Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms.

Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) monoclonal antibody, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly-differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% confidence interval [CI]: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5% and 0%, respectively, and the 12-month overall survival was 73.5% and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort is encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.

Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma.

PURPOSE: Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term. METHODS: In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis-free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model. RESULTS: At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration. CONCLUSION: Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

Autoimmune comorbidities in patients with metastatic melanoma: a retrospective analysis of us claims data.

BACKGROUND: Immunotherapies have advanced the treatment of metastatic melanoma; however, they are associated with immune-related toxicities. Patients with pre-existing autoimmune comorbidities are commonly excluded from clinical trials investigating immunotherapies in metastatic melanoma. Since information on pre-existing autoimmune comorbidities in "real-world" patients with newly diagnosed metastatic melanoma is limited, we sought to estimate the prevalence of autoimmune comorbidities and its change over time. METHODS: Data were obtained from a large US claims database, MarketScan®, from 2004 to 2014. Records of patients with newly diagnosed metastatic or non-metastatic melanoma and of general population were analyzed. Autoimmune comorbidities were defined as presence of autoimmune disorders, which were obtained from the list of diseases at the American Autoimmune-Related Diseases Association web portal ( www.aarda.org ). The prevalence of pre-existing autoimmune comorbidities and its change over the 11-year period were calculated. Logistic regression analyses were performed to evaluate the relationship between clinical and demographic factors and pre-existing autoimmune comorbidities in patients with metastatic melanoma. RESULTS: This study assessed the prevalence and change of prevalence over a period of 11 years of 147 autoimmune comorbidities. Among 12,028 patients with newly diagnosed metastatic melanoma, the prevalence rate of pre-existing autoimmune comorbidities increased from 17.1% in 2004 to 28.3% in 2014 (P < 0.001). The prevalence rates of autoimmune comorbidities increased from 11.7% in 2004 to 19.8% in 2014 in patients with non-metastatic melanoma and 7.9% in 2004 to 9.2% in 2014 in the general population. In addition, patients with bone or gastrointestinal melanoma metastases, those with more comorbid diseases, or female patients, were found to have a higher risk of autoimmune comorbidities. CONCLUSIONS: The prevalence of pre-existing autoimmune comorbidities in patients with newly diagnosed metastatic melanoma was high, and increased over 11 years. In comparison, a lower prevalence of autoimmune comorbidities was seen in patients with newly diagnosed non-metastatic melanoma and in the general population. Increases in prevalence for these population groups were also observed over 11 years. Impact of autoimmune comorbidities on treatment decisions in patients with metastatic melanoma should be explored.

Phase I Trial of Dose-escalated Whole Liver Irradiation With Hepatic Arterial Fluorodeoxyuridine/Leucovorin and Streptozotocin Followed by Fluorodeoxyuridine/Leucovorin and Chemoembolization for Patients With Neuroendocrine Hepatic Metastases.

OBJECTIVES: We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response. MATERIALS AND METHODS: From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization. RESULTS: Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively. CONCLUSIONS: Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials.

BACKGROUND: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. METHODS: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). RESULTS: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025). CONCLUSIONS: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00769704 ( https://clinicaltrials.gov/ct2/show/NCT00769704 ) October 7, 2008.

Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma.

BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016.

Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial.

PURPOSE: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma. METHODS: Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. RESULTS: T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. CONCLUSIONS: Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC.

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis.

INTRODUCTION: Isolated limb perfusion and infusion (ILP/ILI) are therapies for regional metastatic melanoma that allow high doses of anticancer drugs to be delivered directly into the circulation of an affected limb, thereby minimizing systemic drug toxicity. This procedure can lead to high response rates and is recommended in patients with Stage III unresectable metastatic melanoma. However, limited information is available on patterns of use and costs. This study examined patterns of ILP/ILI use and associated costs in patients with melanoma in the United States (US). METHODS: Retrospective, observational study, using administrative claims data from the MarketScan(®) databases, was performed in patients with a diagnosis of melanoma (ICD-9-CM: 172.xx, V10.82) who underwent ILP/ILI (CPT-4: 36823) between January 1, 2002 and March 31, 2013. Patient characteristics, use patterns, length of hospital stay, and costs (per 2014 US $) of ILP/ILI were assessed. RESULTS: One hundred and thirteen patients met the study criteria and were included in the analysis. Mean age was 61.4 years (standard deviation [SD] 13.8) and 38.9% of patients were male; the mean baseline Charlson Comorbidity Index was 0.19; 34.5% of patients were Medicare beneficiaries. The majority of patients (87.6%) had melanoma of the lower limb, 11.5% of the upper limb, and 0.9% of both limbs; 60.2% had lymph node metastasis and 56.6% had skin metastasis. Four patients (3.5%) underwent multiple ILP/ILI. The mean (± SD) length of hospital stay was 5.6 (± 3.5) days and the mean (± SD) cost was US$36,758 (± 27,124) per ILP/ILI procedure. CONCLUSIONS: Isolated limb perfusion and infusion in patients with melanoma were associated with long hospital stays and high costs. These results provide useful source data for the economic evaluation of treatment options for regional metastatic melanoma. FUNDING: This study was funded by Amgen, Inc.

Treatment Outcomes in Very High-risk Prostate Cancer Treated by Dose-escalated and Combined-Modality Radiation Therapy.

OBJECTIVES: The aim of this study was to report treatment outcomes in patients with very high-risk prostate cancer (VHRPC) treated with dose-escalated radiotherapy. METHODS: We conducted a retrospective multi-institutional review on patients with VHRPC (those with at least 2 high-risk factors of prostate-specific antigen >20 ng/mL, Gleason score 8 to 10, or clinical T3 to T4 stage), treated with either dose-escalated external-beam radiotherapy (EBRT) or combined-modality radiotherapy (CMRT) consisting of pelvic irradiation and permanent interstitial brachytherapy. RESULTS: A total of 238 patients with VHRPC were identified. Of them, 69% of patients received EBRT and 31% received CMRT; 88% received androgen-deprivation therapy (ADT), 56% for ≥24 months (long-term ADT). The majority (69%) of patients were above 65 years old and were less likely to receive CMRT than younger patients (25% vs. 43%, P=0.006), although they did not differ from younger patients in tumor characteristics. Median follow-up was 61 months (interquartile range, 38 to 93 mo). Biochemical progression-free survival (BPFS), distant metastasis-free survival (DMFS), and cancer-specific survival (CSS) for all patients at 8 years were (±SE): 50.6%±4.7%, 68.5%±4.3%, 78.7%±3.8%, respectively, and were similar for patients 65 years and below versus above 65 years old (BPFS: HR=0.88, P=0.56; DMFS: HR=0.79, P=0.40; CSS HR=0.99, P=0.99). After adjustment for patient, tumor, and treatment-related covariates on multivariate analysis, CMRT was associated with improved BPFS (HR=0.44, P=0.012) with trends for DMFS (HR=0.52, P=0.10) and CSS (HR=0.55, P=0.21), whereas long-term ADT was independently associated with improved BPFS (HR=0.40, P=0.019), CSS (HR=0.20, P=0.002), and PCSM (HR=0.25, P=0.004). CONCLUSIONS: Dose-escalated EBRT or CMRT with long-term ADT resulted in favorable clinical outcomes for patients with VHRPC.

Development and validation of a novel platform-independent metastasis signature in human breast cancer.

PURPOSE: The molecular drivers of metastasis in breast cancer are not well understood. Therefore, we sought to identify the biological processes underlying distant progression and define a prognostic signature for metastatic potential in breast cancer. EXPERIMENTAL DESIGN: In vivo screening for metastases was performed using Chick Chorioallantoic Membrane assays in 21 preclinical breast cancer models. Expressed genes associated with metastatic potential were identified using high-throughput analysis. Correlations with biological function were determined using the Database for Annotation, Visualization and Integrated Discovery. RESULTS: We identified a broad range of metastatic potential that was independent of intrinsic breast cancer subtypes. 146 genes were significantly associated with metastasis progression and were linked to cancer-related biological functions, including cell migration/adhesion, Jak-STAT, TGF-beta, and Wnt signaling. These genes were used to develop a platform-independent gene expression signature (M-Sig), which was trained and subsequently validated on 5 independent cohorts totaling nearly 1800 breast cancer patients with all p-values < 0.005 and hazard ratios ranging from approximately 2.5 to 3. On multivariate analysis accounting for standard clinicopathologic prognostic variables, M-Sig remained the strongest prognostic factor for metastatic progression, with p-values < 0.001 and hazard ratios > 2 in three different cohorts. CONCLUSION: M-Sig is strongly prognostic for metastatic progression, and may provide clinical utility in combination with treatment prediction tools to better guide patient care. In addition, the platform-independent nature of the signature makes it an excellent research tool as it can be directly applied onto existing, and future, datasets.

Expression of ribonucleoside reductase subunit M1, but not excision repair cross-complementation group 1, is predictive in muscle-invasive bladder cancer treated with chemotherapy and radiation.

The aim of this study was to determine the prognostic and predictive values of ribonucleoside reductase subunit M1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) expression in patients with muscle-invasive bladder cancer treated with chemoradiotherapy. The expression of RRM1 and ERCC1 in pretreatment tumor samples of retrospectively identified patients was determined by immunohistochemical analysis. A total of 39 patients were included in this study; 49% were treated with neoadjuvant chemotherapy and 67% with concomitant chemoradiotherapy; 56% were treated with gemcitabine-based and 51% with platinum-based chemoradiotherapy. The median follow-up was 19 months (interquartile range, 11-50 months). Based on the immunohistochemical analysis, 44 and 32% of the tumors exhibited increased expression of RRM1 and ERCC1, respectively. The complete response (CR) and local recurrence rates following chemoradiotherapy were 79 and 21%, respectively. A low expression of RRM1 was associated with a higher rate of CR to chemoradiotherapy (95 vs. 57%, P=0.012); however, there was no such association with low ERCC1 expression (67 vs. 84%, P=0.39). RRM1 expression predicted an improved CR in patients treated with gemcitabine-based chemoradiotherapy (57 vs. 100%, P=0.036), but not in those treated with other agents (56 vs. 88%, P=0.29). ERCC1 expression was not found to be correlated with CR (67 vs. 84%, P=0.39), even when restricted to patients treated with platinum agents (71 vs. 75%, P=1.0). In the univariate analysis, RRM1 expression, but not ERCC1 expression, was identified as a prognostic marker for worse cancer-specific survival in all the patients and in those treated with gemcitabine-based regimens. No independent prognostic factor was identified in the multivariate model, which included tumor stage, vascular invasion, hydronephrosis and RRM1 status. Although these findings require further validation, they suggest that RRM1 may be a beneficial stratification variable for the selection of chemotherapy regimens for chemoradiotherapy, with patients with low RRM1 expression being considered suitable for gemcitabine treatment.

A prostate-specific antigen doubling time of <6 months is prognostic for metastasis and prostate cancer-specific death for patients receiving salvage radiation therapy post radical prostatectomy.

BACKGROUND: The ideal prostate-specific antigen (PSA) doubling time (PSADT) threshold for identifying patients at high-risk for poor clinical outcome following salvage radiation therapy (SRT) has not been well established. We sought to assess what PSADT threshold is most clinically prognostic in this setting. METHODS: 575 patients who received SRT at a single institution for biochemical recurrence after radical prostatectomy were retrospectively reviewed. We assessed the impact of pre-SRT PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality (OM). Kaplan-Meier methods, hazard ratio (HR) assessment, and Cox Proportional Hazard models were used to assess the discriminatory ability of various PSADT thresholds. RESULTS: Sufficient data to calculate PSADTs were available for 277 patients. PSADT was prognostic for BF, DM, PCSM, and OM on univariate analysis regardless of threshold. HR assessment identified 6 months as a strong threshold. No statistically significant difference was observed in BF, DM, PCSM, or OM between patients with PSADT <3 (n=40) and 3-6 months (n=61) or between 6-10 (n=62) and >10 months (n=114). However significant differences were seen in BF (HR:2.2, [95%CI: 1.4-3.5], p<0.01) and DM (HR:2.2, [95%CI: 1.2-4.3], p=0.02) between a PSADT of 3-6 and 6-10 months. On multivariate analysis a PSADT <6 months predicted BF (HR:2.0, [95%CI: 1.4-2.9], p=0.0001), DM (HR:2.0, [95%CI: 1.2-3.4], p=0.01), and PCSM (HR:2.6, [95%CI: 1.1-5.9], p=0.02). CONCLUSIONS: A pre-SRT PSADT <6 months was a strong predictor of outcomes in our data set, including PCSM. The most common nomogram for SRT uses a 10-month PSADT threshold for assigning points used to assess BF following SRT. If validated, our findings suggest that a PSADT threshold of <6 months should be considered for stratification of patients in future clinical trials in this setting.

Interval to biochemical failure predicts clinical outcomes in patients with high-risk prostate cancer treated by combined-modality radiation therapy.

PURPOSE: To validate the prognostic value of interval to biochemical failure (IBF) in patients with high-risk prostate cancer (HiRPCa) treated with combined-modality radiation therapy (CMRT) with or without androgen deprivation therapy (ADT). METHODS AND MATERIALS: We conducted a retrospective review of HiRPCa (prostate-specific antigen >20 ng/mL, Gleason score [GS] 8-10, or clinical T stage T3-T4) treated with either dose-escalated external beam radiation therapy (EBRT) or CMRT. Interval to biochemical failure was classified as ≤18 or >18 months from the end of all therapy to the date of biochemical failure (BF). Kaplan-Meier methods and Cox proportional hazards regression were used to evaluate the prognostic value of IBF ≤18 months for distant metastasis (DM) and prostate cancer-specific mortality (PCSM). RESULTS: Of 958 patients with a median follow-up of 63.2 months, 175 patients experienced BF. In those with BF, there were no differences in pretreatment clinical characteristics between the EBRT and CMRT groups, except for a higher proportion of patients with GS 8-10 in the CMRT group (70% vs 52%, P=.02). Median IBF after all therapy was 24.0 months (interquartile range 9.6-46.0) in the EBRT group and 18.9 months (interquartile range 9.2-34.5) in the CMRT group (P=.055). On univariate analysis, IBF ≤18 months was associated with increased risk of DM and PCSM in the entire cohort and the individual EBRT and CMRT groups. On multivariate analysis, only GS 9-10 and IBF ≤18 months, but not the radiation therapy regimen or ADT use, predicted DM (hazard ratio [HR] 3.7, P<.01, 95% confidence interval [CI] 1.4-10.3 for GS 9-10; HR 3.9, P<.0001, 95% CI 2.4-6.5 for IBF ≤18 months) and PCSM (HR 14.8, P<.009, 95% CI 2.0-110 for GS 9-10; HR 4.4, P<.0001, 95% CI 2.4-8.1 for IBF ≤18 months). CONCLUSIONS: Short IBF was highly prognostic for higher DM and PCSM in patients with HiRPCa. The prognostic value of IBF for DM and PCSM was not affected by the radiation therapy regimen or ADT use.

The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.

BACKGROUND: The objective of this study was to determine whether the addition of low-dose-rate brachytherapy or androgen-deprivation therapy (ADT) improves clinical outcome in patients with high-risk prostate cancer (HiRPCa) who received dose-escalated radiotherapy (RT). METHODS: Between 1995 and 2010, 958 patients with HiRPCa were treated at Schiffler Cancer Center (n = 484) or at the University of Michigan (n = 474) by receiving either dose-escalated external-beam RT (EBRT) (n = 510; minimum prescription dose, 75 grays [Gy]; median dose, 78 Gy) or combined-modality RT (CMRT) consisting of (103) Pd implants (n = 369) or (125) I implants (n = 79) both with pelvic irradiation (median prescription dose, 45 Gy). The cumulative incidences of biochemical failure (BF) and prostate cancer-specific mortality (PCSM) were estimated by using the Kaplan-Meier method and Fine and Gray regression analysis. RESULTS: The median follow-up was 63.2 months (interquartile range, 35.4-99.0 months), and 250 patients were followed for >8 years. Compared with CMRT, patients who received EBRT had higher prostate-specific antigen levels, higher tumor classification, lower Gleason sum, and more frequent receipt of ADT for a longer duration. The 8-year incidence BF and PCSM among patients who received EBRT was 40% (standard error, 38%-44%) and 13% (standard error, 11%-15%) compared with 14% (standard error, 12%-16%; P < .0001) and 7% (standard error 6%-9%; P = .003) among patients who received CMRT. On multivariate analysis, the hazard ratios (HRs) for BF and PCSM were 0.35 (95% confidence interval [CI], 0.23-0.52; P < .0001) and 0.41 (95% CI, 0.23-0.75; P < .003), favoring CMRT. Increasing duration of ADT predicted decreased BF (P = .04) and PCSM (P = .001), which was greatest with long-term ADT (BF: HR, 0.33; P < .0001; 95% CI, 0.21-0.52; PCSM: HR, 0.30; P = .001; 95% CI, 0.15-0.6) even in the subgroup that received CMRT. CONCLUSIONS: In this retrospective comparison, both low-dose-rate brachytherapy boost and ADT were associated with decreased risks of BF and PCSM compared with EBRT.

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes.

Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.

Secondary malignancies in survivors of breast cancer: how to overcome the risk.

Secondary radiation-induced cancers (SRIC) are rare but well-documented as long-term side effects of radiation in a large population of breast cancer survivors. The estimate of the standardized incidence ratio is 1.2, increasing with time elapsed from irradiation, and influenced by age, genetic and environmental backgrounds of the patient and systemic treatments. The majority of SRIC occurs in or close to high-dose treatment volume in the intermediate dose level. It is a dose- and rate-dependent phenomenon that rarely occurs in tissues with a cumulative dose of <3.5Gy. Careful patient selection, thorough treatment planning and modern radiation equipment can reduce the dose to the surrounding tissues and decrease the incidence of SRIC.

Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience.

The following is a report on the clinical experience of an Israeli referral center for iodine-131 metaiodobenzylguanidine (131-MIBG) therapy for malignant pheochromocytoma (MPCC) and malignant paraganglioma (MPGG). The charts of 10 patients with MPCC (n = 7) and MPGG (n = 3) treated between 2000 and 2008 were reviewed. Response to 131-MIBG therapy was evaluated by tumor, hormone, and symptomatic relief criteria. The median follow-up was 18 months (2-48 months). The number of 131-MIBG treatments ranged from 1 to 4 (mean: 2.1). The average single dose of 131-MIBG was 5.4 +/- 0.2 GBq (145 +/- 5.0 mCi). The average cumulative dose was 11.6 +/- 1.6 GBq (310 +/- 44.0 mCi). There were no complete responses. Three patients (30%) had partial tumor response, 5 (50%) had stable disease, and 2 (20%) progressed after therapy. Five patients (50%) experienced symptomatic response. Hormone response was noted in 5 patients (50%). Progression-free survival was 17.5 months (2-47 months). One patient (10%) had thrombocytopenia and 2 patients (20%) developed subclinical hypothyroidism. Hormonal and symptomatic relief can be achieved with 131-MIBG therapy in patients with MPCC and MPGG with minor side effects.

Functional and developmental properties of human embryonic stem cells-derived cardiomyocytes.

Cardiovascular diseases are the most frequent cause of death in the industrialized world, with the main contributor being myocardial infarction. Given the high morbidity and mortality rates associated with congestive heart failure, the shortage of donor hearts for transplantation, complications resulting from immunosuppression, and long-term failure of transplanted organs, regeneration of the diseased myocardium by cell transplantation is an attractive therapeutic modality. Because it is desired that the transplanted cells fully integrate within the diseased myocardium, contribute to its contractile performance, and respond appropriately to various physiological stimuli (eg, beta-adrenergic stimulation), our major long-term goal is to investigate the developmental changes in functional properties and hormonal responsiveness of human embryonic stem cells-derived cardiomyocytes (hESC-CM). Furthermore, because one of the key obstacles in advancing cardiac cell therapy is the low differentiation rate of hESC into cardiomyocytes, which reduces the clinical efficacy of cell transplantation, our second major goal is to develop efficient protocols for directing the cardiomyogenic differentiation of hESC in vitro. To accomplish the first goal, we investigated the functional properties of hESC-CM (<90 days old), respecting the contractile function and the underlying intracellular Ca(2+) handling. In addition, we performed Western blot analysis of the key Ca(2+)-handling proteins SERCA2, calsequestrin, phospholamban and the Na(+)/Ca(2+) exchanger. Our major findings were the following: (1) In contrast to the mature myocardium, hESC-CM exhibit negative force-frequency relationships and do not present postrest potentiation. (2) Ryanodine and thapsigargin do not affect the [Ca(2+)](i) transient and contraction, suggesting that, at this developmental stage, the contraction does not depend on sarcoplasmic reticulum Ca(2+) release. (3) In agreement with the finding that a voltage-dependent Ca(2+) current is present in hESC-CM and contributes to the mechanical function, verapamil completely blocks contraction. (4) Although hESC-CM express SERCA2 and Na(+)/Ca(2+) exchanger at levels comparable to those of the adult human myocardium, calsequestrin and phospholamban are not expressed. (4) In agreement with other reports, hESC-CM are responsive to beta-adrenergic stimulation. These findings show that the mechanical function related to intracellular Ca(2+) handling of hESC-CM differs from the adult myocardium, probably because of immature sarcoplasmic reticulum capacity.