Bruce A. Woda

Rituximab-CHOP Versus CHOP Alone or With Maintenance Rituximab in Older Patients With Diffuse Large B-Cell Lymphoma

PURPOSE To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. PATIENTS AND METHODS Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. RESULTS Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. CONCLUSION Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.

Androgen Receptor Mutations in Androgen-Independent Prostate Cancer: Cancer and Leukemia Group B Study 9663

PURPOSE The mechanisms responsible for prostate cancer androgen independence are diverse. Mutations of the androgen receptor (AR) gene that broaden ligand specificity have been implicated. Bone marrow specimens containing prostate tumor were obtained from men undergoing antiandrogen withdrawal for AR sequence analysis and clinical correlation. MATERIALS AND METHODS Eligible men enrolled on a trial of antiandrogen withdrawal had a minimum prostate-specific antigen (PSA) level of 5 ng/dL that was increasing on castration therapy including an antiandrogen. With informed consent, marrow biopsies were obtained to collect prostate tumor. Additional samples were obtained from men enrolled on chemotherapy trials. AR cDNA or DNA was polymerase chain reaction-amplified, cloned, and sequenced. The AR CAG repeat length was recorded. RESULTS One hundred eighty-four bone marrow biopsies were obtained, and 48 had prostate tumor detected by light microscopy. The ARs from these 48 samples were sequenced. Overall, five (10%) of 48 tumors had mutated ARs. AR point mutations were detected in the hormone-binding domain involved in transcription factor binding. Three mutations were novel in prostate cancer. One tumor sample had a CAG repeat length of 21, compared with germline length of 22 repeats. There was no association between detectability of AR mutations and antiandrogen withdrawal response or survival. CONCLUSION These data suggest that AR mutations are present in approximately 10% of patients with prostate cancer who experience treatment failure with hormone therapy that included an antiandrogen. Mutations in the AR likely confer a growth advantage for a subset of progressive prostate cancers. Correlation of AR mutation with antiandrogen withdrawal response or survival could not be made.

P504S: a new molecular marker for the detection of prostate carcinoma.

* ون ي ،لوئسم هدنس نسح ناديم ،نارهت ،انيس ناتسراميب ،دابآ يژولوتاپ شخب نفلت : 9 66701041 email: ahmadise@tums.ac.ir فده و هنيمز : رب ديكات دوز فشك طرس ماگنه ب تاتسورپ نا ه كمك ارت يفارگونوسارتلوا سن لاـتكر ،ينزوـس يسـپويب و تسيژولوتاپ ار اه ناطرس صيخشت لضعم اب تـسا هدومن هجاوم كچوك ياه . ارـيخا ̋ زا ركراـم P504S صيخشـت تـهج يسپويب رد ناطرس يعطق تسا هدش هدافتسا كچوك ياه . يسررب شور : گنر ركرام يزيمآ P504S يارب 70 سپويب هنومن ي و تاتسورپ ينزوس شش زر هنومن ك هك ارجم قيرط زا نويس يگمه نوناك يواح ياه كوكشم ) پيتآ ـ ي ك ( و دـندوب زـين 40 هنومن تاتسورپ يعطق ناطرس ، لماش تشه لولس ياراد هنومن فك ياه دولآ (foamy) ب ه دمآ لمع . هتفاي اـه : 36 زا هـنومن 40 ،يعطق ناطرس يسپويب زا يتاجرد گنر يارب يريذپ P504S دـنداد ناشن ) تيساسـح 90 (% ؛ ود و كـچوك ناطرـس ود لولس اب ناطرس فك ياه گنر دقاف دولآ دندوب يريذپ . عومجم زا 76 ،كوكشم دروم 18 ـ ب دروم ه لـخاد يزلاپوـئن ناوـنع يپا لااب هجرد يلايلت (HGPIN) دش هتخانش دن هك 16 دروم اهنآ گنر دنداد ناشن رشتنم طسوتم يريذپ . زا 58 دروم يقاب هدـنام ياراد يلورپ نويسارف كچوك ددغ آ يت كيپ 14 ًايوق دروم ب ه ن ف دوب ناطرس ع هك راهچ گـنر دـقاف اـهنآ دروـم يريذـپ P504S دندوب . رد نيب 44 پيتآ دروم ي ك ب ه عفن شوخ ميخ ي ، 14 پيتآ يموندآ يزلاپرپيه دروم ي ك اب ود گنر دروم فيعـض يريذـپ يعضوم و ود ب يپيتآ دروم ه ب يباتوترپ لابند ا كي گنر دروم و دش هدهاشم يعضوم يريذپ 28 رـگيد هـنومن P504S يـفنم دندوب . هجيتن يريگ : تيساسح P504S يم روصت ًلابق هچنآ زا تاتسورپ ناطرس فشك يارب نيياپ دش تـسا رت . يـفنم يـّقلت ندش ناطرس نكمم كچوك ياه ا ب تس ه گـنر ينوگمهاـن ليلد دـشاب يريذـپ . نويـسارفيلورپ رد كـچوك ددـغ تآ پي ـ ي ،ك گنر رشتنم و تبثم يريذپ P504S گنر مدع يلو تسا ناطرس صيخشت يايوگ ًايوق يـمن در ارنآ يريذپ دـنك . تيساسـحThe ability to diagnose prostate carcinoma would be improved by the detection of a tumor-associated antigen. P504S, a cytoplasmic protein, was recently identified by cDNA library subtraction in conjunction with high throughput microarray screening from prostate carcinoma. The aim of this study was to establish the pattern of expression of P504S in prostate carcinoma and benign prostatic tissue. A total of 207 cases, including 137 cases of prostate carcinoma and 70 cases of benign prostate, from prostatectomies (n = 77), prostate needle biopsies (n = 112), and transurethral prostate resections (n = 18) were examined by immunocytochemistry for P504S. P504S showed strong cytoplasmic granular staining in 100% of prostate carcinomas regardless of Gleason scores and diffuse (>75% of tumor) staining in 92% of cases. In contrast, 171 of 194 (88%) of benign prostates, including 56 of 67 (84%) benign prostate cases and 115 of 127 (91%) cases of benign glands adjacent to cancers were negative for P504S. The remainders of benign prostates were focally and weakly positive for P504S. The staining pattern of these normal glands was different and easily distinguishable from that observed in prostate carcinoma. Expression of P504S was not found in basal cell hyperplasia, urothelial cells/metaplasia and small atrophic glands that may mimic prostate carcinoma. Our findings indicate that P504S is a highly sensitive and specific positive marker for prostate carcinoma.

Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell carcinoma: a retrospective study

BACKGROUND Distant metastasis is the main cause of death from renal-cell carcinoma, and the metastatic potential of tumours is often unpredictable. We aimed to investigate whether IMP3, an oncofetal RNA-binding protein, can be used as a biomarker to predict metastasis and prognosis of renal-cell carcinoma. METHODS We studied 501 primary and metastatic renal-cell tumours. 371 patients with localised primary tumours were further investigated by use of survival analysis. We assessed IMP3 expression in tumour tissues by immunohistochemistry, and IMP3 mRNA and protein expression in selected tissues by quantitative real-time PCR and western blot analysis. FINDINGS Compared with non-metastatic renal-cell tumours, IMP3 expression was greatly increased not only in metastatic tumours but also in a subset of primary tumours that were likely to subsequently develop metastases. Patients with primary localised tumours that did not express IMP3 had a longer metastasis-free survival and overall survival than did those with tumours expressing IMP3 (p<0.0001). Patients with IMP3-positive localised tumours had a much lower 5-year metastasis-free survival than did those with IMP3-negative tumours (for stage I tumours, 44% vs 98%, hazard ratio 17.18 [95% CI 7.82-37.78]; stage II, 41% vs 94%, 10.14 [3.46-29.68]; stage III, 16% vs 62%, 4.04 [2.23-7.31]). IMP3 expression was also associated with reduced 5-year overall survival (stage I, 32% vs 89%, 6.44 [3.63-11.42]; stage II, 41% vs 88%, 6.93 [2.63-18.27]; stage III, 14% vs 58%, 3.46 [1.98-6.05]). Multivariable analysis of IMP3 status (positive vs negative) in primary tumours showed hazard ratios of 5.84 (95% CI 3.60-9.49) for metastasis-free survival and 4.01 (2.66-6.05) for overall survival (both p<0.0001), which were much higher than hazard ratios associated with other independent risk factors. INTERPRETATION IMP3 is an independent prognostic marker that can be used at initial diagnosis of renal-cell carcinoma to identify patients who have a high potential to develop metastasis and who might benefit from early systemic treatment.

Expression of α-methylacyl-coa racemase (p504s) in various malignant neoplasms and normal tissues: a study of 761 cases

α-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids. It has recently been shown that AMACR is highly expressed in prostate cancer and that it may be an important diagnostic marker for prostate carcinoma. However, little is known about expression of AMACR in normal tissues and other malignant tumors. In this study, we investigated expression of AMACR in 539 malignant tumors and 222 normal human tissues of various types by immunohistochemical analysis. mRNA levels of AMACR in normal organs and in selected tumors were assessed by real time PCR. In normal tissue, high expression of AMACR mRNA was identified in liver, kidney and salivary gland, while AMACR protein was detected in liver (hepatocytes), kidney (tubular epithelial cells), lung (only bronchial epithelial cells), and gallbladder (only mucosal epithelial cells). High expression of AMACR mRNA was found in prostate, liver, and kidney cancers but rarely in stomach and bladder cancers. A high percent of adenocarcinomas arising from these organs express AMACR, including 17 of 21 (81%) of hepatocellular carcinomas and 18 of 24 (75%) of renal cell carcinomas. In addition, carcinomas arising from tissues normally not expressing AMACR were also positive for the antigen, including 17 of 18 (94%) prostate carcinomas, 9 of 29 (31%) of urothelial carcinomas, and 4 of 15 (27%) of gastric adenocarcinomas. Two hundred and fifty cases of adenocarcinomas from lung, breast, pancreas, bile duct, adrenal gland, salivary gland, ovary, thyroid and endometrium were negative or rarely positive for AMACR. Neuroendocrine carcinomas rarely expressed AMACR. Melanomas, squamous cell carcinomas, basal cell carcinomas, soft tissue tumors (including epithelioid sarcomas and synovial sarcoma), thymomas, and germ cell tumors were negative for AMACR. Our data provide important baseline information for using AMACR in clinical practice and also are valuable in furthering understanding of the pathogenic role of AMACR in malignant neoplasms.

P504S/α-methylacyl-CoA racemase: A useful marker for diagnosis of small foci of prostatic carcinoma on needle biopsy

Establishing a definitive diagnosis of malignancy in prostate needle biopsies with very small foci of adenocarcinoma is a major diagnostic challenge for surgical pathologists. A positive diagnostic marker specific for prostatic adenocarcinoma may enhance our ability to detect limited prostate cancer and reduce errors in diagnosis. P504S, also known as &agr;-methylacyl-CoA racemase, recently identified by cDNA subtraction and microarray technology, might serve as such a specific marker because it has been demonstrated to be highly expressed in prostatic adenocarcinoma, but not in benign prostatic glands. However, whether small foci of carcinoma can be reliably detected by this marker is a crucial question for its clinical application. The aim of this study was to assess the utility of P504S immunohistochemistry in detecting small amounts of prostate cancer in prostate needle biopsies. A total of 142 prostate needle biopsies, including 73 cases with a small focus of prostatic adenocarcinoma (≤1 mm) and 69 benign prostates, were examined by using immunohistochemistry for P504S and high molecular weight cytokeratin (34&bgr;E12). P504S immunoreactivity was found in 69 of 73 cases (94.5%) of carcinoma but not in any benign prostates (0 of 69) or benign glands adjacent to malignant glands. The 34&bgr;E12 immunostaining confirmed the absence of basal cells in the focus of carcinoma in all 73 cases. The high specificity and sensitivity of P504S in the detection of minimal prostatic adenocarcinoma indicated its potential diagnostic value in clinical practice. Using a combination of P504S and 34&bgr;E12 can help the diagnosis of limited prostatic adenocarcinoma on needle biopsy.

KOC (K homology domain containing protein overexpressed in cancer): a novel molecular marker that distinguishes between benign and malignant lesions of the pancreas.

KOC (K homology domain containing protein overexpressed in cancer) is a novel oncofetal RNA-binding protein highly expressed in pancreatic carcinomas. Recently, Corixa Corporation developed a monoclonal antibody specific for KOC that can be used with standard immunohistochemical techniques. The purposes of this study were 1) to assess KOC mRNA expression in pancreatic carcinoma, 2) to determine the pattern of KOC immunoexpression among benign, borderline, and malignant pancreatic epithelial lesions, and 3) to evaluate the utility of the KOC antibody in distinguishing between these entities. mRNA was isolated from fresh pancreatic tissues (19 carcinomas, 2 normal pancreas, 1 chronic pancreatitis) and amplified using standard RT-PCR techniques. Fifteen of 19 (79%) carcinomas overexpressed KOC mRNA relative to non-neoplastic tissue samples and expression increased progressively with tumor stage: the mean copy number of KOC mRNA transcripts was 1.5, 11.1, 31, and 28 for stage I, II, III, and IV carcinomas, respectively, compared with 0.9 and 1 for normal pancreatic tissue and chronic pancreatitis, respectively. Immunostains using the KOC antibody were performed on 50 surgical resection specimens (38 invasive adenocarcinomas, 3 intraductal papillary-mucinous neoplasms, 2 mucinous cystic neoplasms, 7 chronic pancreatitis). KOC staining was present in 37 of 38 (97%) carcinomas: the staining reaction was moderate or strong in 36 of 38 (94%) and present in >50% of the tumor cells in 35 of 38 (92%) cases. Severe dysplasia of the ductal epithelium, present in 19 foci of intraductal papillary mucinous carcinoma, mucinous cystadenocarcinoma, and grade 3 pancreatic intraepithelial neoplasia (PanIN3) showed strong or moderate staining in 15 (79%) cases, whereas foci of mild and moderate dysplasia (intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms with adenoma and/or moderate dysplasia, PanIN1, and PanIN2) were uniformly negative for this marker in 25 and 22 cases, respectively. In the normal pancreas, weak background staining of acini was present in 12 of 50 (24%) cases but was easily distinguishable from the type of staining identified in neoplastic epithelium, and benign ducts and ductules were negative in all cases. Four of 38 (11%) foci of chronic pancreatitis, present in the 7 resections performed for chronic pancreatitis as well as 31 foci of peritumoral chronic pancreatitis, showed weak staining in <10% of the ductules. We conclude that KOC is a sensitive and specific marker for carcinomas and high-grade dysplastic lesions of the pancreatic ductal epithelium. Therefore, immunostains directed against KOC may be of diagnostic utility in the evaluation of pancreatic lesions, particularly when biopsy material is limited.

Virus-Induced Abrogation of Transplantation Tolerance Induced by Donor-Specific Transfusion and Anti-CD154 Antibody

ABSTRACT Treatment with a 2-week course of anti-CD154 antibody and a single transfusion of donor leukocytes (a donor-specific transfusion or DST) permits skin allografts to survive for >100 days in thymectomized mice. As clinical trials of this methodology in humans are contemplated, concern has been expressed that viral infection of graft recipients may disrupt tolerance to the allograft. We report that acute infection with lymphocytic choriomeningitis virus (LCMV) induced allograft rejection in mice treated with DST and anti-CD154 antibody if inoculated shortly after transplantation. Isografts resisted LCMV-induced rejection, and the interferon-inducing agent polyinosinic:polycytidylic acid did not induce allograft rejection, suggesting that the effect of LCMV is not simply a consequence of nonspecific inflammation. Administration of anti-CD8 antibody to engrafted mice delayed LCMV-induced allograft rejection. Pichinde virus also induced acute allograft rejection, but murine cytomegalovirus and vaccinia virus (VV) did not. Injection of LCMV ∼50 days after tolerance induction and transplantation had minimal effect on subsequent allograft survival. Treatment with DST and anti-CD154 antibody did not interfere with clearance of LCMV, but a normally nonlethal high dose of VV during tolerance induction and transplantation killed graft recipients. We conclude that DST and anti-CD154 antibody induce a tolerant state that can be broken shortly after transplantation by certain viral infections. Clinical application of transplantation tolerance protocols may require patient isolation to facilitate the procedure and to protect recipients.

Expression of α-methylacyl-CoA racemase (P504S) in atypical adenomatous hyperplasia of the prostate

Atypical adenomatous hyperplasia (AAH) of the prostate, also known as adenosis, is characterized by a proliferation of prostatic glands with abnormal architectural patterns, but without significant cytologic atypia. In some cases it may be difficult to distinguish AAH from prostatic carcinoma. Additionally, it is not clear whether AAH is a precursor lesion of prostatic adenocarcinoma. P504S, a protein highly expressed in prostatic adenocarcinoma, has been recently shown to be a marker of prostate cancer. The goal of this study is to examine the expression of P504S in AAH by immunohistochemistry. A total of 80 prostate specimens, including 40 cases of AAH (prostatectomy N = 30, biopsy N = 6, transurethral resection N = 4), 20 cases of prostatic adenocarcinomas, and 20 cases of benign prostatic hyperplasia, were studied. Immunohistochemistry for a prostate cancer marker &agr;-methylacyl-CoA racemase (P504S) and a basal cell-specific marker 34&bgr;E12 was performed in all the cases. The 34&bgr;E12 stain confirmed the presence of patchy basal cells in all 40 cases of AAH. P504S was undetectable in the majority of AAHs (33 of 40, 82.5%), focally expressed in four of 40 (10.0%), or diffusely positive only in three of 40 (7.5%) cases of AAH. Interestingly, two of seven P504S-positive AAHs were found adjacent to adenocarcinoma. In contrast, all benign prostatic hyperplasias (20 of 20, 100%) were negative for P504S, and all 20 cases of prostatic carcinomas (100%) showed a diffuse P504S staining pattern. These findings suggest that AAH is a heterogenous entity. The biologic significance of P504S expression in a small subset of AAH remains to be determined. Because most cases of AAH are negative for P504S, immunostaining of P504S is also of diagnostic value in distinguishing the majority of AAHs from prostatic adenocarcinoma.

Alpha-methylacyl-CoA racemase: a multi-institutional study of a new prostate cancer marker

Aim : To test whether α‐methylacyl‐CoA racemase (AMACR) is a sensitive and specific marker of prostate cancer.