cream has also been used successfully in the treatment of metastatic melanoma that is difficult to remove by surgery . in one report ,
a 58-year - old woman with a superficial spreading melanoma with a breslow thickness 0.75 mm was treated with wide local excision followed by flap reconstruction .
melanoma reemerged 14 months later that was treated with wide local excision followed by split - thickness graft repair .
the patient was enrolled in a melanoma peptide vaccine trial 5 months later without improvement .
twenty - one months later , the patient was treated with imiquimod 5% cream and histopathologic evaluation revealed regression of the widespread cutaneous metastases after 6 months of imiquimod .
any change in the skin should raise the suspicion of metastases in the correct clinical context .
biopsy is mandatory in patients with a history of cancer or those with at high risk of cancer .
immunohistochemical screening methods continue to improve and assist in diagnosing the primary tumors of origin .
immunohistochemical findings can also help direct treatment options . with advances in novel therapies that prolong survival ,

Answer:
skin metastases are rare in the routine clinical practice of dermatology , but are of major clinical significance because they usually indicate advanced disease .
 we reviewed the literature on skin metastasis regarding recent trends in clinical presentation and diagnosis of the most common cutaneous lesions .
 an extensive literature review was conducted using pubmed from may 26 , 2011 to july 16 , 2013 relating cutaneous metastases .
 articles chosen for reference were queried with the following prompts :  cutaneous metastases  ,  clinical presentation  ,  histological features  , and
  immunohistochemistry  .
 further searches included  treatment  and  management  options for  metastatic breast  ,  metastatic colorectal  ,  metastatic melanoma  ,  metastatic lung  , and  hematologic cancers .
  we also reviewed the literature on the current management of melanoma as a model for all cutaneous metastatic disease .
 our own clinical findings are presented and compared to the literature .
 additionally , we highlight the most useful immunohistochemical studies that aid in diagnoses .
 several novel therapies and combination therapies such as electrochemotherapy , vemurafenib , and imiquimod will be discussed for palliative treatment of cancers that have been found to improve cutaneous lesions .
 we review these notable findings and developments regarding skin metastases for the general dermatologist .


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:
benign prostatic hyperplasia ( bph ) is a progressive and androgen - dependent disease that causes lower urinary tract symptoms ( luts ) .
although bph is not a life - threatening disease , it can have a negative effect on the quality of life .
alpha - adrenergic receptor antagonists ( -blockers ) and 5-alpha reductase inhibitor ( 5ari ) are the first - line treatment option in patients with bph .
5ari blocks the conversion of the sex steroid hormone testosterone to dihydrotestosterone ( dht ) , which is an essential component of bph pathogenesis .
previous studies reported that the serum prostate - specific antigen ( psa ) level and prostate volume were decreased by approximately 50% and 20% , respectively , after treatment with 5ari .
however , some clinical questions remain as to how to interpret the psa level in men treated with 5ari .
furthermore , the effects on luts and prostate volume after discontinuation of 5ari are not well understood .
therefore , in the present study , we analyzed the changes in luts , prostate volume , and psa level after discontinuation of 5ari .
from december 2003 to december 2012 , 81 men more than 40 years of age with moderate to severe bph symptoms as determined by the international prostate symptom score ( ipss8 ) and a prostate volume of greater than 25 cm measured by transrectal ultrasonography ( trus ) were collected retrospectively for the study .
two patients ( case 1 , 4.91 ng / ml ; case 2 , 5.43 ng / ml ) with a psa level of 4 or more and with a negative pathologic result on the initial prostate biopsy were included in the study .
patients were excluded from the study if they had chronic urinary tract infection ; a history of prostate or testicular surgery , prostate cancer , acute urinary retention , or chronically large postvoid residual urine volume ; or 5ari treatment history .
the patients were classified into group 1 ( n=42 ) and group 2 ( n=39 ) according to 5ari use .
a combination of dutasteride 0.5 mg with tamsulosin 0.2 mg was given daily to all patients for 1 year .
, group 1 ( n=42 ) received a combination of dutasteride 0.5 mg with tamsulosin 0.2 mg daily , and group 2 ( n=39 ) received -blocker monotherapy only .
the ipss , prostate volume , and psa level were measured at baseline and at 12 and 24 months . with trus ( aloka , tokyo , japan ) , prostate volume was measured by use of the prostate ellipsoid formula and was calculated by multiplying the longest anteroposterior ( height , h ) , transverse ( width , w ) , and cephalocaudal ( length , l ) diameters and 0.524 ( hwl/6 ) .
pasw ver . 18.0 ( ibm co. , armonk , ny , usa ) was used for all statistical analyses .
student t - test was used to compare the baseline values of ipss , prostate volume , and serum psa level in each group .
the repeated - measures analysis of variance was performed to compare the change in ipss , prostate volume , and psa level from 0 to 12 months and also from 12 months to 24 months .
the mean age of the patients ( n=81 ) was 71.70 years ( standard deviation [ sd ] , 7.80 ) .
the mean prostate volume was 43.96 cm ( sd , 17.38 ) and the mean baseline serum psa level was 3.00 ng / ml ( sd , 1.98 ) .
the patients were classified into group 1 ( n=42 ) and group 2 ( n=39 ) .
there were no statistically significant differences between the two groups in mean age , total ipss , baseline prostate volume , or psa level ( table 1 ) .
the differences in total ipss , prostate volume , and serum psa level according to the absence of dutasteride are shown in table 2 . at 1 year after combination therapy , total ipss
had decreased by 17.6% ( from 17.88 [ sd , 7.77 ] to 14.95 [ sd , 7.27 ] ; p<0.001 ) in group 1 and by 13.3% ( from 15.50 [ sd , 7.60 ] to 13.45 [ sd , 2.50 ] ; p<0.001 ) in group 2 . however , at 1 year after dutasteride had been withdrawn , total ipss had increased by up to 7.6% ( from 13.45 [ sd , 2.50 ] to 14.93 [ sd , 5.48 ] ; p<0.001 ) in group 2 ( table 2 ) . at 1 year after combination therapy , the prostate volume was reduced by 21.9% ( from 41.59 cm [ sd , 13.97 ] to 32.95 cm [ sd , 10.10 ] ; p<0.001 ) in group 1 and by 15.5% ( from 45.96 cm [ sd , 23.02 ] to 38.96 cm [ sd , 23.91 ] ; p<0.001 ] in group 2 . at 1 year after dutasteride had been withdrawn , the prostate volume had increased by up to 13.1% [ from 38.96 ( 23.91 ) cm to 43.82 ( 23.45 ) cm ; p<0.001 ] . at 1 year after combination therapy ,
the transition zone volume had been reduced by 20.0% ( from 15.62 cm [ sd , 5.76 ] to 12.23 cm [ sd , 4.50 ] ; p<0.001 ] in group 1 and by 17.6% ( from 17.84 cm [ sd , 10.35 ] to 14.61 cm [ sd , 9.81 ] ; p<0.001 ] in group 2 . at 1 year
after dutasteride had been withdrawn , the prostate volume had increased by up to 14.2% ( from 14.61 cm [ sd , 9.81 ] to 16.46 cm [ sd , 10.06 ] ; p<0.001 ] in group 2 .
the psa level had decreased by 48.4% ( from 3.30 ng / ml [ sd , 2.09 ] to 1.75 ng / ml [ sd , 1.33 ] ; p<0.001 ) in group 1 and by 49.4% ( from 2.67 ng / ml [ sd , 1.82 ] to 1.35 ng / ml [ sd , 0.92 ] ; p<0.001 ) in group 2 .
however , 1 year after discontinuation of dutasteride , the psa level had increased up to 108.2% of the baseline level ( from 1.35 ng / ml [ sd , 0.92 ] to 2.89 ng / ml [ sd , 2.10 ] ; p<0.001 ) in group 2 ( fig .
the changes in ipss , prostate volume , and psa over time also did not differ significantly between groups 1 and 2 ( table 2 ) .
patients discontinued dutasteride in group 2 owing to adverse events , including loss of libido ( n=9 ) or erectile dysfunction ( n=17 ) , lack of therapy efficacy ( n=7 ) , abnormal ejaculation ( n=5 ) , and gynecomastia ( n=1 ) .
these symptoms may be associated with bph , which causes extrinsic compression of the prostatic urethra leading to impaired voiding .
bph is a common disease in aging men that leads to deterioration in symptoms , acute urinary retention , bph - related prostatic surgery , gross hematuria , urinary tract infection , bladder stones , and renal insufficiency .
men who have a prostate volume of more than 30 ml are more likely to have moderate - to - severe symptoms ( 3.5 times ) , decreased flow rates ( 2.5 times ) , and acute urinary retention ( 3 - 4 times ) than are men with a prostate volume of less than 30 ml .
bph can significantly affect quality of life in a negative direction , thus requiring treatment .
bph can be managed medically with alpha - blockers , 5-ari , or a combination of both .
alpha - blockers relax the smooth - muscle tone in the prostate and bladder neck .
however , alpha - blockers do not provide long - term reduction in the risk of acute urinary retention or bph - related surgery .
the main role of 5ari is to induce glandular epithelial atrophy , which causes volume reduction in the prostate .
5ari is responsible for impeding the conversion of testosterone to dht by inhibiting the nuclear - bound steroid 5-reductase ( 5ar ) isoenzymes .
both normal prostate development and hyperplasia of the prostatic transitional zone are regulated by dht .
men taking 5ari have a 57% reduction in the risk of acute urinary retention compared with those taking placebo and a 34% reduction in the risk of surgery .
dutasteride results in a reduction of 20% or more in the size of the prostate and a reduction of 48% in the risk of bph - related surgery . in our study ,
total ipss improvement and prostate volume reduction were evident in all men after treatment with dutasteride 0.5 mg .
few reports have discussed the effect of discontinuation of 5ari on luts , prostate volume , and psa level .
stoner   demonstrated that the prostate volume returned to near the baseline values at 12 weeks after discontinuation of 5ari . in our study , the mean percentage of prostate regrowth had reached 95.5% of the baseline prostate volume 1 year after discontinuation of dutasteride . owing to the complex etiologies of prostate enlargement , the mechanism of prostate regrowth after 5ari withdrawal is not fully understood .
the hyperplastic changes in bph are an androgen - dependent process , and it is possible that the sensitivity to dht is increased or overly activated as a result of the prolonged pharmacologic inhibition of 5-reductase by the 5ari .
androgen receptors , which become more sensitive or up - regulated during treatment with 5ari , may be considered as an alternative mechanism .
our study showed that the total ipss had increased 1 year after cessation of dutasteride .
therefore , we propose that reuse of 5ari is helpful in cases that have aggravated bph symptoms or complications of bph .
the psa level is also commonly used as a screening tool for prostate cancer , and the level of 4.0 ng / ml or greater , or more recently , greater than 2.5 ng / ml , has predictive value for prostate cancer detection .
psa velocity also has some predictive potency for detection of the cancer , especially in men with a psa level of 4.0 ng / ml or less .
the epithelial cells of the prostate secrete psa , and it is synthesized by androgen regulation . at 1 year of 5ari treatment , the treatment results in an approximate 50% decrease in the psa level compared with the baseline serum level . the use of 5ari changes the psa level , and this may distract the clinician 's attention .
the psa level must be multiplied by 2 to maintain its usefulness as a marker .
the psa level increases after discontinuation of 5ari because psa is secreted by the epithelial cells of the prostate . in our study , the psa level had decreased 1 year after combination therapy and had increased 1 year after discontinuation of 5ari . in group 1 ,
two patients had continued psa level elevation , and they were finally diagnosed as having prostate cancer .
thus , regular monitoring of the psa level may be helpful for prostate cancer detection .
although it is not mandatory , we suggest measuring prostate volume by using trus in selected patients with aggravated bph symptoms or a high psa level .
trus can provide psa density , which helps clinicians make decisions about further evaluations such as prostate biopsy .
the limitations of this study include it being a retrospective review and having a small number of cases .
prospective randomized clinical trials with a larger number of cases are needed to fully determine the effect of discontinuing 5ari .
maximal urinary flow rate is needed to evaluate the changes in urinary symptoms with the use of 5ari .
last , our study investigated changes 1 year after the discontinuation of dutasteride , but longer follow - up is necessary to make therapeutic decisions about the effect of 5ari .
our study showed that withdrawal of 5ari during combination therapy resulted in prostate regrowth and deterioration of luts .
the psa level was reduced by the use of 5ari , but discontinuation of the drug resulted in an increase in the psa level . as a result , regular checkup of the ipss and psa level may be helpful for all patients who continue or discontinue use of 5ari .
we recommend measuring prostate volume by using trus in selected patients with aggravated bph symptoms or a high psa level .

Answer:
purposeto assess changes in lower urinary tract symptoms ( luts ) , prostate volume , and serum prostate - specific antigen ( psa ) after discontinuation of 5-alpha reductase inhibitor ( 5ari ) combination therapy in patients with benign prostatic hyperplasia ( bph).materials and methodsfrom december 2003 to december 2012 , data were collected retrospectively from 81 men more than 40 years of age with moderate to severe bph symptoms ( international prostate symptom score [ ipss]8 ) .
 the men were classified into group 1 ( n=42 ) and group 2 ( n=39 ) according to the use of 5ari therapy .
 a combination of dutasteride 0.5 mg with tamsulosin 0.2 mg was given daily to all patients for 1 year .
 for the next 1 year , group 1 ( n=42 ) received the combination therapy and group 2 ( n=39 ) received tamsulosin 0.2 mg monotherapy only .
 the ipss , prostate volume , and psa level were measured at baseline and at 12 and 24 months according to the use of dutasteride.resultsdiscontinuation of dutasteride led to significant deterioration of luts , increased prostate volume , and increased psa level .
 the repeated - measures analysis of variance showed that the changes in ipss , prostate volume , and psa level over time also differed significantly between groups 1 and 2 ( p<0.001).conclusionswithdrawal of 5ari during combination therapy resulted in prostate regrowth and deterioration of luts .
 the psa level is also affected by the use of 5ari .
 therefore , regular check - up of the ipss and psa level may be helpful for all patients who either continue or discontinue the use of 5ari .


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:
idiopathic demyelinating polyneuropathies are not common in the context of acute kidney injury ( aki ) .
poems syndrome ( polyneuropathy , organomegaly , endocrinopathy , monoclonal gammopathy , and skin changes ) is a rare disease characterized by the presence of proliferation of plasma cells with mainly lambda - chain restriction and diverse systemic symptoms occurring over several years , meaning that patients typically visit several clinical departments before obtaining the final diagnosis1 ) . kidney dysfunction is not included in the diagnostic criteria of poems syndrome , but aki can be present with other systemic symptoms2 ) .
a 52-year - old korean man was admitted to this hospital because of abdominal distension and diarrhea .
he had been well until 4 years ago , when he was diagnosed with cerebral infarct at another hospital .
he was a businessman who rarely drank alcohol and had no previous history of medication .
when he was transferred to our hospital 2 years ago , he had the symptom of mild tingling sensation in the left hand .
one and a half years ago , paresthesia of right arm and intermittent difficulties with handwriting developed .
brain magnetic resonance imaging ( mri ) with mr angiography showed neither infarct nor vascular stenosis .
nine months ago , after undergoing health checkups , he was referred to the nephrology , endocrinology , and ophthalmology clinics because of high scr ( 1.52mg / dl ) , elevated thyroid stimulating hormone , and papilledema in both eyes , respectively .
since then , he suffered from gradually increasing paresthesia of both feet , progressing to both ankles and to both lower legs .
he did not feel muscle weakness , but had some difficulties maintaining balance while walking as well as morning stiffness of both arms .
nerve conduction studies showed absent bilateral tibial nerve responses , slow motor responses on bilateral peroneal nerves , decreased sensory responses on bilateral sural nerves on the lower extremities , and slow motor and sensory nerve conduction velocities over the right median nerve .
on cutaneous examination , red papules with diameters of 2 to 6 mm , which developed in the previous year , were scattered on the truncal areas .
hypertrichosis with hyperpigmentation was observed in both hands and lower arms and finger clubbing was present .
the pathologic diagnosis of the papules was glomerular hemangioma . computed tomography ( ct ) of the chest and abdomen
ct of abdomen showed multiple small lymph node enlargements around the aorta as well as a small amount of ascites .
a diagnosis of chronic inflammatory demyelinating polyneuropathy was made and therapy with oral prednisolone was initiated . during the next 2 months , weakness in the patient 's legs increased and he developed a limping gait
. he could not walk on his toes and heels and his perception of vibration decreased in both knees .
the test results for syphilis , hepatitis b and c , and hiv were negative .
tests for autoantibodies such as rheumatoid factor , anti - nuclear antibody , anti - ganglioside antibody , and anti - myelin - associated glycoprotein antibody , were all negative .
tests for vasculitis and anti - phospholipid syndrome were also negative . the levels of serum complements c3 , c4 and immunoglobulins ig g , a , and m were within normal limits .
a small m - peak was noted ( 0.1 g / dl ) in serum protein electrophoresis ( pep ) and no light chain was detected in urine pep .
six months before admission , he was referred to the oncologist for this finding and monoclonal gammopathy of undetermined significance ( mgus ) was a plausible diagnosis .
three months after steroid pulse therapy , his muscle weakness and gait improved , but burning paresthesia persisted .
after 4 months , the steroid dose had been tapered and stopped . after stopping steroid treatment , he noted rapid progression of muscle weakness ( he could not stand from the floor ) and difficulties with walking and balancing .
although his appetite markedly decreased , his body weight increased by 5 kg and leg edema and abdominal girth increased .
he had not taken any nephrotoxic agents including nonsteroidal anti - inflammatory drugs ( nsaids ) .
laboratory results showed an increase in scr to 3.21mg / dl and fena and feurea was 0.24% and 12.3% , respectively .
as abdominal distension increased with ascites he needed therapeutic paracentesis every 4 to 5 days .
light microscopic examination revealed renal cortex and medulla containing about 33 glomeruli , one of which was globally sclerotic .
most glomeruli showed increase in size and cellularity with mild to moderate endocapillary proliferations with diffuse double contours of capillary walls .
there were diffuse interstitial edema and mild interstitial lymphocytes infiltrations with focal tubular atrophy containing hyaline casts destructing of tubular cells .
immunofluorescence study did not show any immunoglobulin or complement deposition or staining for kappa and lambda light chain .
electron microscopic examination revealed that most glomerular capillary lumina were compromised with diffuse duplications of capillary walls and subendothelial widenings with flocculent materials and mesangial interposition .
visceral epithelial cells showed hyperplasia and focal effacement of foot process about 20% of external capillary surfaces .
bone marrow biopsy showed normal bone marrow cellularity ( 60% ) and a normal ratio of the plasma cells ( 2.3% ) .
megakaryocyte hyperplasia was observed and a lymphoid follicle was seen in the bone marrow biopsy .
immunohistochemical staining showed that the majority of plasma cells were positive for lambda light chain ( fig .
the patient 's diagnosis was almost certainly poems syndrome accompanied by recurrent aki ; however , an additional major criterion was required . upon retrospective review of his previous chest and abdomen
ct , we found osteosclerotic bone lesions in thoracic vertebral bones in the chest ct scan ( fig .
3 ) . therefore , poems syndrome was diagnosed based on polyneuropathy , monoclonal plasma cell disorder with iga lambda , sclerotic bone lesion , extravascular volume overload , endocrinopathy , hepatomegaly and skin changes , consistent with proposed diagnostic criteria .
once the diagnosis of poems had been established , the patient was treated with a 28 days cycle of bortezomib and dexamethasone combination followed by autologous hematopoietic stem cell transplantation ( hsct ) at another hospital .
two months after the procedure , the patient showed a notable clinical improvement including polyneuropathy , normal scr ( 0.80mg / dl ) and mobilization was possible with the aid of a walker .
poems syndrome is a rare paraneoplastic syndrome resulting from a proliferative monoclonal plasma cell disorder1 ) .
the diagnosis of poems syndrome must include two mandatory major criteria of ( 1 ) demyelinating polyneuropathy and ( 2 ) monoclonal plasma cell - proliferation ( almost always  type ) .
in addition , one other major criterion must be present ( any one of the following three features : osteosclerotic bone lesions [ almost always present ] , elevated levels of vascular endothelial growth factor [ vegf ] , or castleman disease ) .
in addition , at least one of the following seven minor criteria should be met : organomegaly , extravascular volume overload , endocrinopathy ( excluding diabetes mellitus or hypothyroidism ) , typical skin changes , papilledema , or thrombocytosis , polycythemia1 ) . making a diagnosis can be a challenge as the syndrome is rare and can be mistaken for other neurologic disorders .
the most prominent symptom of this patient was his progressive sensory neuropathy , followed by the development of motor weakness over a period of 4 years .
possible differential diagnoses of polyneuropathy and kidney injury include nutritional deficiency such as pyridoxine or thiamine , human immunodeficiency virus - related neuropathy , amyloid , vasculitis , and paraneoplastic syndrome3 ) .
his laboratory results for viruses and vasculitis revealed no positive findings and his aki had no definite cause .
during the clinical course of this patient , there was no event of renal ischemia caused by nephrotoxic drugs or other systemic hemodynamic change . in the kidney , continuous endothelial injury caused mesangial interposition , mesangial proliferation and finally mesangial sclerosis .
in addition to the glomerular change , ischemic damage caused by obliteration of arterioles and small arteries was proposed to induce recurrent acute kidney injury2 ) .
vegf is a potent microvascular permeability - enhancing mediator and a selective mitogen for vascular endothelial cell8 ) .
therefore , the vegf produced by plasma cells leads to a decrease in intravascular volume by increasing vascular permeability , which may contribute to prerenal aki5 ) .
we might discern from this case that serum and urine pep should be obtained in patients with polyneuropathy and unexplained kidney injury to detect monoclonal gammopathy . however , serum and urine pep of this patient were normal 8 and 6 months ago ( table 1 ) . in poems syndrome ,
the median percent of plasma cells in the bone marrow is less than 5% , which is reflected by the small amount of m - protein , and serum pep often can not detect the m - peak1 ) .
instead , serum and urine ife should be performed to identify the isotype , as these techniques are three times more sensitive in detecting monoclonal immunoglobulin than serum pep4 ) . in kidney biopsy ,
immunofluorescence staining showed no deposition of -light chain and electron microscopy showed no electron - dense deposits .
these are quite different findings from other plasma cell disorders that showed kidney damage with deposition of a monoclonal immunoglobulin4 ) .
instead , renal pathology of this patient showed extensive endothelial cell injury and evidence of increased extravascular permeability .
secretion of vegf from the monoclonal plasma cells in patients with poems syndrome has been suspected to trigger these changes25 ) , but the mechanism remains unknown and must be investigated6 ) .
in contrast to the pathologic lesions , proteinuria was absent and microscopic hematuria was minimal in this patient , which may reflect a relatively intact glomerular basement membrane structure and podocyte functions .
treatment of poems syndrome is directed to target the underlying monoclonal plasma cell disease7 ) and therapeutic strategies for the treatment of multiple myeloma have been reported to show successful patient and renal outcomes and an improvement in morbidities related to treatment67 ) .
as this patient showed bone marrow involvement , he received systemic chemotherapy and had autologous blood stem cell transplantation .

Answer:
poems syndrome is a rare paraneoplastic syndrome and there are few reports of polyneuropathy and monoclonal gammopathy associated with kidney dysfunction . here
 , we report a case of poems syndrome with recurrent acute kidney injury ( aki ) . a 52-year - old man presented with bilateral aggravating paresthesia and latermotor weakness of the lower extremities accompanied by repeated elevation of serum creatinine .
 the patient was finally diagnosed with poems syndrome on the basis of fulfilling the two mandatory major criteria ( polyneuropathy and monoclonal gammopathy ) , one other major criterion ( sclerotic bone lesion ) , and several minor criteria .
 a renal biopsy was performed to clarify the cause of aki and showed membranoproliferative glomerulonephritis - like lesions with mesangiolysis and endothelial cell injury .
 this case illustrates that renal manifestations , not included in the diagnostic criteria for poems , can be apparent before various other systemic symptoms .


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:
in pregnant women with mechanical heart valves , the frequency of valve thrombosis increases due to pregnancy - related hypercoagulability . therefore , effective anticoagulation is critical in pregnant patients with mechanical heart valves but remains problematic because both oral anticoagulation and heparins have been associated with important fetal and maternal side effects ( 1 ) .
coumarin derivatives are anticoagulants of choice for mechanical heart valves , but they cross the placenta and are associated with coumarin - induced fetal loss or embryopathy ( 1 - 3 ) .
unfractionated heparin ( ufh ) provides an alternative therapy that avoids fetal side effects , however , the use of ufh is associated with increased maternal thromboembolic and bleeding complications ( 1 , 4 , 5 ) . low molecular weight heparin ( lmwh ) may be more advantageous than ufh ( 6 ) , and appears a good alternative . however , little clinical information and no reliable data are available regarding its efficacy and safety . no consensus has been reached about optimal antithrombotic therapy in pregnant patients with a mechanical heart valve .
coumarins are contraindicated in pregnancy in north america due to fetal concerns , but european experts have recommended low dose coumarins ( less than 5 mg daily ) throughout pregnancy given a very low frequency of fetal anomalies ( 2 , 3 ) .
reports of lmwh use began to appear , and many physicians now use lmwh because of its good safety profile for both mother and baby ( 7 - 10 ) .
however , treatment failures have been reported ( 11 , 12 ) , and no lmwh has been licensed for use in pregnant patients with mechanical heart valves .
available published data regarding the efficacy and safety of lmwh in this clinical setting have been derived from small case series , and usually enoxaparin has been used . here
, we report our experience of nadroparin treatment , and its associated pregnancy outcomes and maternal complications .
between 1997 and 2005 , 31 pregnancies were analyzed retrospectively in 25 women with mechanical heart valves .
basic characteristics and previous operative data are listed in table 1 . in 23 of these 31 pregnancies ,
nadroparin was used as an anticoagulant during the first trimester with given informed consent , concerning the risks and benefits of lmwh .
others were anticoagulated with coumarin derivatives ( cmd ) with or without aspirin due to unawareness of pregnancy until the first trimester , or because of refusal or poor compliance on self - injected lmwh . in the lmwh - treated group ,
when pregnancy was confirmed , coumarins were stopped and changed to subcutaneous nadroparin ( 7,500 u , twice daily ) , from 6 weeks to 12 weeks of gestation .
aspirin , at 100 mg / day , was also administrated throughout the pregnancy . at gestation week 38
, women were scheduled for labor induction and changed to nadroparin to avoid the delivery of an anticoagulated fetus . after establishing labor
, we carefully checked for hemorrhages and other complications , and babies were examined for congenital anomalies and weight . in the cmd - treated group , coumarins and aspirin were continued throughout the pregnancy and the target international normalized ratio ( inr ) was maintained between 2.5 to 3.5 .
coumarins were changed to nadroparin before 2 weeks prior to the expected delivery date to avoid fetal bleeding complications during delivery .
pregnancy outcomes , namely , numbers of healthy babies , fetal anomalies , fetal losses , and maternal complications , including thromboembolism or bleeding , were analyzed . to evaluate the efficacy and safety of lmwh , eight pregnancies , maintained using coumarins throughout pregnancy , were compared .
data were analyzed using spss for windows version 10.0 software and compared using the student 's t - test , at a level of significance of p<0.05 .
no maternal death or bleeding complication occurred in either the lmwh - treated group or the cmd - treated group .
frequencies of maternal thromboembolism were not different between the two groups ( table 2 ) . a maternal transient ischemic attack ( tia ) occurred in one case in each group , and both patients had previously undergone mitral valve replacement .
prosthetic mitral valve thrombosis occurred in three pregnancies , two in the lmwh group and one in the cmd group ( table 3 ) .
the two of these three patients underwent redo surgery , and other patient was managed on thrombolytic therapy .
numbers of live born and healthy babies were higher in the lmwh group ( table 4 ) . in both groups , two babies had low birth weights of 2.1 kg and 2.4 kg , but were otherwise healthy . in the cmd group , one baby had hydrocephalus . however , the frequency of fetal loss including therapeutic abortion and stillbirth were significantly higher in the cmd group .
two fetal losses occurred in the lmwh group , both occurred in cases of maternal valve thrombosis .
four fetal losses occurred in the cmd group , and one of these involved maternal valve thrombosis .
this study demonstrates that lmwh - based therapy is superior to coumarin therapy in pregnant women with a prosthetic heart valve , and that the use of nadroparin during the first trimester with 100 mg of aspirin throughout pregnancy could be a safe and effective protocol for thromboprophylaxis in these women .
recent recommendations , published in 2004 as part of the 7th american college of chest physicians ( accp ) consensus on antithrombotic therapy ( 12 ) , included the following three regimens : 1 ) aggressive adjusted - dose lmwh throughout pregnancy ; 2 ) adjusted - dose ufh , throughout pregnancy ; or 3 ) either lmwh or ufh between 6 and 12 weeks and close - to - term only and the use of cmd at other times .
our protocol was similar to the third regimen , but we also administered aspirin ( 100 mg daily ) throughout pregnancy to reduce coumarin dosages and the risk of thromboembolism .
the overall frequencies of maternal thromboembolism , including valve thrombosis , were similar in both groups , but the frequencies of live and healthy baby births were higher in the lmwh group .
these results demonstrate that lmwh - based therapy is a good alternative to coumarins , because it has similar anticoagulation effects with lower fetal side effects .
exposure to coumarins during the second part of the first trimester is associated with fetal loss , primarily due to spontaneous abortion or coumarin - induced embryopathy .
the reported frequencies of coumarins - related embryopathy vary for debatable reasons ( 14 , 15 ) , a recent study suggested that coumarin risk is dose related and that adverse effects occur mainly in women taking > 5 mg daily .
, the target inr was maintained with less than 5 mg of coumarins in all patients in the cmd group ; however , a half of these lost their babies due to abortion or stillbirth .
our results represent only observational data , and the effect of dose - related embryopathy remains uncertain .
lmwh does not cross the placental barrier and offers potential advantages compared with ufh in terms of better safety profile with less thrombocytopenia , less bleeding , less osteoporosis with prolonged treatment , a more predictable and rapidly reached anticoagulant effect , and the possibility of self - administration of anticoagulant therapy without laboratory monitoring
. however , treatment failures have been reported , and the use of lmwh for pregnant women with mechanical heart valves has become controversial due to small numbers of patients and a lack of accurate postmarketing data ( 16 ) .
a recent review of 81 pregnancies in 75 women treated with lmwh reported an 8.6% rate of valve thrombosis ( 17 ) , and found that appropriate dose adjustments could reduce the frequency of thromboembolism .
the 7th accp recommendations call for the use of lmwh at levels that achieve peak anti - factor xa values of around 1.0 u / ml ( 12 ) . a recent prospective study with deltaparin reported that dosages based on body weight were inadequate to maintain a therapeutic level of lmwh in pregnancy ( 18 ) .
our data demonstrate that valve thrombosis occurred in 2 patients treated with nadroparin ; a prevalence of 8.7% .
unfortunately , we did not monitor anti - xa levels during nadroparin administration , and thus , we can not conclude that valve thrombosis is associated with an inadequate nadroparin dose .
further studies , with sufficient statistical power , are required to clarify the clinical significance of anti - xa levels . in conclusion , despite the retrospective design of the present study , it might be worth to mention that lmwh appears a safe and effective substitute for any other anticoagulants in pregnant women with mechanical heart valves .
we have experienced that pregnancy outcomes are acceptable with lmwh , but that its efficacy for preventing valve thrombosis remains uncertain .
further studies are needed in order to establish appropriate management protocols for pregnant women with mechanical heart valves .

Answer:
no definitive recommendation is available concerning optimal antithrombotic therapy in pregnant women with a mechanical heart valve . the purpose of the current study was to evaluate the clinical results of nadroparin treatment with respect to pregnancy outcome and maternal complications . from 1997 to 2005 , 31 pregnancies were reviewed in 25 women .
 nadroparin ( 7,500 u , twice daily ) was used in 23 pregnancies between 6 and 12 weeks of gestation and close - to - term only , and coumarin derivatives were used with aspirin at other times .
 eight pregnant women treated with coumarin derivatives throughout pregnancy were compared to evaluate the safety and efficacy of nadroparin .
 no maternal death or bleeding complication occurred in either of the two groups , and frequencies of maternal thromboembolism including valve thrombosis ( 8.7% vs. 12.5% , p>0.05 ) were similar .
 however , the frequencies of live born ( 91.3% vs. 50% , p=0.01 ) and healthy babies ( 90.4% vs. 25% , p<0.01 ) were significantly higher , and the fetal loss rate was significantly lower ( 8.7% vs. 50% , p=0.01 ) in the nadroparin - treated group . regarding the efficacy and safety of antithrombotic treatment in pregnant women with prosthetic heart valves , nadroparin treatment during the first trimester is an acceptable regimen and produces better results than coumarin derivatives .


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:
hepatocellular carcinoma ( hcc ) is a common malignancy and is now one of the major causes of death in asian countries . generally , hccs are often asymptomatic , but fatigue , abdominal distention and low - grade fever
however , fever as a primary symptom in hcc is relatively rare . additionally , high crp in laboratory results is also rare .
hcc with pyrexia has been reported only in a few studies [ 24 ] and the cause of pyrexia has remained unknown .    recently , increased production of proinflammatory cytokines and chemokines , such as interleukin-1  ( il-1 ) , interleukin-1  ( il-1 ) , interleukin-6(il-6 ) , interleukin-8(il-8 ) , and tumor necrosis factor- ( tnf- ) have been reported to be febriferous in acute and chronic inflammatory disease [ 5 , 6 ] . these cytokines are produced by immune cells including various populations of lymphocytes macrophages and other cells . among the proinflammatory cytokines ,
il-8 is a neutrophil chemotactic factor and involved in tumor proliferation and migration , angiogenesis in malignant tumors .
this is often accompanied by rapid growth and poor prognosis in malignant tumors [ 713 ] .
we herein discuss a case of hcc accompanied by prolonged spiking fevers , which disappeared after tumor resection .
a 50-year - old man with a history of liver dysfunction was admitted to iizuka hospital with the chief complaint of a prolonged fever and general fatigue in october , 2005 .
hematological laboratory data on admission were as follows : wbc 9670/ l , alp 552 u / l , crp 16.7 mg / dl , and afp 11.1 ng / ml .
hbs - antigen was positive ( table 1 ) . a computed tomography ( ct ) showed a peripherally enhanced low density mass 7.5 cm in diameter , which located in segment 6 in the right lobe of the liver ( figure 1(a ) ) .
the tumor was accompanied with tumor thrombus to the posterior branch of portal vein ( figure 1(b ) ) .
celiac angiography showed this lesion was hypervascular ( figure 1(c ) ) and portal vein tumor thrombus in posterior segment was observed in the portal phase ( figure 1(d ) ) .
patients have chronic hepatitis b and then tumor was hypervascular and accompanied with portal thrombus , which is the feature of hcc , therefore a preoperative diagnosis was made as hcc with portal vein thrombus and nonsteroidal anti - inflammatory drugs were used to reduce the fever .
a single nodule of disseminated cancer cells was found near the posterior segment on the abdominal wall during the operation .
posterior segmentectomy of the liver and thrombectomy including the dissemination was performed . on the cut section ,
the noncancerous liver tissue showed a moderate chronic inflammatory infiltrate in the fibrous stroma , diagnosed as liver fibrosis .
immunohistochemical stain of il-8 was performed with paraffin embedded sections of liver tissue using mouse monoclonal antibody at dilutions of 1 : 100 ( assay designs , ann arbor , usa ) .
the subsequent reaction was performed by the peroxidase labeled streptavidin - biotin technique using histofine sab - po kit ( nichirei , tokyo , japan ) .
il-8 was observed in the cytoplasm of cancer cells ( figure 3(b ) ) .
after the tumor resection , fever disappeared and crp dropped gradually from 16.7 to 2.7 , but the patient had recurrence with multiple liver metastasis and pleuritis carcinomatosa and died on february 2 , 2006 , 79 days after the operation .
in 1991 , okuda et al .   reported five patients with hcc and pyrexia , for an incidence of less than 1% , in japan .
he also mentioned that very poorly differentiated sarcomatoid hcc may frequently appear with pyrexia and leukocytosis mimicking liver abscess . in 1995 , hayashi et al .   reported hcc with pyrexia
laboratory data revealed high crp . nevertheless , in both case reports , the mechanism of a fever was not revealed . in our case ,
the sarcomatoid change of the cancer cell was not detected , only poorly differentiated hcc .
it is well known that cancer cells produce humoral factors and cause the  paraneoplastic syndrome  . among the clinical symptoms and laboratory data , fever and high crp ,
which is not commonly observed in the patients with hcc , is suspected to be due to humoral factors , especially inflammatory cytokine .
il-8 is a proinflammatory cytokine whose principal role in infection and inflammation appears to be the recruitment and activation of circulating and tissue neutrophils to the site of tissue damage .
it has been demonstrated that il-8 is produced by a wide variety of cell types in vitro , including endothelium , monocytes , eosinophils , astrocytes and keratinocytes . in sepsis patients , for example ,
il-8 concentrations have been reported as being markedly elevated at diagnosis and remaining high during the course of the illness .
this symptom is induced by many humoral factors , including il1 , il-6 , il8 and tnf. zampronio ar reported that il-8 induced fever by prostaglandin independent mechanism .
il-8 resulted in a dose - dependent increase of crp , a decrease in the production of transferring and prealbumin .
therefore , il-8 is related to pyrexia in parts , not all .    in other cancer ,
we examined by immunohistochemical staining of il-8 and tumor tissue stained positive for il-8 in this case .
akiba et al .   reported that a high il-8 level in hcc had a significantly higher frequency of portal vein invasion and venous invasion and bile duct invasion . in vitro
reported il-8 production was enhanced progressively with escalating severity of hepatitis and the development of hcc and the level of il-8 were significantly increased in patients with advanced hcc with distant metastasis , and then this leads to poor prognosis .
ren et al . reported serum il-8 level was correlated with tumor size and tumor stage , and then il-8 level was a significant prognostic factor in terms of disease - free survival and overall survival .
additionally , elevated il-8 levels in the drainage vein of colorectal cancer are related to the occurrence of hepatic metastasis .
this case presented portal vein tumor thrombus , bile duct invasion , intrahepatic metastasis , peritoneal dissemination , early tumor recurrence , rapid tumor regrowth and finally a poor prognosis .
in fact , all patients with il-8 production do not have a high fever , the serum concentration of il-8 or the degree of neutrophil infiltration will be concerned with pyrexia .    in many cancers such as esophageal cancer , gastric cancer and colorectal cancer ,
serum crp was known as a prognostic indicator [ 2023 ] . in particular , some reported that serum crp levels indicated a poor prognosis in hcc patients and portal vein invasion was significantly higher in the serum crp - positive group [ 24 , 25 ] . according to the in vitro previous studies , cultured hcc can produce crp that is regulated in part by proinflammatory cytokines , such as il-6 , il-8 and tnf- [ 18 , 26 , 27 ] . among the many proinflammatory cytokines , recent report il-6 mediates cell cycle arrest in hepatocellular carcinoma through a stat 3-dependent pathway
hcc produce proinflammatory cytokines such as il-8 by autocrine or paracrine , which lead to crp production and inflammatory cascade or tumor progression .
in this report we discussed a patient who had poorly differentiated hcc with pyrexia and high crp .
il-8 production was histologically revealed in this case and may have contributed to the high fever , high inflammatory reaction and poor prognosis .

Answer:
we discuss a patient who had poorly differentiated hcc with pyrexia and high crp in laboratory data , which are not commonly observed in the usual hcc .
 a 50-year - old man with a history of liver dysfunction was admitted with a chief complaint of a prolonged fever and general fatigue .
 preoperative diagnosis was hcc with portal vein tumor thrombus .
 posterior segmentectomy of the liver and thrombectomy was performed .
 rapid tumor recurrence occurred after surgery , and he died 79 days after the operation .
 immunohistochemical stain of hcc in this patient revealed the production of proinflammatory cytokine , interleukin-8 ( il-8 ) .
 il-8 production may have contributed to the high fever , high inflammatory reaction , and poor prognosis in this case .


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:
the treatment of lymphoma depends on the type , location and stage of the disease .
the majority ( 50%90% ) of oal is low - grade mucosa associated lymphoid tissue ( malt ) lymphoma . according to the world health organization modification of the real classification ,
the other 4 main types of oal are follicular cell , mantle cell , diffuse large b cell ( dlbcl ) and lymphoplasmacytic lymphoma .
they are all b cell , non - hodgkin s lymphoma , the subtype derived from various stages of b cell maturation .
the new classification of lymphoma is dependent on histological , immunophenotypic and molecular genetic analysis .
hodgkin s lymphoma does not affect the ocular adnexal structures unless there is widespread systemic involvement or a history of previous systemic hodgkin s lymphoma . according to the ann - arbor staging system lymphoma confined to the orbit
is designated as stage i , involvement of adjacent structures ( sinuses , tonsil and nose ) is stage ii .
stage iii is abdominal nodal disease below the diaphragm and iv by definition refers to disseminated involvement of one or more extra - nodal sites ( eg , liver , bone ) and  e  is used when there is a local extra - nodal extent ( eg , ie , iie , iiie and i ve ) .
the grading system is similar to nodal lymphomas . broadly speaking , oal with systemic involvement
requires systemic treatments whereas low - grade ( emzl or follicular cell ) lymphoma localized to the eye can be very successfully managed with local treatments such as cryotherapy , surgical excision or external beam radiotherapy . when considering local treatment it is important to exclude bilateral ocular involvement . even in the absence of clinical signs
staging investigations should include full blood count , hepatic enzymes including ldh , ct abdomen , chest and pelvis , mri or ct of the orbits , and a bone marrow biopsy and aspirate .
this is only appropriate for low - grade lymphoma localized to the conjunctiva or orbit with no systemic involvement .
surgical excision or cryotherapy is most appropriate for localized stage 1 conjunctival emzl / malt lymphoma.1 this is not curative treatment but can control local disease and relieve local symptoms .
tanimoto et al2 reported very good local control of stage 1 malt lymphoma following biopsy or surgical resection alone .
patients were followed for a median of 7.1 years , 69% of patients did not require any further treatment .
the estimated overall survival rates were 94% at 10 years and 71% at 15 years.2 although , patients should be closely followed for recurrence , histological transformation of the tumor and long - term systemic manifestations of lymphoma .
this has been the mainstay of treatment for localized oal for many years with excellent control rates .
central nervous system prophylactic radiotherapy is not required as metastatic intraocular or brain involvement is rare.3 the dose of radiation is tapered according to the grade of the lymphoma , 28 to 36 gy for low - grade lymphoma and 30 to 40 gy for high - grade .
emzl , lymphoplasmacytic and follicular cell lymphoma are considered low grade , whereas dlbcl and mantle cell are high - grade lymphomas .
five - year local control rates for emzl and follicular lymphoma after a dose of more than 30 gy reach 100%.4 however , high rates of delayed systemic recurrence suggest long - term follow up studies are required to assess the true benefit of radiotherapy.5 there is ongoing debate about use of lens shielding radiotherapy to protect the lens from cataract formation .
some studies show no effect on local recurrence , whereas in others all recurrences have occurred in patients whose lenses were shielded.6,7 partial orbit volume irradiation leads to unacceptable incidence of intraorbital recurrence and is presently not recommended .
ocular complications , including dry eye and cataract are frequently reported in patients that have long - term follow up.8 these localized complications need to be kept in mind by the treating oncologist .
ifn - alpha has been used for the treatment of systemic lymphoma for more than 20 years .
one study treated 5 patients with intralesional ifn - alpha using an intensive protocol.9 an initial complete response was seen in all patients with stage i oal , one patient with more advanced disease at presentation ( stage iia ) died from systemic lymphoma .
long - term follow up studies are required to assess the value of this treatment .
rituximab is a monoclonal antibiotic against cd20 positive b cells , which is being considered as an alternative first line treatment for localized cd20 positive oal to avoid the ocular complications of radiotherapy .
antibody - induced destruction of cd20 positive b cells can occur by apoptosis , complement mediated cytolysis and antibody - dependent , cell - mediated cytoxicity .
rituximab has also been used as monotherapy for localized emzl / malt , in some cases complete regression can be achieved .
initial responses are encouraging but the efficacy of rituximab is lower than that reported for gastric malt lymphoma,10 as long - term distal relapse is seen in 50% of cases . very few case series are published on the effect of single agent rituximab on ocular malt / emzl .
ferreri and associates achieved regression of malt lymphoma using first line single agent rituximab in all 5 newly diagnosed patients ; however early relapse was seen in 4 of the 5 patients.10 therefore , close follow up intervals are required to detect early relapse when rituximab is used alone .
rituximab was not successful for the treatment of local relapse.10 greater success is achieved when rituximab is used in combination with chemotherapy .
rituximab and chlorambucil were used as first - line therapy for 9 patients with newly diagnosed emzl .
treatment achieved complete remission in 89% with a median follow up of 2 years.11 first - line chemotherapy is often treatment of choice for mantle cell oal , as a high proportion of patients have systemic involvement at presentation .
encouragingly , rituximab containing chemotherapy for mantle cell oal had a significantly better 5-year survival than patients receiving chemotherapy alone ( 83% overall 5-year survival verses 8%).12 combination treatment with rituximab and chemotherapy or radioimmunotherapy may achieve a more durable local response and improve patient survival.1113
chemotherapy is reserved for treatment of oal when there is systemic involvement , except for the high - grade dlbcl when systemic chemotherapy is first - line treatment even for stage i disease .
more recently chlorambucil and the purine analogs fludarabine , clardarabine and pentostatin have also been used .
the extranodal lymphoma study group ( ielsg ) is currently recruiting patients to a clinical trial investigating the role of rituximab alone or in combination with chlorambucil for malt lymphoma ( ielsg # 19).14
novel mechanisms of tumor pathogenesis have related lymphoma to infection leading to new approaches to diagnosis and treatment .
chronic antigen stimulation may result in an abnormal lymphoproliferative response that ultimately develops into lymphoma .
this association is most profound for gastric malt cell lymphoma , which is related to chronic gastritis from helicobacter pylori infection in more than 90% of cases.15 h. pylori has been isolated from ocular lymphoma specimens .
however , h. pylori eradication is not effective treatment for oa malt lymphoma.16 chlamydia psittaci infection has also been linked to oal .
ferreri and associates17 identified c. psittaci in 80% of italian oa malt lymphoma specimens . in korea , c. psittaci was isolated in 78% of oa malt lymphoma specimens.18
subsequent reports from south florida , new york state , chicago , netherlands , japan and france failed to identify dna for c. psittaci in any of their oa malt lymphoma specimens.1924 there is wide geographical variation in the prevalence of c. psittaci infection in oa malt lymphoma specimens.25 of the european countries studied , the lowest rate of infection ( 12% ) was present in the uk .
results following first line antibiotic treatment are variable.26 abramson and coworkers27 documented a clinical response following antibiotic treatment in 3 patients with oa malt lymphoma .
ferreri and associates28 recorded an objective response following oral doxycycline in 4 out of 9 patients with c. psittaci positive oa malt lymphoma .
although , grunberger and associates29 were unable to replicate these results . in a multicenter prospective trial ,
27 patients with ocular adnexal malt lymphoma were treated with oral doxycycline . c. psittaci dna positive cases had an overall response rate of 64% , the response was of short duration.30 a clinical response
was also seen in 38% in c. psittaci dna negative cases.30 lack of response to antibiotic therapy may be a reflection of the biological and genetic heterogeneity of this disease .
the extranodal lymphoma study group ( ielsg ) has activated a prospective trial ( ielsg # 27 ) into oal to explore the role of antibiotic treatment and to identify potential infectious agents.14 in summary , advances in our knowledge of the immunophenotypic and genetic alterations in lymphoma cell lines have led to a better understanding of the pathogenesis of the disease .
the interplay between a possible infective agent and the immune response has allowed a new wave of treatment possibilities .
staging the patient at diagnosis guides subsequent management and local treatments should be reserved for localized disease .
however , the practical approach to the patient remains  first do no harm  and with this in mind ocular oncologists are tempted to administer an initial trial of oral antibiotics for stage 1 malt lymphoma .
although , general blanket treatment with antibiotics should be discouraged unless there is proof of an infective agent .
we recommend a diagnostic biopsy with immunophenotyping and genetic analysis to determine the grade of the lymphoma combined with pcr analysis to determine the presence of an infective agent . if h. pylori or c. psittaci infection is found a trial of oral doxycycline ( 100 mg twice daily for 3 weeks )
we have also seen some early impressive responses to systemic rituximab ( weekly intravenous infusion over 6 weeks ) . however , close follow up is required as others have reported early local relapse with rituximab alone.10 at present , despite the ocular side effects , localized radiotherapy still remains the standard first - line treatment for stage i low - grade oal .

Answer:
most lymphomas that involve the ocular adnexal structure are low grade , b cell , non - hodgkin s lymphomas .
 the treatment depends upon the grade and stage of the disease .
 high grade lymhoma requires treatment with systemic chemotherapy whereas the localized low grade ( extranodal marginal zone lymphoma ) can be successfully managed with local radiotherapy .
 chlamydia psittaci infection is associated with low grade ocular lymphoma ; however there is wide geographic variation in the strength of this association .
 blanket antibiotic therapy is not advised unless there is proof of an infective agent .
 the monoclonal antibody , rituximab , may be successful for cd20 positive lymphoma , although it is likely that rituximab will have better long - term results when used in combination with systemic chemotherapy .


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:
the femoral head often leads to healing complications , while the more predictable prosthetic replacements are associated with poorer function and significant complications .
the treatment of these fractures depends on the age of the patient , fracture displacement , bone quality , timing of surgery and activity level of the patient .
displaced fractures in healthy , active patients are best treated by reduction and internal fixation .
there are however , complications unique to femoral neck fractures which are almost impossible to predict . non - union and avascular necrosis
non - union usually can definitely diagnosed within a year of fracture fixation with the same being achieved within 3  months at times . after non - union has been established , intervention is inevitable .
the decision to proceed in the management of failed fixation is based on the careful consideration of various factors . in young patients
revision internal fixation with cancellous or muscle pedicle bone grafting ( vascularised bone graft ) or an osteotomy results in useful outcome .
we report a case of non - union of the fracture of the neck of the femur , who refused additional procedures after his non - union had been established .
the study conforms to the declaration of helsinki and was approved by the institutional ethical board .
a 38-year old male businessman reported to the out door department of our hospital with a history of a fall from height .
clinical and radiological examination revealed a displaced fracture of the neck of the femur which was graded as garden type 4 ( fig .
the patient was operated within 24  h. intraoperatively the garden alignment index was used as a yardstick of acceptable reduction .
the fracture was fixed with 3 ao 6.5  mm cannulated screws in an inverted triangle .
onward the patient complained of persistent but mild groin pain on ambulation which was assisted .
the patients conservative line was continued till 1  year when his symptoms continued and radiologically there was no progress . at this point
twenty - six  months into the post operative followup the patients pain subsided and radiographs started showing signs of union . a radiograph taken 32  months after the fixation showed full union .
non - union after femoral neck fracture can be defined as a lack of radiographic evidence of union 6  months after the fracture .
delayed or non - union often manifests as continued pain with weight bearing beyond 3  months post fixation .
incidence of non - union of femoral neck fractures has been reported to be between 2 and 22% and generally becomes apparent within 1  year [ 69 ] .
3radiograph at 32  months depicting union garden 4 type fracture of the neck of the femur showing persistent non - union at 2  years radiograph at 32  months depicting union anatomical reduction and rigid internal fixation are the two important surgeon controlled factors that may contribute to outcome .
the preferred treatment for symptomatic non - unions in the elderly is prosthetic replacement . in the young active patients ,
if failure is due to technical errors , revision open reduction and internal fixation may be adequate .
our case demonstrates that as long as the implant is holding and the patient is regularly followed up good results might be expected in cases as far as 32  months into the post fixation period .

Answer:
fracture of the femoral neck continues to be a vexing clinical and therapeutic challenge for the orthopedic surgeon .
 the fracture has a propensity for non - union and avascular necrosis .
 it is a challenge for the orthopedic surgeon to decide when to intervene in a case with non - union where the implant continues to be in place .
 we present a case with persistent clinical and radiological non - union signs where the fracture eventually united after 32  months .
 the case bolsters the view that a continued conservative regime might entail good results in such situations .


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:
a 78-year - old woman presented with weakness , fatigue and hemoglobin of 8.3 g / dl , to another clinic in september , 2009 , and she was given erythrocyte suspension replacement .
she had regression in her existing complaints with blood replacement therapy , but after one month , same complaints reappeared with a low hemoglobin value and she was referred for further investigation to the outpatient clinic of hematology of our university faculty of medicine . her hematologic parameters ar that time were as follows : white blood cell count of 6390/mm , neutrophils 3785/mm , hemoglobin 8.1 g / dl , mean corpuscular volume ( mcv ) 95 fl , and platelets 211.000/mm . with the provisional diagnosis of myelodysplastic syndrome due to an isolated anemia unrelated to nutritional status , bone marrow aspiration biopsy was performed .
her bone marrow aspiration showed normal cellularity ; and biopsy revealed increase in the number of megakaryocytes , signs of dismegakaryopoiesis , minimal dysplasia in erythroid series , and normal morphology in myeloid series . upon conventional cytogenetical studies
she had been lost - to - follow up for approximately a year and during that time she had received a total of 4 units of erythrocyte suspension , and erythropoietin treatment was started .
however , erythropoietin treatment discontinued because she did not respond to the maximum dose of 10.000 iu three times a week .
she did not attend to her follow - up visits regularly and in the mean time she had transfusions monthly at another clinic .
since her transfusion dependency increased , she was considered for lenalidomide treatment in april , 2013 .
after 10 days of treatment , her liver enzymes increased more than 3 times of normal values and she had thrombocytopenia ( platelet count : 38.000/mm ) then her treatment was postponed for two weeks she restarted lenalidomide treatment at daily doses of 5 mg after liver enzymes and platelet counts returned to normal . during
further follow - up , increase in liver enzymes and severe thrombocytopenia were not detected ; her hemoglobin value increased and transfusion dependency was not observed ( figure 1 ) .
in myelodysplastic syndrome , interstitial deletion in the long arm of chromosome 5 is a common cytogenetical abnormality seen in 16 - 28% of the patients .
it is characterized by hypoproliferative anemia and normal megakaryocytes with hypolobated nuclei or increased dysplastic megakaryocytes in bone marrow [ 7 , 8 ] .
most of the patients are transfusion - dependent because endogen erythropoietin production is usually increased .
one of the major problems during the progression of the disease in transfusion - dependent mds patients is the iron overload secondary to transfusion and the dependency for chelation therapy to treat iron overload .
the immunomodulatory drug lenalidomide that has additional benefits in the regulation of erythropoiesis , inhibition of angiogenesis , and reorganization of erythroid production , targets the mds clone directly [ 9 , 10 ] .
this syndrome is rarely seen ; therefore , there is not enough data about isolated 5q - syndrome as well as lenalidomide therapy in our country .
isolated 5q - syndrome presents with normal or increased thrombocyte counts in peripheral blood and anemia with frequent transfusion replacement dependency . in clinical studies
lenalidomide provided long term blood transfusion independency and erythroid response in patients with low- risk del(5q ) and without del(5q ) . in a phase ii study of low- risk del(5q ) patients ; after 24 weeks , evaluation of erythrocyte response showed that 67% of the patients with 5q deletion who were treated with lenalidomide became transfusion independent . in low- risk
5q deletion mds patients , daily doses of 10 mg for 21 days are used , and repeated with 28 day - intervals that can be modified if needed . in order to evaluate the response ,
adverse events can be easily overcome with dose modifications . in clinical studies , thrombocytopenia and leukopenia
are frequently observed but these adverse reactions usually appear during the first 8 weeks of treatment .
therefore , weekly clinical follow - up at the beginning of the therapy is recommended .
less often adverse events of fatigue , rash and diarrhea can be noted . in conclusion , in isolated 5q - syndrome which is a mds subgroup and characterized by transfusion dependency ; lenalidomide can decrease transfusion dependency with a tolerable adverse event profile that can be overcome with dose modifications .
assessment of all prevalent cases in our country will be helpful to reveal the efficacy and adverse event profile of lenalidomide .

Answer:
5q - syndrome is a special subgroup of myelodysplastic syndrome in terms of follow - up and treatment .
 lenalidomide is an immunomodulatory drug that is frequently used in the treatment of multiple myeloma .
 some clinical studies have shown that lenalidomide treatment is effective in 5q syndrome and significantly decreases the transfusion dependency in these patients . in this paper
 , we would like to share a dramatic response of lowered transfusion dependency after treatment with low - dose lenalidomide in a patient who received myelodysplastic syndrome diagnosis and isolated 5q anomaly in our clinic .


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:
langerhans cell histiocytosis ( lch ) refers to a clonal , neoplastic expansion of langerhans cells .
stimulation by tumor necrosis factor  and granulocyte - monocyte colony - stimulating factor has been implicated in the pathogenesis ( as has human herpesvirus 6 ) .
it most commonly affects children between the age of 1 and 4 , although cases have been described in all age groups ; the incidence in pediatrics has been estimated at 25 per million / year .
it is exceptional for lch to present with brain involvement as the sole presenting symptom .
this complication is reported as occurring in 14% of patients with multisystem disease , typically 520 years from the initial diagnosis .
he developed depression , anxiety and agitation , which led to his retirement from construction work .
shortly thereafter , he developed episodes described as hyperventilation , lasting from seconds to minutes , mostly in the morning , which were followed by confusion and a severe  pounding headache affecting the whole head , both of which lasted for hours .
one year prior to presentation , his family described personality changes ( it was hard for them to characterize this further ) and worsening confusion , particularly over the preceding 3 months .
three months before presentation , he developed weakness of the right leg , which had been slowly progressing since .
two weeks prior , it became so bad that he needed help walking . at this time
, he also noticed weakness of the right arm and slurring of speech , which led him to seek medical help . he had been diagnosed with peripheral arterial disease ( claudication in his left leg ) 4 months prior to presentation , and paroxysmal atrial fibrillation 1 month prior
his initial review of systems revealed that he was anorexic and had lost 30 lb over the last 2 years .
he also complained of a loss of libido and an occasional shortness of breath when walking . on initial exam ,
he was unable to sustain upward gaze ; vertical saccades were followed by a slow downward drift , then a compensatory saccade .
he had a weakness of the right side of his face , sparing the forehead .
he was weak throughout , with strength of 4/5 on his right side in an upper motor neuron pattern with signs of spasticity ; babinski 's reflex was present on this side .
his initial complete blood count , comprehensive metabolic panel , serum protein electrophoresis and folate were normal apart from a white cell count of 13  10/l ( 95% neutrophils ) and platelets of 570  10/l .
his sodium was initially normal , but , during his admission , it was generally in the range of 145160 mmol / l .
mg / l ( < 10 ) , and the erythrocyte sedimentation rate 60 mm / h ( < 20 ) .
he was hypothyroid with a thyroid - stimulating hormone ( tsh ) level of 5.6 iu / ml ( < 4.9 ) and a free t4 of 0.6 ng / dl ( > 0.7 ) .
he had hypogonadism ( presumably secondary ) with total testosterone of < 20 ng / dl ( > 200 ) .
a lumbar puncture was done shortly after admission , showing 4 red cells , 9 white cells ( 56% lymphocytes , 43% macrophages ) , and a protein level of 45 mg / dl ( < 35 ) .
oligoclonal bands were absent and cytology showed no signs of malignancy . shortly after admission , a complete serum paraneoplastic panel was sent ; this was negative .
the antibodies reported were : anti - neuronal nuclear types 13 , anti - glial nuclear type 1 , purkinje cell types 12 and type tr , amphiphysin , crmp-5-igg , striatal , t / q and n - type calcium channels , ach receptor - binding , ach receptor ganglionic and neuronal voltage - gated k channels .
mri is notable for the presence of t2-hyperintense lesions in the left frontal lobe , the right mesial temporal lobe and the brainstem , which were minimally enhanced .
an mr perfusion scan of the brain showed no significant increase in relative blood volume or relative blood flow in these lesions .
a ct of the thorax , abdomen and pelvis showed 5 small lung nodules ( maximum diameter 6 mm ) and a pneumatocele in the left lower lobe .
as there was nothing further on history , exam or initial investigations to suggest cancer anywhere else , a pet / ct was not performed .
immunohistochemistry shows the lesion to be cd1a- and s100-positive , which is characteristic for histiocytosis .
initially , we were unsure of the cause of his right temporal lesion . given the rarity of lch with onset in the central nervous system ( cns ) in adults , the possibility of another tumor was raised , and so a second biopsy was performed .
in retrospect , it would have been better to avoid performing this , as the diagnosis was already clear and his other lesions were attributable to lch .
furthermore , the procedure precipitated status epilepticus and led to preventable complications which ultimately contributed to his death .
this illustrates mild edema , hypercellularity and reactive changes , all of which are consistent with the edge of an inflammatory process .
septic shock ( likely due to ventilator - associated pneumonia ) and a pulmonary embolism complicated his course thereafter .
histiocytosis affecting his skull was thought to be in remission as a result of the treatment , as there was no sign of new or enlarging lytic lesions .
after discharge from the icu , he showed signs of critical illness myopathy / neuropathy .
there was widespread muscle atrophy and generalized weakness . he was unable to stand without support and his tracheostomy remained in place .
given the suspicion of paraneoplastic brainstem inflammation , he was started on intravenous immune globulin ( ivig ) 400 mg / kg  5 days .
two weeks after the initial treatment , the brainstem showed some improvement in the degree of flair hyperintensity ( fig .
an mri 1 month after a second course of ivig showed these changes to be stable overall , with some increase in pontine enhancement ( fig .
he then developed recurrent pneumonia and septic shock , again requiring an icu admission . following this , his family elected a palliative approach to care and he died 6 months after his initial presentation .
our patient 's episodes of hyperventilation followed by confusion are typical for seizures involving the right mesial temporal lobe ; the similarity to panic attacks has previously been identified in a case series .
the development of status epilepticus following biopsy of this region lends support to this being an epileptogenic focus . in
his cerebrospinal fluid ( csf ) , the finding of a high proportion of macrophages is striking .
we were unable to find literature specifically addressing the significance of this finding ; classically it is said to be associated with meningitis due to fungi or tuberculosis .
none of the other case reports we studied , including one with langerhans cells in the csf , reported this finding .
one series has shown elevations of neurofilament protein light chain , glial fibrillary acid protein and total tau protein in the csf of patients with lch affecting the brain .
these advise the use of cladribine for patients such as ours with multisystem and cns involvement ( cytarabine is thought be a reasonable alternative ) .
myelosuppression is the main dose - limiting toxicity ; this has best been studied in the setting of hairy cell leukemia where neutropenia was reported in 70% , anemia ( hb < 8 g / dl ) in 35% and thrombocytopenia in 10% of patients .
the most recent and thorough description of the neuropathology of lch comes from a series of 12 cases from grois et al .   in 2005
the authors divide the pathology into 3 categories : ( 1 ) the typical circumscribed granulomas found in other organs ; ( 2 ) infiltrating granulomas with profound t - cell dominated inflammation and severe neurodegeneration ; ( 3 ) neurodegenerative lesions lacking langerhans cells , typically affecting the brainstem and cerebellum and resembling paraneoplastic encephalitis .
it appears that the temporal and frontal lesions in our patient were of the second type ; it is probable that the biopsy came from the neurodegenerative part of the lesion rather than that containing langerhans cells .
the mri appearances of the brainstem in our patient are typical of the third type .
the presence of inflammation without langerhans cells has led to the view that these lesions are paraneoplastic in origin and that the neurodegeneration seen is thus autoimmune .
the langerhans cells are thought to take up normal neuronal antigens , provoking an immune response to these ; alternatively , the immune system may target antigens shared by langerhans cells and microglia . if an antigen is involved , the pathology reported by grois et al .
the antigens responsible for this phenomenon have not been identified and thus it was to be expected that our patient 's paraneoplastic panel was negative . using multiple immunosuppressants
langerhans cells in their normal form are thought to have a lifespan of months , and lch is characteristically a slowly progressive disorder .
by contrast , cytotoxic t - cells typically have a half - life of 2448 h when activated .
when used in the treatment of leukemia and lymphoma , it is typically given every 4 weeks .
thus , the initial doses of cladribine would have been expected to lead to the death of a majority of neoplastic histiocytes while the t - cell - mediated inflammation would have been expected to resume within 34 weeks .
ivig would not have been expected to affect the viability of langerhans cells , but should have reduced t - cell activity for 34 weeks .
it leads to a selective decrease in t - cells overall and an increase in regulatory t - cells . in children with lch
, ivig has been reported to contribute to a stabilization of inflammation in 4/5 patients treated and to enable long - term remission in 1 case [ 11 , 12 ] .
it has been suggested that ivig be given prophylactically to prevent the development of cns complications of lch , particularly diabetes insipidus , which tends to be irreversible .
alternative agents reported to treat the paraneoplastic inflammation in lch include vincristine / cytarabine and all - trans - retinoic acid .
the use of steroids in our patient would not have been expected to have had long - lasting effects .
bearing the above in mind , as well as the results of treatment in other t - cell - mediated paraneoplastic conditions , strong consideration should be given to agents that primarily target t - cells : steroids , ivig , plasma exchange and mycophenolate mofetil or cyclophosphamide .
other paraneoplastic disorders recognized in patients with lch include cancer - associated retinopathy and spinocerebellar degeneration .
brain imaging should always be undertaken in an older patient with episodes suggestive of seizures , diabetes insipidus of central origin or symptoms suggestive of pituitary dysfunction .
once a diagnosis of lch is made , a brain biopsy is not essential if the mri appearances are typical for the inflammatory processes that accompany this condition .
once lch appears stable , prolonged treatment may be needed to prevent recurrence of inflammation .
ivig appears to be a reasonable adjunct to cladribine , particularly in a case such as this where cytopenias or infections limit the use of conventional chemotherapy .

Answer:
we report a case of langerhans cell histiocytosis in a 64-year - old male who presented with symptoms and signs of brain involvement , including seizures and hypopituitarism .
 the diagnosis was confirmed with a biopsy of a lytic skull lesion .
 the disease affecting the bone showed no sign of progression following a short course of cladribine .
 signs of temporal lobe involvement led to an additional biopsy , which showed signs of nonspecific neurodegeneration and which triggered status epilepticus .
 lesions noted in the brainstem were typical for the paraneoplastic inflammation reported in this condition .
 these lesions improved after treatment with cladribine .
 they remained stable while on treatment with intravenous immune globulin .