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Transitional cell carcinoma of the urinary bladder has a poor prognosis, once the muscle layers of the bladder wall have been invaded, irrespective of whether operative or radiation therapy is chosen for local treatment. The main reason for this is probably the existence of disseminated micrometastases at the time of primary treatment. Thus, a combination of systemic and local treatment would seem logical. The present study reports the response to chemotherapy in 30 patients with muscle-invasive urinary bladder tumours and the findings at subsequent cystectomy. The chemotherapy comprised cisplatin, methotrexate and leucovorin rescue and was tolerated without any alarming side-effects or increase in perioperative morbidity or mortality. The complete response rate was 43% (13/30) and, in 27% (8/30), there was a partial response with conversion into a more superficial tumour stage. The total, beneficial response rate was thus 70%.

All patients in a randomized study comparing chemotherapy with chemotherapy plus radiotherapy for patients with astrocytomas grade 3 and 4, were considered for reoperation when tumour progression was established. Fifty-eight patients were reoperated and 85 were not. Different prognostic factors, such as age, sex, Karnofsky performance status and reoperation were evaluated univariately and simultaneously in a multivariate model. The Karnofsky index and age were found to be independent prognostic factors, while re-operation could not be demonstrated to prolong life when controlled for age and the Karnofsky index. We review the literature on re-operation of malignant astrocytomas.

Re: Randomized Phase III Trial on Gemcitabine Versus Mytomicin in Recurrent Superficial Bladder Cancer : Evaluation of Efficacy and Tolerance

Proliferative cell nuclear antigen (PCNA) expression was analyzed in formalin-fixed and paraffin-embedded specimens from patients with urinary bladder cancer using three different anti-PCNA monoclonal antibodies. In 20 recent cases a positive correlation was found between the extent and intensity of PCNA staining and grade of malignancy. In 95 specimens, three to six years old, extensive positive staining was detected in 15 and 23% of grade 2B and 3-4 tumors, respectively. No equivalent staining was found in the grade 1 and 2A tumors. In material more than six years old, a remarkably weak staining was observed regardless of grade. Similarly, in a test of archival material of tonsils a very weak immuno-reactivity was found as compared with fresh material. However, antigen retrieval by microwave heating of the tissue sections was possible in the majority of all cases, and the difference in extent and intensity of the staining between low and high grade tumors remained.

Background: A previous study has shown that pentoxifylline in combination with vitamin E can reverse radiation induced fibrosis. Our aim in the present study was to investigate if the same drugs could prevent radiation induced side effects in women with breast cancer.Patients and Methods: A randomised, placebo-controlled, double blind, parallel group trial was performed. Women with breast cancer were treated for 12 months with pentoxifylline 400 mg t.i.d. or placebo, in combination with vitamin E 100 mg t.i.d. starting 1-3 months after the completion of radiotherapy. The primary endpoint was passive abduction of the shoulder, and the secondary endpoint was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623.Results: 83 patients were included in the study; 42 in the pentoxifylline + vitamine E group and 41 in the placebo + vitamine E group. Both treatments were generally well tolerated. Seven patients were withdrawn from treatment due to disease progression; four in the pentoxifylline group and three in the placebo group. At inclusion patients had impaired passive abduction of the shoulder. During treatment both groups improved significantly. With one year of follow-up median improvement from baseline was 3.7° (p=0.0035) in the pentoxifylline group and 9.4° (p= 0.0041) in the placebo group, but no difference between the groups was detected (p=0.20). Arm volumes increased over time in the placebo group (1.04%), but not in the pentoxifylline group (0.50%). This difference between the groups was statistically significantl(p=0.0172).Conclusions: The combination of pentoxifylline and vitamin E was safe and may be used for prevention of some radiation induced side effects. We found that pentoxifylline in combination with vitamin E diminished development of lymphoedema.(Accepted for publication in European Journal of Cancer)Updated results with longer follow-up will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4100.

Abstract #1076 Purpose: Histological grade, tumor size, age, hormone receptor, and HER2 are established prognostic indicators for distant recurrences in node negative breast cancer. However, the role of the proliferation marker Ki-67 as a prognostic factor is still under debate. The aim of this study is to evaluate the additional prognostic value of Ki-67 in lymph node negative breast cancer. Patients and methods: In 200 consecutive premenopausal women with lymph node negative breast cancer, Ki-67 was determined using the monoclonal MIB-1 antibody on tissue microarray. High Ki-67 proliferation index was defined as >20% positive tumor cells. Cox proportional hazards regression was used to model the impact of the prognostic factors on distant disease-free survival (DDFS). Due to non-proportional hazards, the analysis was restricted to the first 5 years after diagnosis, a time period during which 38 patients developed distant recurrences. Results: Strong positive correlations were observed between Ki-67, histological grade, S-phase, and HER-2. In univariate analysis, Ki-67 was a prognostic factor for DDFS (HR 2.9 95%CI: 1.5-5.7, p=0.002), as well as HER2, histological grade, age and ER. Tumor size was not a significant factor. In multivariate analysis, Ki-67 was an independent prognostic factor for DDFS (HR 2.3 95% CI: 1.0-5.0, p=0.044) together with HER2 and age, whereas tumor size and ER were not significant factors. Models including both Ki-67 and histological grade were not fitted due to colinearity. When stratifying for ER status Ki-67 was a significant prognostic factor in the ER positive group only (HR 5.1 95% CI: 2.0-13, p=0.001, univariate analysis) and significant interaction between the two markers was found (p=0.02). When stratifying for histological grade, Ki-67 could divide the patients with histological grade 2 (n=69; 10 distant recurrences) into two separate groups with significant difference in DDFS (HR 15 95% CI: 3.7-57, p=0.0001). This remained significant after adjustment for age and HER2 status. In histological grade 1 and 3, Ki-67 provided no additional prognostic information. Conclusion: This study demonstrates that Ki-67 is an independent prognostic factor for premenopausal patients with lymph node negative breast cancer. It is noteworthy that Ki-67 adds prognostic information in ER positive patients, but not in ER negative, and in patients with histological grade 2, but not in patients with histological grade 1 and 3. Taken together, Ki-67 may be clinically helpful for prognostic considerations and for selection of adjuvant treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1076.

Abstract #5128 Purpose: To study long term loco-regional recurrence rate and survival after postmastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer. Study design: A three-armed randomised, multicenter, phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT+C) and 3) cyclophosphamide only (C). Radiotherapy was administered with 48 Gy in 20 fractions to chest wall and locoregional lymph nodes (Arwidi Å, Acta Oncol Scand 18:273-281, 1979). Cyclophosphamide was prescribed as 12 courses of 130 mg/m2 od for14 days every 4 weeks. Patients and methods: 367 patients from 15 departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978-1983; n=124 (RT), n=118 (RT+C), n=125 (C). Median age was 47 years, median tumour size was 25 mm, and 33 % of the patients were lymph node negative. Median follow up for survival was 24 years and 21 years for other events. Results: RT reduced the risk at twenty years for locoregional recurrence in C treated patients with 75 %, 13.9 vs 3.5 %. The risk reduction was highly significant in both N0 and N+ patients. RT did not decrease systemic disease or mortality, see table 1. Chemotherapy did not decrease mortality when added to radiotherapy, though difficult to evaluate because of lack of information on delivered doses in many cases. Conclusion: Postmastectomy radiotherapy reduces loco regional recurrences in this premenopausal population, but no effect was seen on mortality at 20 years. Possible explanations are 1) low number of loco regional recurrences and superior survival in comparison to other trials investigating postmastectomy radiotherapy, which might have modified the effect of RT on survival, 2) too low intensity of adjuvant, single agent chemotherapy, and 3) chance, since relatively small study with little power. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5128.

Abstract #6057 *Würtz SØ and Klintman M contributed equally, Malström P and Brünner N shares the senior authorship. Background. Predictive markers are scarcely represented in breast cancer. TIMP-1 has in a previous study (n = 173) performed in our laboratory been shown to carry predictive information for the response to chemotherapy in metastatic breast cancer as high tumor tissue levels of TIMP-1 were significantly associated with a low objective response rate to treatment with the most frequently used chemotherapeutic drugs (CMF or anthracyclines). The purpose of the present study was to validate these previous results with a new independent patient population. Methods. The TIMP-1 level was measured using a validated ELISA in 168 primary tumor extracts from patients with metastatic breast cancer and levels were associated with the objective response to CMF and anthracyclines. Patients were included in the study provided that they had received chemotherapy for their metastatic disease and that frozen tumor tissue as well as data on their objective response to chemotherapy was available. Results. The median TIMP-1 level in responders was 17.3 (2.9 – 75.8) ng TIMP-1/mg protein and in non-responders it was 19.6 (0-190.3) ng TIMP-1/mg protein. When analysed as a continuous log-transformed variable, increasing tumor levels of TIMP-1 were associated with a decreasing probability of objective response to CMF or anthracyclines (OR = 1.59, 95% CI: 0.97 – 2.62, p = 0.07). This is very similar to the original study and thus supporting previous data. Next, we used a more clinically relevant approach for analysing the data from the validation study. For this analysis, objective response was scored as complete or partial response versus stable disease lasting at least six months (clinical benefit) versus progressive disease (non-response). This analysis showed that increasing levels of TIMP-1 were associated with a poor clinical benefit rate from chemotherapy (OR = 1.56, 95% CI: 0.98 - 2.51, p=0.06). The original study has not previously been analysed using this endpoint. When performing this analysis, similar results were found (OR = 1.62, 95% CI: 1.06 - 2.48, p = 0.02). Combining the new population and the original population in a pooled analysis (n = 341) using a random effects model showed that high levels of TIMP-1 were highly significantly associated with a poor clinical benefit rate from chemotherapy compared with patients with low levels (OR = 1.59, 95% CI: 1.16 - 2.18, p=0.003). Conclusion. The present validation study supports previous findings that primary tumor tissue levels of TIMP-1 carries predictive information in metastatic breast cancer treated with chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6057.

9518 Background: Amplification of the HER-2/neu and topoisomerase IIα (TOP2A) genes has been linked to the effects of anthracyclines. Their role in predicting outcome of anthracycline-based adjuvan...

Re : extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study.

In a phase III study of disseminated malignant melanoma performed in Sweden and Norway, 326 patients were randomized to receive treatment with the combination Dacarbazine (OTIC) and Vindesine (VDS) with or without addition of Cisplatin (CDDP). The study was designed to reveal a clinically significant survival difference when the three drugs were combined. DTIC was given i.v. at a dose of 250 mg/sqm days 1 to 5 every four weeks and VDS was given i.v. at a dose of 3.0 mg/sqm day 1 weekly. CDDP was given i.v. at a dose of 100 mg/sqm day 1 every 4 weeks. There was no statistical significant difference regarding total survival between the treatment arms (P = 0.22). What was clearly demonstrated was an increased toxicity in the treatment arm containing CDDP. Two hundred and sixteen patients were evaluable for response in compliance with the WHO criteria. With the DTIC-VDS regimen 9.9% patients obtained a complete remission and 10.8% patients a partial remission with an overall response rate of 20.7%. With the triple regimen DTIC-VDS-CDDP 16.2% patients obtained a complete remission and 15.2% patients a partial remission with an overall response of 31.4%. The difference in objective response rates observed between the treatment arms is not statistically significant (P = 0.1011). In conclusion this study did not show any significant increases in median survival time or objective response rate. The study has demonstrated a clinically significant increase in toxicity and we suggest that this triple regimen does not merit further use in patients with disseminated malignant melanoma, which earlier phase II studies have indicated.

Spleen cells from WF rats immunized to allogeneic lymphoid cells or to syngeneic colon carcinomas and from unimmunized controls were separated by countercurrent distribution in aqueous two-phase systems. The cells were assayed for cytotoxicity to allogeneic fibroblasts or syngeneic colon carcinoma cells and to syngeneic fibroblasts in a 24-hr 51 Cr-release assay. Cells from immunized rats which selectively lysed the specific target cells were repeatedly found in one area of the distribution separate from the majority of cells, which nonselectively lysed syngeneic fibroblasts as well. A similar subpopulation which nonselectively lysed all target cells assayed was recovered from the spleens of unimmunized rats. The cells were also assayed for the ability to lyse antibody-coated thymocytes in a 4-hr 51 Cr-release assay. The peak of K cells was found to overlap partially that of cells with nonselective cytotoxicity.

A retrospective study of 232 bladder tumours with minimum follow-up 5 years is presented. The carcinoma was superficial in 66%, muscle-invasive in 31% and could not be staged in 3%. Primary treatment was mainly transurethral resection for superficial tumour, but was cystectomy or radiotherapy in 22 of 29 T1 G3. Of the superficial tumours, 71% recurred. Progression to higher T stage occurred in 15% of Ta and 29% of T1 tumours, and half of these patients died of bladder cancer. The corrected 5-year survival rates in grades 1, 2A, 2B and 3-4 were 96, 84, 64 and 43%, and in stages Ta, T1, T2 and T3 they were 94, 69, 40 and 31%. All patients with T4 tumour died within 4 years. Among the 45 patients with 40 Gy irradiation + cystectomy, the corrected 5-year survival rate was 83% in superficial and 64% in muscle-invasive tumours, and among the 38 with radical radiotherapy the rates in T1-3 were 46, 36 and 13%. Transurethral resection was successful in most Ta cases. Most T1 tumours were, like T2-4, of higher grade than Ta. Prognosis was worse in T1 than in Ta. After progression to muscle-invasive disease, even during close follow-up the outlook was poor, as poor as for patients with primary muscle-invasive disease.

From November 1981 through 1983, salvage cystectomy was performed on five men with recurrent bladder carcinoma after definitive irradiation; three of the men were 75 years or older. There were no deaths, but the complication rate was fairly high, though acceptable. Salvage cystectomy was further performed, together with radical extirpation of reproductive organs, in two women with recurrent gynaecologic malignancy and a history of local irradiation. The authors conclude that salvage cystectomy is a fairly safe procedure, even in elderly patients, relieving discomfort and probably also prolonging survival.

A consecutive series of 230 patients with transitional cell carcinoma of the urinary bladder was analyzed with respect to the DNA content of the primary tumor, as determined by flow cytometry on material obtained from paraffin blocks. A new method for this analysis was elaborated, based on proteolytic digestion with protease (type VII, Sigma) and density separation of the nuclei by Percoll centrifugation. The method provided DNA flow histograms with less baseline debris and a smaller coefficient of variation in the peaks than published techniques. In eight of 70 cases tested (11%) the method revealed aneuploid peaks that were not distinguished with the original technique and in 197/230 case (86%) interpretable DNA histograms were obtained. The distribution of diploid and aneuploid tumors in different grades and T categories was assessed. None of the grade 1 tumors was aneuploid; 11% of grade 2A, 63% of grade 2B and 83% of grade 3-4, respectively, were aneuploid. The corresponding figures for categories Ta, T1, T2, T3 and T4 were 16, 55, 72, 65 and 100%, respectively.

Lymphocytes from human peripheral blood were separated by Countercurrent distribution (CCD) in a charged aqueous two-phase system composed of Dextran T 500 and polyethylene glycol 6000. Maximal responses to the T-cell mitogens phytohemagglutinin and concanavalin A were detected in a part of the distribution corresponding to the area where the highest percentage of E rosetting cells were seen. Antibody-dependent cellular cytotoxicity was mediated by lymphocytes located in a restricted part of the distribution separate from the majority of T lymphocytes. Lymphocytes with natural killer activity against K 562, adherent melanoma cells, and fibroblasts were detected in the same region. This area of the distribution also contained the peak of lymphocytes with high-affinity Fc receptors. It was further investigated whether affinity separation may be possible in two-phase systems on the basis of cell to cell interaction. Affinity CCD utilizing the interaction between sheep erythrocytes (SRBC) and T lymphocytes was shown to redistribute the majority of T cells into the area in which SRBC were located, while other lymphocytes were not affected. Lymphocytes mediating natural killing to adherent target cells were not redistributed, indicating that they lack high-affinity receptors for SRBC.

Summary During the decade 1957 through 1966, sixty-three cholecystostomies in sixty-two patients were performed in the Surgical Department, University of Lund. Fifty-five of these sixty-two patients were followed up. The mean age was seventy-one years for both sexes. The primary mortality was 20 per cent: a third died of circulatory and respiratory insufficiency; three quarters died of peritonitis, abscess, and renal failure; half of the surviving patients had delayed wound healing. The mean hospital stay for the survivors was nineteen days. During the follow-up period, sixteen later required cholecystectomy, nine electively and seven for a recurrence of acute cholecystitis. Nine had another attack of cholecystitis after cholecystostomy. Another four had continuous symptoms; five more died of the gallbladder disease. It is concluded that cholecystostomy should be restricted to very ill patients and should be planned and carried out with the patient under local anesthesia. In all other patients, early primary cholecystectomy should be performed with cholangiography performed during the operation.

The expression of ABH blood group isoantigen was determined with the avidin-biotin-peroxidase complex method in a retrospective consecutive material of 230 patients with transitional cell bladder carcinoma. The follow-up period was 5 to 9 years. The five-year corrected survival for 65 patients whose primary tumours showed predominant expression of ABH antigens ('positive') was 80% and for 146 patients with predominant deletion ('negative') 60% (p less than 0.01). Of 107 patients with superficial tumours there were 60 negative and 47 positive. In an analysis of early progression, the negative tumours were found to progress more frequently than positive ones (p less than 0.03). Twenty-three per cent of the negative tumours finally progressed during the whole follow-up, compared with 15% of the positive ones; this difference was not significant. Almost all progressing tumours became negative when they reached an advanced stage.

Background Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. Methods 32 K tiling microarray-based comparative genomic hybridization (aCGH) was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. Results Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 × 10-5) unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29) displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. Conclusion Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and underscores the importance of evaluating the clonality of multiple tumors for optimal patient management. In summary, our findings demonstrate the importance of evaluating the properties of both tumors in order to determine the most optimal patient management.

Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we used gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated, and 48 non-BRCA1/2–mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter methylation but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter–methylated basal-like tumors, 13% of non-BRCA1–deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1 hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer but rarely in BRCA2 hereditary breast cancer and non-BRCA1–deficient sporadic breast cancers. Together, our findings show the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1 status. Cancer Res; 72(16); 4028–36. ©2012 AACR.

Introduction Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information. Methods We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation. Results Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-). Conclusion A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.