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PURPOSE: To examine the association between race and clinical outcomes (pathological complete response [pCR]; recurrence free survival [RFS], and overall survival [OS]) in patients diagnosed with triple-negative (TNBC) or HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC). METHODS: Patients who self-identified as non-Hispanic white (NHW) or non-Hispanic Black (NHB) and were diagnosed with Stage I-III TNBC (n=171 including 124 NHW and 47 NHB) and HER2-positive (n=161 including 136 NHW and 25 NHB) breast cancer who received NAC from 2000–2018 at Roswell Park Comprehensive Cancer Center were included. Associations of race with pCR and survival outcomes were evaluated using logistic and Cox regression models, respectively. RESULTS: There was no statistically significant difference in pCR between NHB and NHW patients with TNBC (31.9 vs 29.8%; OR: 1.11, 95% CI 0.54–2.29) or HER2-positive breast cancer (36.0 vs 39.7%; OR: 0.87, 95% CI 0.36–3.11). After controlling for potential confounders, including age, stage, treatment regimens, insurance status, and comorbidities, no statistically significant difference in OS or RFS was observed between NHB and NHW patients within either subtype. CONCLUSION: TNBC or HER2-positive breast cancer patients treated at a single academic center in Buffalo, NY, showed similar outcomes independent of patients’ race. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography and clinical outcomes are warranted.

PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

Background Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. Methods IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. Results The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. Conclusions The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. Trial registration “Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry” (NCT02670577) retrospectively registered on Jan 27, 2016.

Testicular cancer is relatively uncommon and accounts for 50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

Background:Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC.Methods:We included patients diagnosed with stage I–III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with aPResults:Among all patients with breast cancer treated at these centers, 3,016 fit the inclusion criteria. Training cohort (n=2,112) bivariable analyses identified disease stage, insurance type, age, body mass index, race, and income as being associated with rrTNBC (PP24 months), we found that insurance type and young age remained significant.Conclusions:Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.

Purpose Outcome data on hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2) nonamplified (HER2−) metastatic breast cancer (MBC) treated with palbociclib after treatment with everolimus are lacking. The PALOMA-3 trial, showing benefit of palbociclib plus fulvestrant compared to fulvestrant alone in HR+HER2− MBC after progression while receiving endocrine therapy excluded women previously treated with everolimus. The objective of this study was to examine outcomes of HR+HER2− MBC with prior exposure to everolimus while receiving palbociclib-based therapy. Patients and Methods A retrospective, single-institute review was conducted of HR+HER2− MBC from January 2014 to November 2016 in patients treated with palbociclib after prior treatment with everolimus. Progression-free survival (PFS) was defined as the time from initiation of palbociclib to the date of progression as determined by the treating physician based on radiologic, biochemical, and/or clinical criteria. Response rates were determined on the basis of available radiologic data. Objective response rate (ORR) was defined as the rate of any complete or partial responses; clinical benefit rate (CBR) was the rate of complete response, partial response, or stable disease for at least 24 weeks. Results Twenty-three patients with a mean (range) age of 68 (42-81) years were identified. Kaplan-Meier estimate showed median PFS of 2.9 months (95% confidence interval, 2.1-4.2); ORR was 0 of 23 and CBR was 4 (17.4%) of 23. In the PALOMA-3 trial, median PFS, ORR, and CBR of palbociclib cohort were 9.5 months (95% confidence interval, 9.2-11.0), 19%, and 67%, respectively. Conclusion There is a limited clinical activity of palbociclib combinations after progression with everolimus combination therapy. Further studies are necessary to confirm these findings.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma.

These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m2 i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m2 orally twice daily, days 1–14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45–0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44–0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71−1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand–foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. Clin Cancer Res; 19(10); 2745–54. ©2013 AACR.

Objectives To evaluate the effect of suboptimal dosing on the outcomes of patients who received neoadjuvant chemotherapy (NAC) and robot-assisted radical cystectomy (RARC). Patients and Methods We retrospectively reviewed 336 consecutive patients with urothelial carcinoma of the bladder who were treated with NAC and RARC at three academic institutions. Outcomes were compared between 3 groups: patients who received optimal NAC; patients who received suboptimal NAC; and those who did not receive NAC. To adjust for potential baseline differences between the three groups, propensity-score-based matching was performed. The suboptimal dose group was defined as those who received fewer than three cycles of cisplatin-based chemotherapy, received decreased dosage, or one's not treated with cisplatin. Primary outcomes analyzed were recurrence-free survival (RFS) and overall survival (OS). Secondary outcomes were perioperative complications and readmissions after RARC. Results Within the cohort after propensity-score matching, 69 patients received optimal dose NAC, 41 received suboptimal NAC and 69 did not receive NAC. Complication rates and readmission rates between the 3 groups did not differ significantly. On multivariable analysis, suboptimal dosing and no NAC were independent predictors of worse RFS (HR: 2.5, 95%CI: 1.2-5.7, p=0.01 and HR 2.4, 95%CI 1.28-5.16, p=0.01) and worse OS (HR 4.5, 95%CI 1.6-15.0, p

Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m 2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.

This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 A mu g) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations

US Oncology Research Trial 9735 reported that TC improved overall survival when compared to doxorubicin and cyclophosphamide in early-stage breast cancer. Despite 61% grades 3-4 neutropenia in the TC arm, only 5% of patients developed febrile neutropenia (FN) without primary prophylactic GCSF (ppGCSF). TC has risen in popularity, particularly in older patients or in those where an anthracycline is contraindicated. Other studies examining the toxicity of TC without ppGCSF reported a higher incidence of FN between 23 and 46%. We reviewed our institutional experience with ppGCSF and the TC regimen. Women treated with adjuvant TC and pegfilgrastim at Roswell Park Cancer Institute were identified from the pharmacy database between 8/2006 and 11/2010. Patient characteristics and comorbidities were abstracted. Endpoints included incidence of FN, hematologic toxicities, relative dose intensity (RDI), and other acute complications. Docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) were given every 21 day/cycle for a planned four cycles. All patients received pegfilgrastim 6 mg on day 3. One hundred and eleven women with median age of 56 years (27-79) were identified. Twenty-two percent of patients were ≥ 65 at diagnosis. Eight patients developed FN (7%). Ninety-five patients (86%) were able to complete four cycles. Completion rate was significantly lower in patients with age ≥ 65 (71% vs. 90%; P = 0.02). Incidence of hospitalization, delay, RDI85%, and dose reduction were not significantly different between the age groups. The overall incidence of FN was 7%. Older patients were significantly less likely to complete four cycles of TC as planned. ppGCSF should be strongly considered in breast cancer patients receiving adjuvant TC chemotherapy.

BACKGROUND Preclinical evidence supports the role of estrogen receptor signaling in prostate cancer. In this trial we investigated the tolerability and efficacy of fulvestrant, a pure estrogen receptor antagonist, in the treatment of castration resistant prostate cancer (CRPC). METHODS Patients with CRPC were enrolled after written informed consent. Fulvestrant was administered by intramuscular injection at a dose of 500 mg on day 0, then 250 mg on day 14, day 28 and monthly thereafter. History, physical examination, serum prostate specific antigen (PSA) levels and toxicity was evaluated monthly. Radiographic studies were repeated every 3 months to assess disease. Treatment was continued until disease progression, unacceptable toxicity, non-compliance or consent withdrawal. RESULTS Twenty patients were enrolled over a period of six months. All patients were Caucasians with median age of 69.5 years [range: 47–85 years]. Sixteen patients (80%) had radiological evidence of metastasis and four patients (20%) had rising PSA as the only evidence of progressive disease. Patients received a median of three treatment cycles of fulvestrant [range: 1–11]. Median time to progression was 4.3 months (95% confidence interval of 3–5.7 months) and median overall survival was 19.4 months (range: 9.9–19.4 months) after a median follow-up of 16 months. No patient showed ≥50% reduction in PSA or radiologic improvement. Few adverse events were noted, none of which were attributed directly to fulvestrant. CONCLUSION Fulvestrant was well tolerated but failed to produce clinical or PSA response in men with CRPC. Prostate 68: 1461–1466, 2008. © 2008 Wiley-Liss, Inc.

There is a need for chemotherapy regimens active against anthracycline- and taxane-refractory breast cancer. Data from preclinical and pilot studies performed at Roswell Park Cancer Institute (RPCI) suggested that when irinotecan (IRN) is given with 5-fluorouracil (5-FU) efficacy is affected by the sequence of drug administration. Pretreatment with IRN 24 h before 5-FU increased the number of tumor cells in S-phase and the antitumor activity in a preclinical system. These data provided the rationale for the evaluation of IRN and capecitabine, a 5-FU prodrug, sequentially administered in patients with metastatic breast cancer. The main objective of the study was to determine the MTD and identify dose-limiting toxicities (DLTs) of capecitabine and IRN. Additionally, the degree of accumulation of cells in S-phase in tumor biopsies obtained at 24 h after the first dose of IRN was measured in consenting patients.Metastatic breast cancer patients who experienced disease progression after at least one (taxane or anthracycline based) chemotherapy regimen and an expected survival of at least 3 months and ECOG performance status 0-2 were eligible. Twelve patients were enrolled and treated. The starting doses were IRN 80 mg/m(2) given over 90 min on days 1, 8, 22, 29, and capecitabine 1,500 mg/m(2)/day given days 2-15 and 23-36. Evaluation for response was performed after the first cycle. Sequential tumor biopsies were performed on five patients.The first three patients treated exhibited modulation in cyclin A index on tumor biopsy as defined by the study, defining the modulatory dose of IRN as 80 mg/m(2). Overall, 4/5 biopsies showed modulation. Dose Limiting Toxicities (DLTs) were assessed during the first cycle of therapy. Two DLTs (Grade 3 nausea vomiting and dehydration; grade 3 pneumonia, hypoxia, hypotension) were seen at dose level 2 of capecitabine (2,000 mg/m(2)/day) and the first cohort was expanded. There were no DLTs for patients treated at DL 1. No grade 3-4 toxicities occurred at DL 1. Seven patients were evaluable for response following one cycle of treatment (partial response 1, stable disease 4, progressive disease 2) Of the five inevaluable patients, two experienced DLT, one received 50% of the planned capecitabine dose, one progressed prior to evaluation, and one withdrew consent.IRN 80 mg/m(2) days 1, 8, 22, 29 in combination with capecitabine 1,500 mg/m(2)/day in divided dose days 2-15 and 23-36 has an acceptable toxicity profile and resulted in modulation of S-phase in 4/5 specimens examined. Further studies of the activity of this combination and modulatory effect of IRN are warranted.

This is a retrospective study of the length of survival (LOS) in hospice of patients with cancer treated at a major cancer center compared to other treatment sites. Of 670 patients, the 185 (28%) treated at a major cancer center had unique characteristics, including higher median Palliative Performance Score (PPS) at the time of hospice enrollment (45 versus 40, p = 0.009), and longer median LOS in hospice (35 versus 21 days, p = 0.02: log rank test). Additional variables that predicted longer LOS were higher PPS, Medicare or Medicaid, self-referral, unmarried status, and non-executed advance directives. After adjusting survival for PPS with a Cox proportional hazard model, the hazard ratio for PPS remained statistically significant (95% confidence interval [CI]: 0.95-0.97] while that for the treatment site was not (95% CI: 0.73-1.04]. The performance status, and not the treatment site, was the dominant predictor of the LOS of patients with cancer in hospice.

No predictors of a complete pathologic response (pT0) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma have been established. We performed a retrospective analysis of 50 patients to identify potential predictors. Our results showed that the presence of additional transitional cell variants on pathologic examination (mixed tumors) predicted against pT0, suggesting the avoidance of NAC and its morbidity in these patients with mixed tumors.Randomized trials have supported the use of cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma (MIBC) owing to the survival advantage, which has correlated with downstaging of the cancer to pT0. Only 30% to 40% of patients receiving NAC have attained a pT0 response at cystectomy; the remaining have either residual disease or progression. We aimed to identify the factors that could predict a pT0 response to NAC.Of 336 patients who had undergone robotic cystectomy at our institute from May 2007 to March 2014, we identified 50 patients who had undergone NAC for MIBC. We conducted a retrospective study, dividing these 50 patients into 2 groups, those with and without a pT0. Factors, including age, histologic features, hydronephrosis at initial presentation, and chemotherapy type, were examined by both univariate and multivariate logistic regression analysis.Of the 50 patients, 14 (28%) had pT0 at cystectomy, 20 (40%) had progressive disease, and 16 (32%) had residual disease. The median age was 67.5 years, the median glomerular filtration rate at presentation was 87.5 mL/min, the patients had undergone a median of 3 NAC cycles, and the median time from the end of chemotherapy to surgery was 4 weeks. The odds of a pT0 response for pure urothelial carcinoma (UC) were approximately 11 times greater relative to cancers with transitional cell variant histologic features or mixed tumors (odds ratio 0.09, 95% confidence interval 0.021-0.380; P = .0011), including squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, lymphoepithelioma-like, and plasmacytoid variants.The presence of pure UC favored a pT0 response to NAC compared with those with variant histologic features or mixed tumors. These potential predictors warrant prospective validation to allow the ideal selection of patients for NAC.

Purpose: To develop and validate a model that can be used to predict the overall survival probability among metastatic hormone-refractory prostate cancer patients (HRPC). Patients and Methods: Data from six Cancer and Leukemia Group B protocols that enrolled 1,101 patients with metastatic hormone-refractory adenocarcinoma of the prostate during the study period from 1991 to 2001 were pooled. The proportional hazards model was used to develop a multivariable model on the basis of pretreatment factors and to construct a prognostic model. The area under the receiver operating characteristic curve (ROC) was calculated as a measure of predictive discrimination. Calibration of the model predictions was assessed by comparing the predicted probability with the actual survival probability. An independent data set was used to validate the fitted model. Results: The final model included the following factors: lactate dehydrogenase, prostate-specific antigen, alkaline phosphatase, Gleason sum, Eastern Cooperative Oncology Group performance status, hemoglobin, and the presence of visceral disease. The area under the ROC curve was 0.68. Patients were classified into one of four risk groups. We observed a good agreement between the observed and predicted survival probabilities for the four risk groups. The observed median survival durations were 7.5 (95% confidence interval [CI], 6.2 to 10.9), 13.4 (95% CI, 9.7 to 26.3), 18.9 (95% CI, 16.2 to 26.3), and 27.2 (95% CI, 21.9 to 42.8) months for the first, second, third, and fourth risk groups, respectively. The corresponding median predicted survival times were 8.8, 13.4, 17.4, and 22.80 for the four risk groups. Conclusion: This model could be used to predict individual survival probabilities and to stratify metastatic HRPC patients in randomized phase III trials.

BACKGROUND Mitoxantrone in combination with a low-dose glucocorticoid has been shown to produce more favorable outcomes among men with hormone-refractory prostate carcinoma than glucocorticoid alone. Therefore, the authors sought to determine the safety and activity of higher doses of mitoxantrone in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) and a glucocorticoid in preparation for a possible Phase III trial comparing standard to dose-escalated mitoxantrone. METHODS This Phase II trial enrolled 45 patients from October 1996 to March 1998. Twenty-one patients without pelvic irradiation (Arm I) received 21 mg/m2 of mitoxantrone every 3 weeks, and 24 patients who had received pelvic irradiation (Arm II) were given 17 mg/m2 on the same schedule. All patients received 40 mg of hydrocortisone in divided doses daily and GM-CSF at 500 μg/daily for a minimum of 10 days per cycle beginning on the third day of the cycle. RESULTS In Arm I, 33% of assessable patients achieved a partial response, 50% had a ≥ 50% decline in their PSA, and 35% had a ≥ 75% decline in PSA values. The comparable numbers in Arm II were 24%, 48%, and 35%, respectively. The median survival times were 12 months in Arm I and 14 months in Arm II. Treatment had to be discontinued in 13% of patients because of thrombocytopenia. No other significant toxicities were encountered. CONCLUSIONS Higher doses of mitoxantrone (17 and 21 mg/m2) were associated with activity comparable to many estramustine combinations and generally were well tolerated. However, because the degree and frequency of thrombocytopenia were greater than that observed with standard dose mitoxantrone (12–14 mg/m2), and because the median survival is apparently comparable to standard dose mitoxantrone, this approach to HRPC cannot be recommended for Phase III testing. Cancer 2002;94:665–72. © 2002 American Cancer Society. DOI 10.1002/cncr.10217

BACKGROUND It is known that total PSA values are often greater than the sum total of free-PSA (f-PSA) and PSA–ACT complex. It is primarily because other PSA complexes are present in the patient serum and currently cannot be quantified. Our studies were aimed in developing methodology that will permit recovery of all molecular forms of PSA from various biological fluids. METHODS Thiophilic interaction (3S,T-gel) chromatography procedure was used to isolate various PSA molecular forms present in biological fluids. f-PSA and PSA complexes were shown to have strong affinity for T-gel. PSA forms eluted from the column were analyzed by SDS–PAGE/Western blot and were identified by immunostaining with antibody-specific to PSA and to various protease inhibitors. The identity of PSA complexes was also confirmed by Enzyme-linked Immunosorbent-assay (ELISA). RESULTS One step affinity chromatography procedure (3S,T-gel) was used to isolate different molecular forms of PSA in seminal plasma, patient sera, and in prostate cancer cell culture medium. Seminal plasma was shown to contain f-PSA, PSA–ACT, PSA–A2M, and PSA–PCI. Sera from prostate cancer patients at different stages of the disease contained f-PSA, PSA–ACT, and PSA–A2M. Besides these PSA forms, some patients at late stage of the disease (T3 and T4) also contained two additional PSA-complexes that have not been identified as of yet. Conditioned medium from LNCaP cells was shown to contain f-PSA, PSA–ACT, and PSA–A2M complexes. CONCLUSIONS Thiophilic gel has strong affinity for all known molecular forms of PSA present in any biological material. Visualization of PSA molecular forms in Western-blot analysis was feasible only after patient serum was processed through T-gel. Our procedure can be used to screen hybridoma and antibodies specific to the individual PSA complex. The PSA molecular forms isolated from patient serum after T-gel procedure may provide useful internal calibrators, and thus may significantly enhance the reliability of PSA measurements. Prostate 50: 145–153, 2002. © 2002 Wiley-Liss, Inc.

PURPOSE: To assess the activity and toxicity of the combination of gemcitabine and cisplatin in the treatment of chemotherapy-naive patients with metastatic urothelial cancer. PATIENTS AND METHODS: Forty-six patients with measurable stage IV carcinoma of the urothelium were enrolled onto this trial. Gemcitabine 1,000 mg/m2 was administered intravenously for 30 to 60 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin was administered after gemcitabine on day 1 of each cycle. The first 11 patients received an initial cisplatin dose of 100 mg/m2. Due to the hematologic toxicity observed in several of these patients, the dose was reduced to 75 mg/m2 in the remaining 35 patients. Patients were treated with six cycles, unless disease progression or severe toxicity necessitated earlier discontinuation. RESULTS: Ten of the 46 patients achieved a complete response and nine showed a partial response. The overall response rate was 41%. The median time to treatment failure was 5.5 months. The median survival was 14.3 months, and the 1-year survival probability was 54%. Most of the toxicities were hematologic and, in general, easily manageable. CONCLUSION: Gemcitabine plus cisplatin is active in the treatment of metastatic urothelial cancer in chemotherapy-naive patients and has an acceptable clinical safety profile. Studies are under way to further define the place of gemcitabine in combination with other chemotherapeutic agents in the treatment of metastatic urothelial cancer.

At present, a combination of cisplatin, methotrexate, vinblastine and doxorubicin is the most widely used chemotherapy for metastatic bladder cancer. However, long-term follow-up shows that this combination may have little effect on survival. In addition, this regimen is toxic. New agents are needed which combine efficacy with good safety profiles. Agents which have been investigated include gallium nitrate, interferon-alpha and paclitaxel both as single agents and in combination with established cytotoxic drugs. A number of studies have been conducted in bladder cancer with the novel nucleoside analogue, gemcitabine. Response rates of up to 33% have been recorded in two phase II studies. Gemcitabine was well tolerated in both studies with few of the side-effects normally associated with cytotoxic drugs. A third study is ongoing.

Inflammatory breast cancer (IBC) carries an ominous prognosis. Before 1988, women with IBC at our institution were treated with neoadjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without vincristine and prednisone (CMF/VP). After 1988, women with IBC were treated with cyclophosphamide, doxorubicin, and 5-fluorouracil (FAC). This study compares these two regimens with regard to response and survival.The records of all women presenting between January 1973 and December 1991 with a stage IIIB (T4d, any N, MO) breast cancer with proven dermal lymphatic invasion by tumor cells were reviewed retrospectively.The study comprised 38 women; 28 received CMF (22 CMF, 6 CMF/VP), and 10 received FAC. The overall response rate to induction chemotherapy in the CMF/VP group was 57% (40% PR, 17% CR), and 100% (60% PR, 40% CR) in the FAC group. The median overall survival for women receiving CMF/VP was 18 months compared with 30 months for women receiving FAC (p = 0.02). The median disease-free survivals for the CMF/VP and FAC groups were 6 and 24 months, respectively (p0.001). When comparing responders and nonresponders with CMF/VP induction therapy, the responders had a significantly longer overall median survival (24 versus 10 months) (p0.001) and disease-free median survival (8 versus 2 months) (p0.001). All of the five patients remaining alive received FAC with 80% (four of five) having a complete response. These four patients subsequently underwent mastectomy and radiation.This study suggests that a doxorubicin-containing chemotherapy regimen improves overall and disease-free median survivals when compared with the previously used CMF combination in the treatment of IBC. A favorable response to induction chemotherapy also appeared to be associated with an improved survival.

Mortality improvements in young women with breast cancer (BC) may be attributable to treatment advances; screening likely plays a less significant role as mammography is not recommended

Objective To analyze trends in perioperative chemotherapy and optimize use of neoadjuvant chemotherapy for bladder cancer. Methods From 2005-2012, 284 consecutive patients underwent robot-assisted radical cystectomy at our facility. Patients with disease ≥T2 and nodal involvement and positive surgical margins were reviewed and considered candidates for referral to medical oncology for chemotherapy. The study was conducted in two phases: phase 1 included 242 consecutive patients between 2005 and 2011, and phase 2 analyzed the effect of changes in 42 patients during a 1-year period (2011-2012). Results In phase 1, 148 patients (61%) were candidates for neoadjuvant chemotherapy (NAC). Consultation for NAC was sought for 44 patients (29%), and 104 (71%) did not receive consultation. Of the 44 patients, 36% received NAC, 7% refused, 32% were recommended for immediate cystectomy, and 25% did not receive NAC for other reasons. Phase 2 was more stringent, with a multidisciplinary approach. Significant improvement in referral and NAC use was seen. About 78% vs 30% of patients were seen by medical oncology for consideration of NAC before robot-assisted radical cystectomy and 71% vs 36% received NAC compared with phase 1. The NAC utilization rate improved from 10.8% to 55% over 1 year with a diligent multidisciplinary approach. Medical comorbidities were the main reason for patients not receiveing adjuvant chemotherapy (AC; 30% and 33%). Conclusion A multidisciplinary approach and coordination of services can help optimize the use of neoadjuvant chemotherapy for bladder cancer.

Purpose NY-ESO-1 cancer testis (CT) antigen is an attractive candidate for immunotherapy as a result of its high immunogenicity. The aim of this study was to explore the potential for NY-ESO-1 antigen directed immunotherapy in triple negative breast cancer (TNBC) by determining the frequency of expression by immunohistochemistry (IHC) and the degree of inherent immunogenicity to NY-ESO-1. Experimental Design 168 TNBC and 47 ER+/HER2- primary breast cancer specimens were used to determine NY-ESO-1 frequency by IHC. As previous studies have shown that patients with a robust innate humoral immune response to CT antigens are more likely to develop CD8 T-cell responses to NY-ESO-1 peptides, we evaluated the degree to which patients with NY-ESO-1 expression had inherent immunogenicity by measuring antibodies. The relationship between NY-ESO-1 expression and CD8+ T lymphocytes was also examined. Results The frequency of NY-ESO-1 expression in the TNBC cohort was 16% versus 2% in ER+/HER2- patients. A higher NY-ESO-1 score was associated with a younger age at diagnosis in the TNBC patients with NY-ESO-1 expression (p = 0.026). No differences in OS (p = 0.278) or PFS (p = 0.238) by NY-ESO-1 expression status were detected. Antibody responses to NY-ESO-1 were found in 73% of TNBC patients whose tumors were NY-ESO-1 positive. NY-ESO-1 positive patients had higher CD8 counts than negative patients (p = 0.018). Conclusion NY-ESO-1 is expressed in a substantial subset of TNBC patients and leads to a high humoral immune response in a large proportion of these individuals. Given these observations, patients with TNBC may benefit from targeted therapies directed against NY-ESO-1.

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.

The use of clinicopathologic features in decision-making in early stage estrogen receptor (ER)-positive breast cancer (BC) may lead to over or under treatment. We investigated the effect of the Oncotype Dx (ODX) on chemotherapy (CTX) utilization in two cancer centers. 276 cases of node-negative ER-positive BC had ODX between 2005 and 2009. Age at diagnosis, tumor size, grade, and progesterone receptor (PR) status were abstracted from records and provided to two medical oncologists blinded to the ODX score. A recommendation for or against CTX was made based on clinicopathologic characteristics. Median age was 55 years. Mean tumor size was 1.6 cm. The median 10-year Adjuvant! Online (AO) mortality risk was 8. The median Nottingham Prognostic Index (NPI) was 3.3. The median ODX recurrence score was 17. Without knowledge of the ODX, oncologists were more likely to recommend CTX to younger women (P0.0001), women with negative PR status (P0.0001), higher NPI (P0.012), and tumors1 cm (P = 0.033). On average, CTX recommended patients had larger tumors (2.0 vs. 1.2 cm) and higher AO 10-year mortality (11.4 vs. 4.4%). ODX resulted in a change in management for 38% of women. Of 188 total patients who did not receive CTX, 71 had a recommendation favoring CTX by an oncologist blinded to the ODX score. In our multi-institutional cohort, the ODX score had a significant impact on the receipt of adjuvant CTX and altered management for 38% of women.

BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 μg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 μg over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 μg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC. Cancer 2010. © 2010 American Cancer Society.

Summary Background Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. Methods We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Findings Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8·94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0·76, 95% CI 0·64–0·91; p=0·002) but only marginally for the secondary endpoint of overall survival (HR 0·83, 0·68–1·01; p=0·057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0·84, 0·70–1·01; p=0·061) or overall survival (HR 0·90, 0·73–1·10; p=0·30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Interpretation Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. Funding National Cancer Institute (US National Institutes of Health).

This retrospective study examined 180 hospice patients referred from a comprehensive cancer center over 6 months in 2002 to (1) identify the variables associated with shorter length of survival (LOS) in hospice and (2) examine the LOS in hospice for those who previously participated in clinical trials and/or phase I studies. The median LOS in hospice for this cohort was 35 days. In multivariate analysis, low Palliative Performance Score (PPS) at hospice enrollment and male gender were associated with shorter LOS in hospice: males with low PPS had the shortest LOS while females with high PPS had the longest LOS. No correlation was found between the LOS in hospice and prior participation in clinical trials and/or phase I studies.

The examination of sequential karyotypes in hematologic disorders has demonstrated that karyotypic changes are often associated with concurrent changes in clinical behavior. Acquired abnormalities that recur among different patients may also suggest genomic areas important to tumor progression. We therefore examined sequential karyotypes in 21 patients with non-Hodgkin lymphoma (NHL). Sixteen of the 21 karyotypes demonstrated changes, including the majority of 6 small lymphocytic, 11 follicular, and 4 intermediate and high-grade diffuse lymphomas. The t(14;18)(q32;q21) occurred in ten initial karyotypes was retained in all cases. The band most frequently affected by newly acquired abnormalities was 14q32 (n = 5); chromosomes 1 and 2 (n = 5, each), and the 17p arm (n = 4) were also commonly affected. The acquired deletion of all or part of 17p appeared to be associated with a poor prognosis. Histologic transformation and karyotypic change did not correlate. This study of sequential karyotypes in NHL 1) confirms the primary importance of the t(14;18), 2) suggests that the 14q32 band is involved frequently in both primary and secondary cytogenetic events, and 3) suggests other genomic regions of potential significance to progression.

Background. To evaluate responses of residents to a hematology/oncology rotation.Methods. A self-administered mail survey among internal medicine residents in a university-based training program who were required to complete a hematology/oncology rotation at a comprehensive cancer center.Results. The majority of the residents rated the duration of the rotation as adequate and quality as excellent or good. It had a positive impact on certain knowledge areas, general opinion about hematology/oncology, preparation for board examination, and motivation to pursue this subspecialty, especially among residents who had performed additional electives.Conclusion. A hematology/oncology rotation received a generally positive evaluation from internal medicine residents.

Purpose: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients. Experimental Design: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m2 as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done. Results: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied. Conclusions: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.

Our objective was to determine the degree with which mammographic features predict the presence and size of invasive carcinomas associated with malignant mammographic microcalcification lesions without a mass.Mammographic features were correlated with pathologic features in 304 consecutive breast carcinomas manifested by mammographic calcifications only in a prospective evaluation.Mammographic calcifications associated with breast carcinoma had the final pathologic diagnoses of pure ductal carcinoma in situ (DCIS) in 65% of patients, DCIS with a focus of invasion in 32%, and invasive carcinoma only in 4%. Invasive foci were more likely associated with mammographic calcification size of 11 mm and greater (40%, 77/194) compared with 1-10 mm (26%, 29/110; p = 0.019). Invasive foci were also more likely associated with linear calcifications (44%, 55/126) compared with granular calcifications (29%, 51/178; p = 0.007). The frequency of invasion did not increase with calcification extents greater than 10 mm. The frequency of invasion ranged from 22% for less than or equal to 5-mm granular calcifications to 45% for linear calcifications of 11 mm and greater. Only 11% of cancers characterized by fine granular calcifications were associated with invasion as compared with 32% of those with coarse and mixed granular calcifications (p = 0.002).Mammographic calcification features of malignant lesions cannot predict the absence of invasion with greater than 90% predictive value or predict the presence of invasion with greater than 45% predictive value. Increased extent of calcifications greater than 10 mm was not associated with greater likelihood of invasion.

The topoisomerase I inhibitor topotecan had demonstrated good antitumor activity in several murine tumor systems and in human clonogenic assays by 1993. In that year, the Cancer and Leukemia Group B (CALGB) began a phase II trial to determine its activity in patients with breast cancer who had previously received one course of chemotherapy for advanced breast cancer. Between April 1993 and June 1994, 53 patients of performance status 0-2 entered the study, of whom 47 were eligible and 40 were evaluable. Topotecan was given at a dose of 1.5 mg/m2 over 30 minutes daily for 5 days every 21 days. In the absence of progression or withdrawal of consent, therapy was continued indefinitely. The median age was 58 years (range 30-79). There were no complete responses and four partial responses, resulting in an objective response rate of 10% (95% CI: 3-24%). Responses were noted in lymph nodes, liver, and skin. The median duration of response was 5 months. The median survival was 12 months. Life-threatening toxicities were almost exclusively hematologic. However, myelosuppression was not cumulative. It was concluded that topotecan has only modest activity among women with advanced breast cancer who have previously received one course of chemotherapy. Given its modest activity and predominant hematologic toxicity, it does not appear to be a promising drug for either single-agent or combination chemotherapy in the salvage setting of advanced breast cancer.

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11 diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1 h i.v. infusion every 12 h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t1/2 of 0.12 h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of > or = 83 mg/m2/day.

Glucocortoid receptor (GR) levels have not been extensively studied in untreated patients with chronic lymphocytic leukemia (CLL). We have measured tumor GR levels using a whole cell assay in 18 untreated patients with CLL and correlated these levels with various in-vitro and in-vivo data. In 12 of these patients, tumor cells from more than one tissue were simultaneously studied. Measurable GR levels were found in all 36 specimens studied with median total GR levels in blood, bone marrow, and lymph nodes being 3018 (n = 17), 3524 (n = 12) and 3102 (n = 7) sites/cell respectively. GR levels did not correlate with in-vitro sensitivity, as measured by inhibition by dexamethasone of radiolabelled leucine, uridine, and thymidine uptake, nor with the clinical or laboratory features examined. Nine patients were treated with dexamethasone as a single agent; blood GR levels were not predictive of antitumor response. We conclude that in patients with CLL, malignant cells from all involved tissues have measurable numbers of GRs, but these are not correlated with in-vitro sensitivity to glucocorticoid. Blood GR levels do not correlate with antitumor response; further studies are required to see if bone marrow or lymph node receptor levels correlate with antitumor response to steroids.

Purpose Patients with non-Hodgkin's lymphoma who fail to achieve a complete remission or who relapse are rarely cured with conventional therapies. For this group of patients, intensive therapy and bone marrow rescue may be curative. Our goal was to assess the effects of autologous transplantation in patients with B-cell lymphomas and a poor prognosis. To avoid occult or overt contamination with lymphoma, monoclonal antibodies BA-1, BA-2, and BA-3 were used for ex vivo marrow treatment. Patients and methods Seventeen patients underwent intensive therapy and autologous bone marrow transplant using the forementioned marrow. Ten of the 17 patients (Group I) had disease that was in complete or partial remission. The other seven patients either had disease that was not responsive to treatment or had bone marrow transplant as their initial therapy at relapse. Results The ex vivo treatment did not adversely affect engraftment. For those patients who could be evaluated, the median time to white cell engraftment was 24 days; the median durations of red cell and platelet support were 24 and 29 days, respectively. Eleven of the 17 patients had complete remissions at the evaluation 28 days after transplant. Three patients subsequently experienced a relapse, three died while their disease was in complete remission, and five are alive and disease-free 405 to 1,674 days after transplant. Group I patients had an estimated 40 percent disease-free survival rate at three years compared with 0 percent for Group II patients (p Conclusion Our data support autologous bone marrow transplantation as an important treatment modality for the non-Hodgkin's lymphomas. With the current preparative regimens available, however, its use should be limited to patients with disease that is still responding to conventional therapies.

Heredity is generally felt to play a minor role in the development of cancer. This review critically examines this assumption. Topics discussed include evidence for heritable predisposition in animals and humans; the potential importance of genetic-environmental interactions; approaches that are being used to successfully locate genes responsible for heritable predisposition; comparability of genetic findings among heritable and corresponding sporadic malignancies; and future research directions. Breast, colon, and lung cancer are used to exemplify clinical and research activity in familial cancer; clinical phenotypes, segregation and linkage analyses, models for environmental interactions with inherited traits, and molecular mechanisms of tumor development are discussed. We conclude that the contribution of heredity to the cancer burden is greater than generally accepted, and that study of heritable predisposition will continue to reveal carcinogenic mechanisms important to the development of all cancers.

Germ cell tumors (GCTs) account for 95% of testicular cancers. Testicular GCTs constitute the most common solid tumor in men between the ages of 20 and 34 years, and the incidence of testicular GCTs has been increasing in the past 2 decades. Testicular GCTs are classified into 2 broad groups--pure seminoma and nonseminoma--which are treated differently. Pure seminomas, unlike nonseminomas, are more likely to be localized to the testis at presentation. Nonseminoma is the more clinically aggressive tumor associated with elevated serum concentrations of alphafetoprotein (AFP). The diagnosis of a seminoma is restricted to pure seminoma histology and a normal serum concentration of AFP. When both seminoma and elements of a nonseminoma are present, management follows that for a nonseminoma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer outline the diagnosis, workup, risk assessment, treatment, and follow-up schedules for patients with both pure seminoma and nonseminoma.

Tumor cytogenetic analysis was done for 68 patients with newly diagnosed non-Hodgkin lymphoma, and recurring cytogenetic abnormalities were correlated with achievement of complete remission, duration of complete remission, and survival. Among all patients, the presence of normal metaphases in tumor material was associated with a higher complete remission rate and longer survival. However, the duration of complete remission did not correlate with the presence or absence of chromosomal changes. Among patients with follicular lymphomas, the presence of normal metaphases in the tumor material was again associated with a higher rate of complete remission and with longer survival. Patients with structural abnormalities of chromosome 17 had a shorter survival than patients without these abnormalities. Among the patients with diffuse large-cell and immunoblastic lymphomas, those with breaks in the short arm of chromosome 2 had a longer survival than those without these breaks. We conclude that chromosomal abnormalities are predictive of clinical outcome in malignant lymphoma.