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Introduction: We report the results of a phase II trial testing the hypothesis that adding the hypomethylating agent G to the PDL1 inhibitor A in patients with mUC who developed primary or acquired resistance to checkpoint blockade (CB) will overcome this resistance by (1) eliciting viral mimicry in the tumor tissue to potentiate and reinvigorate anti-tumor immunity, (2) epigenetic reprogramming of T lymphocytes to overcome exhaustion. Methods: Pts with mUC resistant to CB accrued at 3 centers were treated with G 45mg/m2 daily days 1-5 every 6 wks and A 1200mg every 3 wks. After initial safety lead in with 6 patients, trial was designed to add 37 additional patients. The primary endpoint was ORR. Correlative analyses included analysis of peripheral blood T cells and tumor tissue collected at baseline and once during treatment. Results: 21 pts were enrolled. 20 pts were evaluable for response. Best response was PD (16), SD (4). 10 patients progressed clinically prompting earlier than scheduled (12 wk) imaging. Four pts exhibited a “hyperprogression” phenotype exhibiting rapid acceleration of tumor growth rate starting with initiation of therapy. At presepcified interim analysis it was determined that the trial would not meet its primary endpoint and it closed early. Median PFS 2.6 mo, median OS 8 mo. The 4 patients with SD maintained that status for median 13 months (range 9-15 mo). Global DNA methylome and transcriptome profiles from pre- and post-treatment tumor samples revealed a lack of transposable element-induced viral mimicry activation, which correlated with minimal DNA demethylation being induced in the tumors. Of note, flow cytometry-based immune profiling of peripheral blood from patients suggests a correlation between increased progression-free survival (PFS) with 1) lower expression of DNAM-1 on mature NK cells and 2) lower expression of CD39 on CD8+ effector T cells at time of inclusion on the trial. Conclusions: While no responses were seen, both prolonged SD and hyperprogression were seen. Further tissue and peripheral blood based analyses are ongoing to elucidate the biological determinates of this dichotomy. Citation Format: Elizabeth R. Plimack, Kerry Campbell, Jean-Pierre J. Issa, Noah M. Hahn, David I. Quinn, Hyo Sik Jang, Galen Hostetter, Peter W. Nichols, Woonbok Chung, Jozef Madzo, Hitoshi Ohtani, Hui Shen, Toshinori Hinoue, Stephen B. Baylin, Peter A. Jones. A Phase II trial of guadecitabine (G) plus atezolizumab (A) in patients with metastatic urothelial carcinoma (UC) progressing after initial checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT121.

// Sameer Chopra 1,* , Jie Liu 2,* , Mehrdad Alemozaffar 1 , Peter W. Nichols 3 , Manju Aron 3 , Daniel J. Weisenberger 4 , Clayton K. Collings 1 , Sumeet Syan 1 , Brian Hu 5 , Mihir Desai 1 , Monish Aron 1 , Vinay Duddalwar 6 , Inderbir Gill 1 , Gangning Liang 1 and Kimberly D. Siegmund 2 1 Department of Urology, Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 2 Department of Preventive Medicine, Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 3 Department of Pathology, Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 4 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 5 Department of Urology, Loma Linda University, Loma Linda, CA, USA 6 Department of Radiology, Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA * These authors have contributed equally to this work Correspondence to: Gangning Liang, email: // Kimberly D. Siegmund , email: // Keywords : small renal mass, tumor classification, DNA methylation, kidney cancer Received : July 29, 2016 Accepted : September 20, 2016 Published : September 27, 2016 Abstract Purpose: The clinical management of small renal masses (SRMs) is challenging since the current methods for distinguishing between benign masses and malignant renal cell carcinomas (RCCs) are frequently inaccurate or inconclusive. In addition, renal cancer subtypes also have different treatments and outcomes. High false negative rates increase the risk of cancer progression and indeterminate diagnoses result in unnecessary and potentially morbid surgical procedures. Experimental Design: We built a predictive classification model for kidney tumors using 697 DNA methylation profiles from six different subgroups: clear cell, papillary and chromophobe RCC, benign angiomylolipomas, oncocytomas, and normal kidney tissues. Furthermore, the DNA methylation-dependent classifier has been validated in 272 ex vivo needle biopsy samples from 100 renal masses (71% SRMs). Results: In general, the results were highly reproducible (89%, n =70) in predicting identical malignant subtypes from biopsies. Overall, 98% of adjacent-normals ( n =102) were correctly classified as normal, while 92% of tumors ( n =71) were correctly classified malignant and 86% of benign ( n =29) were correctly classified benign by this classification model. Conclusions: Overall, this study provides molecular-based support for using routine needle biopsies to determine tumor classification of SRMs and support the clinical decision-making.

Adequate infiltration through Permeable Interlocking Concrete Pavements (PICPs) is critical to their hydraulic and stormwater treatment performance. Infiltration is affected by clogging caused by the trapping of fines in the PICP surface, which, over time, reduces treatment performance. Clogging can be reduced by periodic maintenance such as vacuum sweeping and/or pressure washing. Maintenance requirements can be indicated by measuring reduced infiltration rates. This paper compared infiltration results using the standard test (C1781M-14a) with the results of a new stormwater infiltration field test (SWIFT) developed in Australia to evaluate the maintenance requirements of PICPs. A strong correlation (Pearson’s r = −0.714) was found between results using the two methods. This study found that the SWIF T was a reliable method for es timating the degree of clogging of PICPs while successfully overcoming some of the problems with the more technical existing test methodology such as horizontal water leakage (use of sealant), unrealistic pressure heads, speed of test, and portability. The SWIFT test is a simple, fast and inexpensive way for asset managers and local government employees to quickly assess the maintenance requirements of PICP installations in the field.

Adequate infiltration through Permeable Interlocking Concrete Pavements (PICPs) is critical to their hydraulic performance. Detected by monitoring infiltration performance, reduced infiltration rates can indicate that maintenance is required. Measurement of infiltration rates has previously been problematic on PICPs because of a lack of accepted standard methodologies and the practical difficulties in modifying existing testing methodologies. On large sites, standard methodologies necessitate multiple measurements to achieve accuracy. Standard methods also contend with practical issues such as sealing the rings to the surface to prevent lateral water flow. This study examined the performance of two PICP surface infiltration rate measurement methods: a modified double-ring infiltrometer (DRIT), and a specially designed rainfall simulation infiltrometer (RSIT). A positive correlation (R2 = 0.85) of results was found between the two, demonstrating that the RSIT was comparable to the DRIT. The modified DRIT produced surface infiltration results approximately 60% higher than the RSIT results. The RSIT provided lower variation between tests, requiring fewer measurements in large sites whilst still maintaining accuracy, thereby improving testing efficiency. The new RSIT method also eliminates some of the practical difficulties with existing methodologies such as unrealistic pressure heads artificially increasing infiltration rates, and the use of sealant under test measurement infiltration rings.

The classification working group of the International Society of Urological Pathology consensus conference on renal neoplasia was in charge of making recommendations regarding additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of the group performed an exhaustive literature review, assessed the results of the preconference survey and participated in the consensus conference discussion and polling activities. On the basis of the above inputs, there was consensus that 5 entities should be recognized as new distinct epithelial tumors within the classification system: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors. There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon that multicystic clear cell RCC is best considered as a neoplasm of low malignant potential. There was agreement that subtyping of papillary RCC is of value and that the oncocytic variant of papillary RCC should not be considered as a distinct entity. The hybrid oncocytic chromophobe tumor, which is an indolent tumor that occurs in 3 settings, namely Birt-Hogg-Dubé Syndrome, renal oncocytosis, and as a sporadic neoplasm, was placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, advances in our understanding of angiomyolipoma, including the epithelioid and epithelial cystic variants, were considered. In addition, the apparent relationship between cystic nephroma and mixed epithelial and stromal tumor was discussed, with the consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.

The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus, "the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

history. Without doctor’s explanation the CRR was decreased in patients with urologic medical history. CONCLUSIONS: The RR of FVC was increased by doctor’s explanation in patients aged

Background The value of lymph node dissection (LND) in the treatment of bladder urothelial carcinoma is well established. However, standards for the quality of LND remain controversial. Objective We compared the distribution of lymph node (LN) metastases in a two-institution cohort of patients undergoing radical cystectomy (RC) using a uniformly applied extended LND template. Design, setting, and participants Patients undergoing RC at the University of Southern California (USC) Institute of Urology and at Oregon Health Sciences University (OHSU) were included if they met the following criteria: (1) no prior pelvic radiotherapy or LND; (2) lymphatic tissue submitted from all nine predesignated regions, including the paracaval and para-aortic LNs; (3) bladder primary; and (4) category M0 disease. The number and location of LN metastases were prospectively entered into corresponding databases. Measurements LN maps were constructed and correlated with preoperative and pathologic characteristics. Kaplan-Meier curves were constructed to estimate overall survival (OS) and recurrence free survival (RFS) among LN-positive (LN+) patients. Results and limitations Inclusion criteria were met by 646 patients (439 USC, 207 OHSU), and 23% had LN metastases at time of cystectomy. Although there was a difference in the median per-patient LN count between institutions, there were no significant interinstitutional differences in the incidence or distribution of positive LNs, which were found in 11% of patients with ≤pT2b and in 44% of patients with ≥pT3a tumors. Among LN+ patients, 41% had positive LNs above the common iliac bifurcation. Estimated 5-yr RFS and OS rates for LN+ patients were 45% and 33%, respectively, and did not differ significantly between institutions. Conclusions LN metastases in regions outside the boundaries of standard LND are common. Adherence to meticulous dissection technique within an extended template is likely more important than total LN count for achieving optimal oncologic outcomes.

Background: Aetiology of acute myeloid leukaemia (AML) is not well understood, perhaps because of its distinct subtypes. High-dose ionising radiation is a known risk factor, but less is known about risk from low-dose exposure such as from diagnostic radiography. Methods: Subjects were 412 matched case-control pairs. Ten-year subject histories of diagnostic radiography were based on interview and medical records. Results: There was no convincing association between AML risk and ionising radiation exposure from diagnostic imaging procedures, either for AML overall or for any AML subtype. Conclusion: The association between diagnostic radiography and AML risk remains uncertain.

Few predictive markers exist for response to adjuvant chemotherapy in breast cancer. The 78-kDa glucose-regulated protein (GRP78) is a potent antiapoptotic factor, conferring drug resistance. Recently, we reported that high GRP78 expression in breast cancer specimens predicts a shorter recurrence-free survival in patients who received doxorubicin-based adjuvant chemotherapy. Interestingly, the opposite effect was observed in 25 patients who additionally received a taxane. To confirm this potentially paradigm shifting finding, we investigated whether GRP78 is associated with recurrence-free survival in an independent cohort of taxane-treated breast cancer patients. Immunohistochemical staining of GRP78 was performed on archival paraffin-embedded formalin-fixed tumor specimens obtained from 48 female breast cancer patients before chemotherapy treatment. These patients received doxorubicin and cyclophosphamide, followed by paclitaxel or docetaxel on a clinical trial. GRP78 expression level was evaluated by a pathologist, masked to all clinical and outcome data. Association between GRP78 expression and recurrence-free survival was evaluated. GRP78 positivity predicts a better recurrence-free survival, independent of other prognostic factors [hazard ratio (HR) for moderate positivity: 0.40 (95% confidence interval (CI): 0.087-1.83); HR for strong positivity: 0.16 (95% CI: 0.018-1.50); p(trend) = 0.053]. In a pooled analysis with the previous 25 patients, almost identical HRs were obtained with p(trend) = 0.024. This provides further evidence that GRP78 is a potential independent predictor for response to taxane-based adjuvant chemotherapy in breast cancer.

To use a clinical model of androgen-deprivation therapy (ADT) followed by radical prostatectomy (RP) to test the hypothesis that prostatic intraepithelial neoplasia (PIN, a premalignant lesion of the prostate causally linked to prostate cancer) is heterogeneous for hormone responsiveness, which might explain aspects of the heterogeneity of the natural history of prostate cancer, for although ADT has been used to reduce prostate cancer, there are controversial data on the effect of ADT on PIN.We assessed retrospectively patients with biopsy-confirmed prostate cancer who had RP; some patients had receivedor=3 months of ADT at the discretion of their surgeons, and patients from the same cohort who did not have ADT were used as controls. Patients were sequentially selected from the database and their pathology slides were reviewed by a pathologist unaware of the initial presence of PIN (assessed by an independent observer). Fisher's exact test was used to compare the proportions of patients who had residual PIN in the study and control groups. Exact logistic regression was used to evaluate the duration of ADT on PIN regression.Eighteen patients initially diagnosed with PIN who had no ADT were identified, and 28 with PIN who had ADT were also assessed. All patients who had had no ADT had residual PIN, whereas seven of 28 receiving ADT had no residual PIN (P=0.043). The evaluation of ADT between responders and nonresponders showed a statistically significant association between PIN regression and the duration of ADT (P0.001). However, the response of PIN to ADT was not uniform, as 16% of patients on ADT for6 months had residual PIN, suggesting variable sensitivity of PIN to ADT.These results show that ADT causes PIN to regress, and that there is heterogeneity in this effect with the duration of ADT. We propose future prospective, multicentre, randomized trials in which the effect of ADT on PIN is characterized further.

Objectives To determine whether any differences exist in neuroendocrine (NE) cell differentiation in normal prostates among various ethnic groups because the incidence and mortality from prostate cancer vary across racial groups. Methods Archived paraffin-embedded prostate samples not containing any malignancy were obtained from cystoprostatectomy specimens. Prostatic tissue was obtained from 15 African Americans, 13 Hispanics, 15 Asians, and 16 whites. NE cells were identified based on immunoreactivity for chromogranin A. The mean number of NE cells per high power field (HPF) for each patient was determined using a visual quantitative method by two observers who were unaware of the race of the patients. Results The geometric mean number of NE cells was 6.1/HPF for Asians, 5.6/HPF for whites, 4.0/HPF for Hispanics, and 0.7/HPF for African Americans. A highly significant difference was observed in the distribution of NE cells between African Americans and each of the other races (P ≤0.003). A trend toward greater NE expression was noted in Asians and whites compared with Hispanics; however, this difference did not reach statistical significance. Conclusions We found a fivefold to eightfold difference in the distribution of NE cells in the normal prostates of African-American men compared with that of other races. The comparatively low NE cell expression in African-American men may play a role in the greater rate of prostate carcinogenesis seen in this ethnic group.

Transitional cell carcinoma (TCC) of the bladder that extends directly into contiguous organs (pT4) portends a poor prognosis. The 2002 American Joint Committee on Cancer staging system does not include seminal vesicle involvement by primary TCC of the bladder. In this analysis we evaluated the clinical outcomes and prognostic significance of seminal vesicle involvement with TCC of the bladder after radical cystectomy.From 1971 to 2001, 1,682 patients underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer. Only those tumors that involved adjacent organs through the bladder wall (pT4) were included. Overall 132 male patients with a median age of 68 years (range 36 to 98) qualified for analysis. Patients were stratified into 4 subgroups of 1) direct extravesical prostatic stromal involvement only in 37 patients (28%), 2) prostatic stroma and seminal vesicle involvement in 37 patients (28%), 3) seminal vesicle involvement only in 10 patients (8%) and 4) other contiguous pelvic organ involvement (stage pT4b) in 48 patients (36%). Overall 88 patients (67%) received some form of adjuvant therapy. At a median followup of 12.5 years (range 0 to 15.2) clinical outcomes were analyzed including overall and recurrence-free survival using Kaplan-Meier plots.There was no significant difference in clinical outcomes or prognosis for groups 2 and 3, thus they were combined for analysis. Five-year overall survival for any seminal vesicle involvement (10%) was significantly worse than prostatic stromal involvement only (38%) but was similar to pT4b tumors (7%, p0.0001). The 5-year recurrence-free survival for seminal vesicle involvement (14%) was also significantly worse than prostatic stromal involvement alone (68%) but similar to that pT4b disease (25%, p = 0.01). Results were controlled for lymph node status.Patients with extravesical tumor extension into seminal vesicles and contiguous pelvic organs are at high risk for recurrence and progression. Involvement of the seminal vesicles by direct extension of bladder TCC portends a prognosis similar to that of pT4b disease and should, therefore, be classified as such.

The benefits of nationally coordinated schemes to manage the introduction of new stormwater quality improvement devices (SQIDs) have been acknowledged in various countries. This review compares the existing frameworks used in Australia, Austria, Germany, New Zealand, Switzerland, and the United States. The review describes the framework and structure of each system, and their individual components are presented. The Australian and New Zealand protocols have yet to be formally adopted and remain largely untested. The Australian and New Zealand protocols are compared with successfully established processes operating in Austria, Germany, Switzerland, and the United States. Adequate resourcing of administrative processes and having the technical capability to review test results were found to be a critical component of the successfully adopted certification schemes. Based on the level of success of the introduction of alternative certification systems, the most successful have been integrated into the formal legislative frameworks found in each country. The creation of a successful SQID certification pathway in Germany has been driven by the implementation of new fees on the release of stormwater from private property, with exemptions where stormwater is actively managed at source. The review presented in this paper may be of benefit to countries considering the development of their own SQID evaluation and verification protocols.

Purpose: We determined the extent of p53 immunoreactivity in pathological stage C prostate cancer as well as its correlation to tumor grade, substage, recurrence and proliferation rate. To define better the temporal relationship of p53 nuclear reactivity in prostate cancer p53 immunoreactivity was evaluated in all associated prostatic intraepithelial neoplasia lesions.Materials and Methods: Using immunohistochemistry p53 status and proliferation rate were determined in 96 tumors from patients with pathological stage C prostate cancer. Single strand conformational polymorphism in exons 5 to 8 was used in a subset of specimens to assess the association of p53 nuclear accumulation with mutations in the p53 gene.Results: p53 Nuclear reactivity was demonstrated in 10 tumors (10.4%), including 6 with high and 4 with low level nuclear reactivity. Of the tumors 86 (89.6%) had no evidence of p53 immunoreactivity. Each of the 6 tumors with high level p53 reactivity had associated areas of prostatic intraepi...

International audience; The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.

A high frequency (24%) of acute promyelocytic leukemia (APL) was noted among acute myelocytic leukemia (AML) cases at the Los Angeles County-University of Southern California (LAC-USC) Medical Center, in comparison with the expected frequency of 5% to 15%. Because of the high proportion of Latinos in this center, we questioned if APL is more common in this ethnic group. The proportion of APL among the 80 AML patients of Latino origin was significantly higher (30; 37.5%) when compared with the 62 non-Latinos (4; 6.5%) (P = .00001). In an attempt to verify this finding on a larger group of patients, we analyzed 276 pathologically verified cases of AML in patients aged 30 to 69 years from the entire County of Los Angeles, registered on an ongoing population-based epidemiologic study of AML. APL was more frequent among the 47 Latinos (24.3%) than in the 229 non-Latinos (8.3%) (P = .0075). APL is seen in younger patients with AML, but Latino AML patients also had a higher frequency of APL after accounting for their younger age (age-adjusted odds ratio for APL among Latinos in LAC-USC Medical Center, 9.4 [95% confidence interval (CI) 2.9, 30] P = .0002; among Latinos in the population-based study, 3.0 [95% CI 1.3 to 6.9] P = .01). The different ethnic distribution of AML was found to be due to a higher proportion of APL cases per se, and not to a lower proportion of any other French-American-British subtype (P = .0004). These results, from two different populations of AML patients, indicate that Latinos with AML have a higher likelihood of the APL subtype of disease, which may suggest a genetic predisposition to APL and/or exposure to distinct environmental factor(s).

Background : Tumor stage, histologic grade, and regional lymph node status are currently used to obtain prognostic information about bladder cancers. However, additional prognostic indicators are needed to aid clinicians in selecting patients who would benefit most from specific therapies. A majority of studies assessing the prognostic value of measuring tumor angiogenesis (i.e., measurement of tumor microvessel densities) have found a positive association between increasing microvessel densities and worsening prognosis. Purpose : We explored the relationship between established prognostic indicators and the extent of tumor-associated angiogenesis in patients with invasive transitional cell carcinoma (TCC) of the bladder, and we determined whether tumor microvessel density measurement could be used independently to predict bladder tumor behavior. Methods : Tumor tissue was obtained from 164 patients with invasive primary TCC of the bladder. The extent of tumor-associated angiogenesis in this tissue was evaluated by immunohistochemical methods using HPCA-1, a mouse monoclonal antibody directed against the endothelial cell antigen, CD34. The number of microvessels in a 200x microscopic high-power field (hpf) containing the area of greatest neovascularization within or immediately adjacent to each tumor was determined. The patient population was then divided into three equivalently sized groups, with tumors containing low (≤64), intermediate (65-99), or high (≥100) numbers of microvessels per hpf. Kaplan-Meier product limit estimates of overall survival and the complement of cumulative incidence curves for recurrence-free survival were plotted. When analyzing survival or recurrence, the logrank test was used to compare groups of patients with and without stratification according to tumor stage. Analysis of variance was used to test for an association between microvessel density and established prognostic variables. Reported P values are from two-sided tests. Results : Microvessel density was significantly associated with disease-free (P

We have previously demonstrated a strong association between nuclear accumulation of p53 protein, as determined by immunohistochemical analysis, and mutations in the p53 gene. The purpose of this study was to determine the relation between nuclear accumulation of p53 and tumor progression in transitional-cell carcinoma of the bladder.Histologic specimens of transitional-cell carcinoma of the bladder (stages Pa, noninvasive disease, to P4, disease with direct extension into adjacent organs or structures) from 243 patients who were treated by radical cystectomy were examined for the immunohistochemical detection of p53 protein. Nuclear p53 reactivity was then analyzed in relation to time to recurrence and overall survival.The detection of nuclear p53 was significantly associated with an increased risk of recurrence of bladder cancer (P0.001) and with decreased overall survival (P0.001). In patients with cancer confined to the bladder, the rates of recurrence for stage P1, P2, and P3a tumors that had no detectable nuclear p53 reactivity at five years were 7, 12, and 11 percent, respectively, as compared with 62, 56, and 80 percent, respectively, for tumors that had p53 immunoreactivity. Similar results were obtained when the presence or absence of p53 in the nuclei of the tumor cells was studied in relation to overall survival. In a multivariable analysis stratified according to grade, pathological stage, and lymph-node status, nuclear p53 status was an independent predictor (and in cancer confined to the bladder, the only independent predictor) of recurrence and overall survival (P0.001).In patients with transitional-cell carcinoma confined to the bladder, an accumulation of p53 in the tumor-cell nuclei detected by immunohistochemical methods predicts a significantly increased risk of recurrence and death, independently of tumor grade, stage, and lymph-node status. Patients with transitional-cell carcinoma confirmed to the bladder that demonstrates nuclear p53 reactivity should be considered for protocols of adjuvant treatment.

Portal vein thrombosis occurred in a patient who bled from gastric varices that developed after obliteration of esophageal varices by endoscopic sclerotherapy. This complication was recognized only at surgery when thrombectomy and endovenectomy preceded the successful placement of an end-to-side portocaval shunt. At histopathology, the presence of an amorphous, eosinophilic material staining negatively for fibrin and similar to sclerosant injected at sclerotherapy was observed within the clot. This latter finding, previously unreported, provides convincing evidence for the causal relationship of portal vein thrombosis to endoscopic sclerotherapy.

✓ A case of an intradural epithelial cyst at the craniovertebral junction is reported in a 37-year-old man. The classification of these rare lesions is discussed.

Malignant granular cell tumors are rare; to the authors' knowledge, fewer than 30 cases have been reported. The histological origin of these tumors is presumed to be the Schwann cell, based on cytological and immunohistochemical similarities. The authors report a case of malignant granular cell tumor arising near the orbital apex. Clinically, the tumor originated within the confines of the third nerve, providing strong evidence for Schwann cell origin. Immunohistochemistry corroborates a Schwann cell origin. The patient had regression of this tumor after radiation therapy, emphasizing the potential usefulness of this treatment for these rare tumors.

The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to “time to recurrence” (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies. (Cancer Res 2006; 66(16): 7849-53)

We determined the prognostic significance of lymphovascular invasion (LVI) in patients treated for invasive transitional cell carcinoma of the bladder with radical cystectomy.From August 1971 to June 2004, 2,005 patients underwent radical cystectomy for primary bladder cancer with intent to cure. All patients with nontransitional cell carcinoma histology, palliative procedures, unknown lymphovascular status, less than pT1 pathological stage, or any neoadjuvant or adjuvant chemotherapy/radiation therapy were excluded, leaving 702 comprising the study cohort. Of the 702 patients 249 (36%) had LVI.Median followup was 11.0 years (range 8 days to 23.2 years). Overall 5 and 10-year survival was 51% and 34%, while 5 and 10-year recurrence-free survival was 66% and 64%, respectively. Ten-year recurrence-free survival in patients without LVI was 74% compared with 42% in those with LVI (p0.0001). Similarly 10-year overall survival was 43% in patients without LVI compared with 18% in those with LVI (p0.0001). In the organ confined/lymph node negative and lymph node positive pathological subgroups survival outcomes were significantly worse if LVI was present. Although a trend was observed, LVI status was not statistically significant in patients with extravesical node negative disease. Stepwise Cox regression analysis revealed that pathological subgroup (organ confined, extravesical and lymph node positive) (p0.0001) and LVI status (p = 0.0004) were independent prognostic variables for recurrence-free and overall survival.Lymphovascular invasion appears to be an important and independent prognostic variable in patients with invasive bladder cancer treated with radical cystectomy. LVI status should be determined in cystectomy specimens, which may provide further risk stratification in patients following radical cystectomy.

Purpose: Primary neuroendocrine tumors of the bladder are rare and they include small and large cell variants. We reviewed our experience with treating these tumors with radical cystectomy to evaluate their histopathological characteristics and clinical outcomes. Materials and Methods: From August 1971 to June 2004, 2,005 patients underwent radical cystectomy for primary bladder cancer at our institution, of whom 25 (1.2%) had neuroendocrine tumors of the bladder, including small cell carcinoma in 20 and large cell carcinoma in 5. Pure neuroendocrine-type histology was identified in 16 cases, including 1 with small and large cell features, while the remaining 9 had mixed histology, that is transitional cell carcinoma in 8 and adenocarcinoma in 1. Multi-agent chemotherapy was administered to 14 patients. Results: Median patient age was 68 years (range 40 to 82) and 19 patients were male (76%). A total of 19 patients (76%) had lymph node involvement, of whom 2 had small liver metastases found intraoperatively, while only 4 (16%) had organ confined tumors and 2 (8%) had extravesical, node negative disease. These tumors tended to have a flat, ulcerative gross appearance with lymphovascular invasion, carcinoma in situ and necrosis present microscopically. Median followup was 11.8 years (range 18 days to 15.1 years). Five-year overall and recurrence-free survival was 10% and 13%, respectively. There was no significant survival difference between small and large cell carcinoma. Mixed histologies tended to do better than pure neuroendocrine tumors, although this did not attain statistical significance (p = 0.064). Patients receiving multimodality therapy had significantly better overall (p = 0.051) and recurrence-free (p = 0.003) survival than those treated with cystectomy alone. Conclusions: Neuroendocrine tumors of the bladder usually present with advanced pathological stage and portend a poor prognosis. Adjuvant chemotherapy protocols may provide improved survival compared with cystectomy alone.

Chemotherapy is a well-established risk factor for acute myeloid leukemia (AML) but little is known about other prescription drugs and AML risk. We report data from a population-based Los Angeles County study in which 299 matched case-control pairs had complete data on prescription drug use and 88% of cases were subtyped according to the French-American-British (FAB) criteria. Cases were diagnosed between 1987 and 1994. Prescription nonsteroidal anti-inflammatory drug (NSAID) use for at least 4 weeks in the 2 to 10 years before diagnosis was associated with decreased risk (odds ratio = 0.5, 95% confidence interval = 0.3, 1.0; p = 0.04) with dose-response most evident for FAB subtype M2 (OR = 0.6, CI: 0.1, 2.9 for duration ≤6 months; OR = 0.2, CI: 0.0, 1.6 for >6 months). For subtype M4, ORs increased with increasing duration of benzodiazepine use in the 2 to 10 years before diagnosis (OR = 1.5, CI: 0.3, 9.0 for ≤6 months vs. OR = 5.0, CI: 0.6, 42.8 for >6 months). These results suggest that prescription drugs other than chemotherapy may have FAB subtype-specific effects on AML risk. © 2004 Wiley-Liss, Inc.

Few studies have examined the role of alcohol consumption in risk of adult acute myeloid leukemia (AML). Two previous case-control studies resulted in inconsistent findings. We report data from a Los Angeles County population-based case-control study in which 164 matched case-control pairs were asked about lifetime history of alcohol consumption and 136 cases were subtyped according to the French-American-British (FAB) criteria. Estimated categorical odds ratios (OR) adjusted for smoking and education were suggestive of a possible protective effect but trend tests were non-significant. Analyses by FAB subtype did not reveal subtype-specific associations but generally suffered from lack of power. Larger studies are needed to more thoroughly investigate the relationship between alcohol consumption and AML risk.

Acute myelogenous leukemia (AML) is a heterogeneous disease with distinct histologic subtypes likely to have distinct risk factors. The authors examined smoking and the risk of adult AML by French-American-British (FAB) subtype in a Los Angeles County, California, population-based case-control study of 412 cases diagnosed between 1987 and 1994 and 412 matched controls. Consistent with previous studies, smoking was not a substantial risk factor for AML overall (odds ratio (OR) = 1.2, 95% confidence interval (CI): 0.9, 1.6). However, increased risk was observed for FAB subtype M2 (OR = 2.3, 95% CI: 1.1, 4.4), particularly for subjects aged 60-75 years (OR = 3.3, 95% CI: 1.1, 10.0). For M2, significant dose-response was associated with total years smoked (p = 0.02), cigarettes per day (p = 0.007), and product filter status (filtered vs. nonfiltered; p = 0.03). The authors estimate that 42% (standard error = 13%) of M2 cases are attributable to smoking. There were no or weak associations between smoking and increased AML risk for other FAB subtypes. The finding by this study of an association between smoking and FAB subtype M2 confirms a previously published report and suggests that earlier findings of no or weak smoking-AML associations may have been due to lack of subtype-specific analysis.

Staging of transitional cell carcinoma of the bladder relies on an accurate assessment of the depth of tumor invasion within the bladder wall and surrounding structures. Fat adjacent to muscle invasive carcinoma is often interpreted to represent full-thickness invasion of the bladder wall with extension into the perivesical tissues. We present a case report highlighting our finding of significant regions of fat within the lamina propria of the urinary bladder and its clinical importance with respect to the overstaging of carcinoma of the bladder.

From August 1971 through June 1989, 591 consecutive patients underwent curative pelvic lymphadenectomy with en bloc radical cystectomy for bladder cancer. Of these patients 132 (22%) had pathologically proved nodal metastases. The incidence of positive nodes increased with increasing pathological stage of the primary tumor: stage PIS (0.75%), stage P1 (13%), stage P2 (20%), stage P3a (24%), stage P3b (42%) and stage P4 (45%). The median followup for the 31 patients still alive was 5.5 years (range 2.6 to 18.8). Recurrent bladder cancer was documented in 89 patients (67%) with a median interval to progression of 1.5 years. Pelvic recurrence as the first site of progression was uncommon, occurring in 15 patients (11%). The actuarial 2, 3, 5 and 10-year survival rates were 55%, 38%, 29% and 20%, respectively. Increased risk of progression and death was associated with advanced pathological tumor stage (stage P3b or greater, p0.001 and p0.001, respectively) and 6 or more positive nodes (p0.001 and p = 0.012, respectively). There was no significant difference in survival and interval to progression among patients who received preoperative irradiation or adjuvant chemotherapy compared to those treated with surgery alone. This retrospective analysis further substantiates the philosophy that single stage pelvic lymphadenectomy with en bloc radical cystectomy can provide long-term progression-free survival, particularly for patients with localized primary tumors and minimal metastatic nodal disease.

We assigned 91 patients with deeply invasive, pathological stage P3, P4 or N+ and Mo transitional cell carcinoma of the bladder (with or without squamous or glandular differentiation) to adjuvant chemotherapy or to observation after radical cystectomy and pelvic lymph node dissection. For most patients chemotherapy was planned as 4 courses at 28-day intervals of 100 mg./M.2 cisplatin, 60 mg./M.2 doxorubicin and 600 mg./M.2 cyclophosphamide. A significant delay was shown in the time to progression (p = 0.0010) with 70% of the patients assigned to chemotherapy free of disease at 3 years compared to 46% in the observation group. Median survival time for patients in the chemotherapy group was 4.3 years compared to 2.4 years in the observation group (p = 0.0062). In addition to treatment groups, important prognostic factors included age, gender and lymph node status. The number of involved lymph nodes was the single most important variable. We recommend adjuvant chemotherapy for patients with invasive transitional cell carcinoma after definitive surgical resection.

Between January 1979 and 1987, 411 consecutive patients were considered candidates for bilateral pelvic iliac lymph node dissection and radical cystectomy for the management of bladder cancer. From this group 160 were identified as having pathological stage P2 or less disease, including 11 who also had positive nodes. The 5-year actuarial survival rate for the respective stages at 95% confidence limits was 100% for stage P0/A, 80% for stage P1, 78% for stage P1 with stage PIS, 85% for pure stage PIS, 76% for stage P2 and 87% for stage P2 with stage PIS. Additionally, we identified a group of patients with stage P2 transitional cell carcinoma who were at significant risk for development of metastatic disease. Of 46 patients with stage P2 transitional cell carcinoma 18 had vascular space invasion resulting in 6 of 18 cancer-related deaths (33%). Our study demonstrates that radical cystectomy has been highly effective in curing patients with high grade superficial disease, including those with superficially invasive disease associated with nodal metastases.

To clarify the clinical characteristics of large noncleaved lymphoma (LNC-FCC; intermediate grade, large cell, noncleaved, Working formulation), 53 patients were studied. Thirty-one were male and 22 female. Median age was 54 years. Initial symptoms included lymphadenopathy (40%), pain (34%), and B symptoms (21%). Stage I disease was present in 6, Stage II in 9, Stage III in 14, and Stage IV in 24 (72% Stage III or IV). Gastrointestinal (GI) tract involvement was present in 13. Central nervous system (CNS) disease was present at diagnosis in two patients, occurred during therapy in two, and was the sole site of relapse in two. Bone marrow involvement was found in 7 of 50 patients (14%). Complete remission was attained in 60% of all patients. Twenty-nine Stage III and IV patients received intensive multiagent chemotherapy; complete remission (CR) was attained in 69%. In contrast, zero of nine patients with Stage III or IV disease who did not receive an anthracycline-containing regimen, attained CR. Median survival for the entire group was 25 months. It was concluded that, in our patients with LNC-FCC, GI involvement was prominent (25%) and CNS disease was not uncommon (11%). Long-term disease-free survival may be achieved in patients with more advanced disease after the administration of anthracycline-containing combination chemotherapy.

Twelve cases of central nervous system lymphoma diagnosed by stereotaxic brain biopsy are reviewed to determine the most effective method to establish the diagnosis given the small amount of tissue obtained by this technique. The stereotaxic biopsy material was examined cytologically, histologically, and immunocytochemically. The diagnosis was established by a smear made at the time of biopsy in eight cases. Histologic sections were diagnostic of lymphoma in 11 of 12 cases. Accurate classification according to the Working Formulation was possible in six cases, with diagnoses of diffuse small non-cleaved non-Burkitt’s in three, large cell immunoblastic in two, and mixed small and large cell type in one. Five additional cases were diagnosed as high-grade lymphoma but could not be further subclassified because of the small biopsy size or for-malin fixation. Immunocytochemical stains for lymphoid markers on paraffin-embedded material confirmed the diagnosis in ten cases, and, in one of these, the demonstration of monoclonality on air-dried cytospins identified an atypical polymorphous lymphocytic population as neoplastic.

The authors studied 161 cases of primary non-Hodgkin's lymphomas and pseudolymphomas of lung. Small lymphocytic proliferations, which they believe to be lymphomas, constituted 31.6 per cent of cases; plasmacytoid lymphocytic and small cleaved follicular center cell lymphomas (Lukes-Collins system), 22.4 and 11.8 per cent of cases, respectively; and the remaining follicular center cell lymphomas and B-immunoblastic sarcomas, 5.6 per cent of cases. Pseudolymphomas constituted 14 per cent of cases. Most patients were elderly and asymptomatic; in most cases a solitary nodule or infiltrate was observed on a chest radiograph. Radiographic evidence of effusion was found in both lymphomas and pseudolymphomas, but hilar adenopathy was restricted to lymphomas. A few peribronchial reactive germinal centers and intralesional giant cells/granulomas were seen frequently in unequivocal lymphomas, so their presence cannot be used to exclude neoplasia. A generally monomorphic cell population and invasion of bronchial cartilage or visceral pleura are suggestive of malignancy, whereas primitive cytologic appearance and invasion of lymph nodes or parietal pleura are pathognomonic of malignancy. Diffusely admixed mature lymphocytes and plasma cells with numerous reactive follicles suggest pseudolymphomas. Immunologic determination of clonality may be diagnostically definitive. Most localized lesions in lung were treated by surgical resection, whereas in cases of extensive pulmonary disease, biopsies were performed and patients were treated by chemotherapy or irradiation. Both lymphomas and pseudolymphomas recurred, most often within three years. Pseudolymphoma recurred only in lung. When distant spread of lymphoma occurred, it commonly involved extranodal sites. Only 18 of 101 patients with lymphoma died with or of tumor, and no patient with pseudolymphoma died of disease. Neither histologic subtype among the "small cell" lymphoid lymphomas nor the presence of regional node involvement was prognostically significant, but pleural effusion on the initial chest radiograph was a significant predictor of both recurrence and mortality.

Lymphomatoid granulomatosis is an angiocentric and angiodestructive lymphoproliferative disorder that involves multiple organs including the lung, skin, kidney and central nervous system. A case of lymphomatoid granulomatosis with ocular involvement is reported herein. Bilateral peripheral retinal vasculitis involving both arterioles and veins, with posterior uveitis, is the prominent clinical finding.

The occurrence of multiple lymphoreticular and hematological malignancies in the same households

Rhinoscleroma is a chronic disease of the respiratory system. Its onset is insidious and its symptoms are often nonspecific. Yet rhinoscleroma is a progressive disease that can lead to significant disability. The proper diagnosis is difficult because of the nonspecific presentation and rarity of rhinoscleroma. Biopsy tissue often is not properly cultured. Diagnostic histologic features may not be readily apparent or may be overlooked by the unsuspecting pathologist. A case of rhinoscleroma is reported in which an immunoperoxidase technique was applied to retrospectively confirm the diagnosis. The usefulness of this new technique in the diagnosis of rhinoscleroma is discussed.

An epidemiological case-control study of non-Hodgkin's lymphomas revealed an excess of male patients with large-cell lymphomas primary to the gastrointestinal tract and oral cavity who had evidence of substantial exposure to asbestos. Between 1977 and 1981, 28 men with large-cell lymphomas primary to these sites were interviewed about previous environmental exposure. Pathology slides from 26 of these cases were reviewed by haematopathologists, who confirmed each to be a non-Hodgkin's lymphoma of large-cell type. Neighbourhood controls were matched to patients for age, race, and sex. 13 matched pairs were discordant for asbestos exposure, and in 12 of these the exposed individual was a lymphoma patient. 10 patients and 1 control also reported a history of malaria.

The histogenesis of lymphomatoid granulomatosis has been controversial since it was first defined by Liebow and colleagues. We report a typical clinical and histopathologic case of lymphomatoid granulomatosis. Immunologic markers indicate the lymphocytes comprising this patient's initial lesion were predominantly T lymphocytes.

In 45 of 165 male cystectomy patients with bladder cancer (27 per cent) incidental adenocarcinoma of the prostate was found during the diagnostic evaluation or histological examination of the cystoprostatectomy specimens. Of the patients 37 had stage Al or A2 and 8 had stage C or Dl prostate cancer. Clinical presentation, stage and grade distributions for each primary and prognostic variable are reviewed. Over-all, 67 per cent of the patients currently are alive with a 3-year actuarial survival rate of 60 per cent. The presence of incidental stage G or Dl prostate cancer in the surgical specimen implies incomplete surgical excision and it may warrant additional postoperative treatment. However, a significantly increased mortality rate among these patients has not been identified during the limited median followup of 25 months.

Hodgkin’s Disease (HD) is relatively well studied epidemiologically. Although a clear understanding of the etiology remains elusive, the descriptive epidemiology of HD has been useful in developing hypotheses regarding etiology.

Immunohistologic analysis of cellular changes in serial lymph node biopsies of eight patients with persistent generalized lymphadenopathy (PGL) syndrome was performed and correlated with clinical and laboratory findings to better determine the natural history of human immunodeficiency virus (HIV) infection. The authors observed decreased follicle size and area in the second biopsies of six of the eight patients, associated in some with increased numbers of B-cells in medullary regions (four of eight) and more involuted follicles (four of eight). Five cases showed progressively increased paracortical areas in the second biopsies, with increased numbers of T-cytotoxic/suppressor cells and decreased T-helper cells. Seven of the patients also had a progressive loss of T-helper cells in the peripheral blood. These findings provide tissue and peripheral blood evidence for progressive immunologic deterioration in some patients with PGL.

Immunohistochemical analysis of 40 formalin-fixed, paraffin-embedded malignant melanomas (12 primary mucosal, 16 primary cutaneous, and 12 metastatic cutaneous) was performed to study the possible differences in immunostaining profiles according to location. The majority of melanomas were reactive with a polyclonal antibody to S100 protein (P-S100; 85%), a monoclonal melanoma-specific antibody (HMB-45; 88%), and a monoclonal antibody to vimentin (90%), and there were no differences in staining profiles for these antibodies by anatomic location. In contrast, while 13 of 16 cutaneous melanomas (81%) and ten of 12 metastatic melanomas (83%) were reactive with a monoclonal antibody to S100 protein (MoAb-079), only five of 12 mucosal tumors (42%) showed positive staining for MoAb-079. Similarly, 14 cutaneous melanomas (88%) and 11 metastatic melanomas (92%) showed positive staining for neuron specific enolase (NSE), while only four mucosal melanomas (33%) were NSE-positive. Of the 40 melanomas, all but two were reactive with either P-S100, MoAb-079, or HMB-45. These findings suggest that MoAb-079 and NSE may be less sensitive markers than P-S100 and HMB-45 for routinely processed mucosal melanomas as compared with cutaneous and metastatic tumors.

Ten patients with refractory B cell lymphomas were treated with weekly intravenous infusions of escalating doses of murine monoclonal antibody (MoAb) LYM-1 over four weeks. LYM-1 is a recently developed IgG2a murine MoAb that recognizes a polymorphic HLA-Dr antigen on surfaces of normal and malignant B cells but does not bind to any other normal tissues. MoAb LYM-1 has several advantages for serotherapy, since the antigen it recognizes is not shed from the cell surface and does not modulate in response to MoAb therapy. Furthermore, in vitro studies have indicated significant anti-tumour activity against lymphoma cell lines. In the current trial, dose-dependent levels of free LYM-1 were detected in the serum of all patients, but penetration of extravascular tumour tissues was poor. No significant toxicity or human anti-mouse antibody responses were observed in any patient. Clinical responses were minor and appeared to correlate with the number of infiltrating T cells seen in the initial lymphoma specimens. LYM-1 appears to be well-tolerated and has demonstrated several potential advantages as a therapeutic agent in patients with lymphoma. The mechanism of anti-tumour effect and plans for further clinical studies are discussed.