Does Suture Technique Affect Re-Rupture in Arthroscopic Rotator Cuff Repair? A Meta-analysis.

PURPOSE: To evaluate the effects of suture configuration, repair method, and tear size on rotator cuff (RC) repair healing. METHODS: We conducted a literature search of articles that examined surgical treatment of RC tears published between January 2003 and September 2014. For single-row (SR) repairs, we calculated rerupture rates for simple, mattress, and modified Mason-Allen sutures while stratifying by tear size. All double-row repairs-those using 2 rows of suture anchors (DA) and those using a suture bridge (SB)--were performed using mattress sutures, and we compared rerupture rates by repair method while stratifying by tear size. A random-effects model with pooled estimates for between-study variance was used to estimate the overall rerupture proportion and corresponding 95% confidence interval for each group. Statistical significance was defined as P < .05. RESULTS: A total of 682 RC repairs from 13 studies were included. For SR repairs of tears measuring less than 3 cm, there was no significant difference in rerupture rates for modified Mason-Allen sutures versus simple sutures (P = .18). For SR repairs of tears measuring 3 cm or more, there was no significant difference in rerupture rates for mattress sutures versus simple sutures (P = .23). The rates of rerupture did not differ between SB and DA repairs for tears measuring less than 3 cm (P = .29) and 3 cm or more (P = .50). CONCLUSIONS: For SR repairs, there were no significant differences in rerupture rates between suture techniques for any repair method or tear size. All DA and SB repairs were secured with mattress sutures, and there were no differences in the rates of rerupture between these methods for either size category. These findings suggest that suture technique may not affect rerupture rates after RC repair. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies.

Breast cancer resistance protein (BCRP) and excision repair cross complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy.

BACKGROUND: Esophageal cancer patients face a dismal outcome despite tri-modality management and median survival remains 15-18 months. Breast cancer resistance protein (BCRP) is an ATP-dependent efflux protein associated with chemotherapy resistance. The role of BCRP expression in esophageal cancer and normal esophageal cells is not known. Excision repair cross complement-1 (ERCC1) overexpression has been correlated with poorer response to cisplatin based chemotherapy. We examined the expression of BCRP and ERCC1 in patients with esophageal cancer and correlated it with survival in patients receiving irinotecan and cisplatin based chemotherapy. METHODS: With IRB approval, 40 cases of esophageal cancer diagnosed from 2004-2008, were stained for BCRP and ERCC1 expression by immunohistochemistry and scored by a pathologist blinded to clinical data. Baseline demographics, therapy given and survival data were collected and correlated with BCRP and ERCC1 expression. Fisher's exact test was used to determine association between BCRP and ERCC1 expression and demographics. Cox proportional hazards model was used for association of BCRP and ERCC1 with survival. RESULTS: On immunohistochemistry, 30/40 cancers (75%) expressed BCRP. Interestingly, down-regulation of BCRP expression in tumor compared with normal cells was seen in 40% of patients. ERCC1 positivity was seen in 15/30 cases (50%). Median overall survival (OS) was 19 months with no difference in survival between BCRP positive and negative patients (P=0.13) or ERCC1 positive and negative patients (P=0.85). Estimated hazard ratio (HR) of death for BRCP positive patients was 2.29 (95% CI: 0.79-6.64) and for ERCC1 positive patients was 1.09 (95% CI: 0.46-2.56). There was no association of BCRP and ERCC1 expression with disease stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line chemotherapy, there was no difference in survival based on BCRP or ERCC1 status. CONCLUSIONS: BCRP expression is seen in a majority of esophageal cancers and normal esophageal mucosa. ERCC1 expression is seen in about half of the patients with esophageal cancer. Irinotecan based studies with esophageal and gastric cancer suggest response rates of 14-65%. Whether the 40% of tumors in our study found with down regulation of BCRP expression, constitute a majority of these responders needs to be prospectively validated in a larger data set. It should include markers such as ERCC1 predicting response to 5-fluorouracil and platinum based chemotherapy, to enable individualizing therapy for this cancer.

Management of comorbidities in diabetics with renal cell carcinoma: past utilization and current outcomes.

OBJECTIVES: This study evaluated whether particular diabetes mellitus (DM), hyperlipidemia, or hypertension pharmacotherapy was associated with improved renal cell carcinoma (RCC) outcomes in diabetics with emergent RCC. METHODS: All DM cases newly diagnosed with RCC at Roswell Park Cancer Institute (January 01, 2003-December 31, 2010) were included (n = 95). Baseline demographic information, clinical history, and cancer outcomes were documented after chart review. Fisher's test was used for the analysis of categorical outcomes across different treatment groups. Univariate and multivariate analyses for the comparisons of the overall survival and progression-free survival across treatment groups were assessed using Kaplan-Meier log-rank test and Cox proportional hazards models. RESULTS: We found that DM pharmacotherapy users, which may represent a more advanced disease as compared to those controlled by diet alone, displayed significantly greater mortality (P = .01). Additionally, we found that cholesterol-lowering pharmacotherapy use was associated with decreased RCC mortality (hazard ratio = 0.54, P = .06). Individuals receiving combined hypertension regimens had a lower chance to present with baseline metastasis; however, hypertension pharmacotherapy use added no survival benefit. CONCLUSION: Reinforcing guidelines compliance for hyperlipidemia management in patients with DM may provide a considerable cancer benefit if diagnosed with RCC. Studies evaluating the need for cholesterol-lowering pharmacotherapy in guidelines-noncompliant DM cases upon RCC diagnosis are currently needed.

Computed tomography scans as an objective measure of disease severity in chronic rhinosinusitis.

OBJECTIVES: A truly objective method of measuring disease severity in chronic rhinosinusitis (CRS) has only recently existed. We evaluated computed tomography (CT) scans of CRS patients using this novel objective 3D computerized system and compared results with a novel 2D computerized analysis of a single coronal slice through the osteomeatal complex (OMC) and subjective methods including Lund-Mackay and Zinreich's modified Lund-Mackay. STUDY DESIGN: Prospective multicenter study. SETTING: Two academic tertiary referral centers. SUBJECTS AND METHODS: Forty-six adults with a diagnosis of CRS underwent CT examination and received an intramuscular triamcinolone injection, dosage weight dependent, followed by CT scan 4 to 5 weeks later. Recruitment lasted 21 months. Scans were evaluated with all 4 scoring methods over 5 months. RESULTS: The Lin's concordance class correlation (CCC) of the OMC method revealed the best correlation to the 3D volumetric computerized values (0.915), followed by the Zinreich (0.904) and Lund-Mackay methods (0.824). Posttreatment results demonstrated that both the OMC (0.824) and Zinreich's (0.778) methods had strong agreement with the 3D volumetric methods and were very sensitive to change, whereas the Lund-Mackay (0.545) had only moderate agreement. CONCLUSION: Computerized CT analysis provides the most comprehensive, objective, and reproducible method of measuring disease severity and is very sensitive to change induced by treatment intervention. A 2D coronal image through the OMC provides a valid, user-friendly method of assessing CRS and is representative of CRS severity in all sinuses. Zinreich's subjective method correlated well overall, but the Lund-Mackay method lagged behind in disease representation and sensitivity to change.

Mouse mammary gland is refractory to the effects of ethanol after natural lactation.

Ethanol is a dietary factor that dose-dependently increases breast cancer risk in women. We previously have shown that ethanol increases mammary epithelial density through increased branching after dietary exposure during puberty in CD2/F1 mice. To extend these studies to parous mice in a breast cancer model, we used a transgenic mouse model of human parity-associated breast cancer, the FVB-MMTV-Her2/Neu mouse, which overexpresses wildtype EGFR2, resulting in constitutive activation of growth signaling in the mammary epithelium. Here we describe the short-term effects of ethanol feeding on progression through involution. Mice were fed diets supplemented with 0%, 0.5%, 1%, or 2% ethanol for 4, 9, or 14 d starting on day 21 of lactation (that is, at the start of natural postlactational involution). Unlike peripubertal mice exposed to ethanol, postlactational dams showed no changes in body weight; liver, spleen, and kidney weights; and pathology. Ethanol exposure had no effect on mammary gland lobular density and adipocyte size throughout involution. Likewise, the infiltration of inflammatory cells and serum oxidized lipid species were unchanged by diet, suggesting that ethanol feeding had no effect on local inflammation (leukocyte infiltration) or systemic inflammation (oxidized lipids). In conclusion, ethanol exposure of parous dams had no effect on mammary gland structure or the regression of the lactating mammary gland to a resting state. The period of involution that follows natural lactation appears to be refractory to developmental effects of ethanol on mammary epithelium.

Risk of colorectal adenomas in women with prior breast cancer.

BACKGROUND AND AIMS: Longer life expectancy in patients with prior breast cancer may increase their risk of developing other primary cancers, including colorectal cancer (CRC). Whether the risk of developing CRC in this patient population is higher in comparison to those with no prior cancer remains unclear. The purpose of this study was to compare the prevalence of colorectal adenomas and any CRC in breast cancer survivors with those who have no history of prior cancer and assess any difference with use of antiestrogen therapy. METHODS: We compared the prevalence of colorectal cancer and adenomas in breast cancer survivors with that of a group of matched controls. Eligible survivors were ≤85 years of age; had initially been diagnosed with stage 0, I, II, or III breast cancer; had completed all cancer treatments with the exception of adjuvant antiestrogen therapy; and had no evidence of recurrence on follow-up. We used the screening colonoscopy database at our institution to identify age-, sex-, and race-matched controls with no history of cancer. RESULTS: We identified 302 study-eligible breast cancer survivors and 302 matched controls. No colorectal cancers were found in either group. Forty-one breast cancer survivors and 30 controls had tubular adenomas; four survivors and three controls had villous adenoma; and eight survivors and ten controls had advanced adenoma. Multivariate regression analysis revealed that adjuvant antiestrogen therapy was not significantly associated with an increased risk of advanced adenoma. CONCLUSIONS: The prevalence of colorectal adenomas in breast cancer survivors and controls was similar. Breast cancer survivors, including those receiving adjuvant antiestrogen therapies may follow the colorectal screening guidelines used for average-risk population.

Folate exacerbates the effects of ethanol on peripubertal mouse mammary gland development.

Alcohol consumption is linked with increased breast cancer risk in women, even at low levels of ingestion. The proposed mechanisms whereby ethanol exerts its effects include decreased folate levels resulting in diminished DNA synthesis and repair, and/or acetaldehyde-generated DNA damage. Based on these proposed mechanisms, we hypothesized that ethanol would have increased deleterious effects during periods of rapid mammary gland epithelial proliferation, such as peripuberty, and that folate deficiency alone might mimic and/or exacerbate the effects of ethanol. To test this hypothesis, weight-matched 28-35 day old CD2F1 female mice were pair-fed liquid diets ±3.2% ethanol, ±0.1% folate for 4 weeks. Folate status was confirmed by assay of liver and kidney tissues. In folate deficient mice, no significant ethanol-induced changes to the mammary gland were observed. Folate replete mice fed ethanol had an increased number of ducts per section, due to an increased number of terminal short branches. Serum estrogen levels were increased by ethanol, but only in folate replete mice. These results demonstrate that folate deficiency alone does not mimic the effects of ethanol, and that folate deficiency in the presence of ethanol blocks proliferative effects of ethanol on the mammary ductal tree.

Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma.

Overexpression of the Bcl-2 family of genes results in increased transcription of anti-apoptotic proteins. In vitro data suggest that this may enhance acquired chemoresistance and correlate with extramedullary invasion. This has led to pursuing the Bcl-2 family of proteins as therapeutic targets in several malignant disorders, including multiple myeloma (MM). The impact of novel therapeutic agents such as bortezomib on these molecular markers is not known. We investigated the association between the expression of anti-apoptotic members of the Bcl-2 family and the efficacy of bortezomib in patients with relapsed/refractory MM. Gene expression data generated prospectively from large clinical trials were utilized. Hypothesis testing using a multisample test for equivalence was performed. The association between Bcl-2 expression levels and clinical response was negated in bortezomib-treated patients (p = 0.014), while not so in dexamethasone-treated patients (p = 0.92). Similar results were noted for variant 2 of the Mcl-1 gene (p = 0.003). Results for Bcl-xl did not meet the level of significance. Thus, the importance of the Bcl-2 family of proteins as prognostic markers in MM should be reassessed in the novel therapeutic agent era. Our data suggest that bortezomib may overcome the prognostic effect conferred by overexpression of some of the anti-apoptotic Bcl-2 family of genes in patients with relapsed/refractory MM.

Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of immune activation and antitumour response.

Lenalidomide has demonstrated impressive antileukaemic effects in patients with chronic lymphocytic leukaemia (CLL). The mechanism(s) by which it mediates these effects remain unclear. Clinically, CLL patients treated with lenalidomide demonstrate an acute inflammatory reaction, the tumour flare reaction that is suggestive of an immune activation phenomenon. Samples from CLL patients treated with lenalidomide were used to evaluate its effect on the tumour cell and components of its microenvironment (immune cellular and cytokine). Lenalidomide was unable to directly induce apoptosis in CLL cells in vitro, however it modulated costimulatory (CD80, CD83, CD86) surface molecules on CLL cells in vitro and in vivo. Concurrently, we demonstrated that NK cell proliferation was induced by lenalidomide treatment in patients and correlated with clinical response. Cytokine analysis showed increase in levels of TNF-α post-lenalidomide treatment, consistent with acute inflammatory reaction. Furthermore, the basal cytokine profile (high IL-8, MIG, IP-10 and IL-4 levels and low IL-5, MIP1a, MIP1b, IL12/p70) was predictive of clinical response to lenalidomide. Collectively, our correlative studies provide further evidence that the antileukaemic effect of lenalidomide in CLL is mediated not only through modulation of the leukaemic clone but also through elements of the tumour microenvironment.

Improved survival following surgery and radiation therapy for olfactory neuroblastoma: analysis of the SEER database.

BACKGROUND: Olfactory Neuroblastoma is a rare malignant tumor of the olfactory tract. Reports in the literature comparing treatment modalities for this tumor are limited. METHODS: The SEER database (1973-2006) was queried by diagnosis code to identify patients with Olfactory Neuroblastoma. Kaplan-Meier was used to estimate survival distributions based on treatment modality. Differences in survival distributions were determined by the log-rank test. A Cox multiple regression analysis was then performed using treatment, race, SEER historic stage, sex, age at diagnosis, year at diagnosis and SEER geographic registry. RESULTS: A total of 511 Olfactory Neuroblastoma cases were reported. Five year overall survival, stratified by treatment modality was: 73% for surgery with radiotherapy, 68% for surgery only, 35% for radiotherapy only, and 26% for neither surgery nor radiotherapy. There was a significant difference in overall survival between the four treatment groups (p < 0.01). At ten years, overall survival stratified by treatment modality and stage, there was no significant improvement in survival with the addition of radiation to surgery. CONCLUSIONS: Best survival results were obtained for surgery with radiotherapy.

Effect of 25-hydroxyvitamin D status on serological response to influenza vaccine in prostate cancer patients.

BACKGROUND: Epidemiologic data suggest that there is an association between vitamin D deficiency and influenza infection. We conducted a prospective influenza vaccination study to determine the influence of vitamin D status on serological response to influenza vaccine in prostate cancer (CaP) patients. METHODS: During the 2006-2007 influenza season, CaP patients treated at Roswell Park Cancer Institute were offered vaccination with the trivalent influenza vaccine (Fluzone®, 2006-2007) and sera collected for hemagglutination inhibition (HI) assay titers before and 3 months after vaccination. Response to vaccination was defined as ≥1:40 titer ratio or a fourfold increase in titer at 3 months, against any of the three strains. Serum 25-hydroxyvitamin D (25-D3) levels were measured using DiaSorin ¹²5I radioimmunoassay kits. RESULTS: Thirty-five patients with CaP participated in the study. Median baseline 25-D3 level was 44.88 ng/ml (range: 9.16-71.98 ng/ml) Serological response against any of the three strains was noted in 80%. There was a significant effect of baseline 25-D3 level when tested as a continuous variable in relation to serological response (P = 0.0446). All patients in the upper quartile of 25-D3 level responded by mounting a serological response (P = 0.0344). None of the other baseline variables (age, race, chemotherapy status, or white cell count) had an effect on serological response. CONCLUSIONS: In this study in CaP patients, a replete vitamin D status was associated with more frequent serological response to influenza vaccine.

Does circular stapled esophagogastric anastomotic size affect the incidence of postoperative strictures?

BACKGROUND: Postoperative anastomotic strictures produce significant morbidity after esophagectomy. Previous reports have described a variable association between the diameter of the circular end-to-end anastomosis (EEA) stapler commonly used in esophagogastric anastomoses and the incidence of stricture formation. Stapler technology has improved. We investigated an association between stapler diameter and the incidence of postoperative anastomotic strictures in a contemporary series. This has renewed importance given the limited diameter of trans-oral staplers that are being increasingly used. METHODS: Retrospective chart review revealed that of 194 patients undergoing an esophagectomy over a 10-y period (10/1998-8/2008) at our institution, an EEA stapler was used in 91. EEA size information and follow-up were available in 89 patients. Patients were divided into two groups based on EEA size: 'small' = 23-25 mm (n = 24) and 'large' = 28-33 mm (n = 65). Patients with strictures were identified based on symptoms of dysphagia requiring an esophageal dilation procedure. Patients with postoperative leaks were excluded when analyzing for the association of stricture with EEA size, as postoperative leaks are known to be associated with stricture. Wilcoxon and Fisher's exact tests were used for statistical analysis; a 5% α error was accepted. RESULTS: Fifteen (16.8%) of 89 patients developed a stricture postoperatively. The anastomotic leak rate was 3.3%. There was no statistically significant association between EEA size group and stricture formation (P = 0.7506). CONCLUSIONS: No association was found between the size of the EEA stapler used and stricture formation. EEA size should be determined at surgery by the native esophageal diameter.

Hypoxia-inducible factor-1α protein expression is associated with poor survival in normal karyotype adult acute myeloid leukemia.

We examined the predictive impact of HIF-1α protein expression on clinical outcome of 84 normal karyotype acute myeloid leukemia (NK-AML) patients (median age 66.5 years) at our institute. Thirty percent of NK-AML cells expressed cytoplasmic HIF-1α. In univariate analysis, low HIF-1α (≤ 5%, n = 66) was associated with improved event-free survival (p = 0.0453, HR = 0.22). Multivariate analysis incorporating age, complete remission, FLT3-ITD mutation, and marrow blast percentage demonstrated that HIF-1α was independently associated with poorer overall and event-free survival. HIF-1α expression correlated with VEGF-C but not VEGF-A, marrow angiogenesis, FLT3 ITD or NPM1 mutations. These results support HIF-1α as an outcome marker for NK-AML.

Aflibercept exerts antivascular effects and enhances levels of anthracycline chemotherapy in vivo in human acute myeloid leukemia models.

We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients.

Genomic, immunophenotypic, and NPM1/FLT3 mutational studies on 17 patients with normal karyotype acute myeloid leukemia (AML) followed by aberrant karyotype AML at relapse.

Normal karyotype (NK) is the most common cytogenetic group in acute myeloid leukemia (AML) diagnosis; however, up to 50% of these patients at relapse will have aberrant karyotype (AK) AML. To determine the etiology of relapsed AK AML cells, we evaluated cytogenetic, immunophenotypic, and molecular results of 17 patients with diagnostic NK AML and relapsed AK AML at our institute. AK AML karyotype was diverse, involving no favorable and largely (8 of 17) complex cytogenetics. Despite clear cytogenetic differences, immunophenotype and NPM1/FLT3 gene mutation status did not change between presentation and relapse in 83% (10 of 12) and 94% (15 of 16) cases, respectively. High-resolution array-based comparative genomic hybridization (aCGH) performed via paired aCGH on NK AML and AK AML samples from the same patient confirmed cytogenetic aberrations only in the relapse sample. Analysis of 16 additional diagnostic NK AML samples revealed no evidence of submicroscopic aberrations undetected by conventional cytogenetics in any case. These results favor evolution of NK AML leukemia cells with acquisition of novel genetic changes as the most common etiology of AK AML relapse as opposed to secondary leukemogenesis. Additional studies are needed to confirm whether AK AML cells represent selection of rare preexisting clones below aCGH detection and to further characterize the molecular lesions found at time of AK AML relapse.

Analysis of second primary lung cancers in the SEER database.

BACKGROUND: We sought to examine the outcomes of second primary lung cancers in the large population-based Surveillance Epidemiology and End Results (SEER) database. We also sought to study the outcomes of synchronous second non-small-cell lung cancers (NSCLCs), classified as stage IVA (M1A) according to the seventh edition of the TNM staging for lung cancer. METHODS: Data of patients with at least two primary lung cancers were obtained. All available variables potentially associated with the incidence of a second primary lung cancer were examined. The overall survival of patients with synchronous NSCLC was compared with those with metachronous and stage IV NSCLC. RESULTS: A small proportion (1.5%) of patients with lung cancer developed a second primary. A second primary is associated with younger age, female gender, earlier stage, and white race. The median survival of patients with metachronous NSCLCs (n = 3352) was worse than those with synchronous NSCLCs (n = 1858) (median survival 22 mo versus 29 mo, respectively; P < 0.01). After adjusting for age, race, gender, stage, and histology of both primaries, this difference in survival between patients with synchronous and metachronous second primary lung cancers was not statistically significant, but was better than those with stage IV NSCLC (n = 127,654; median survival 4 mo). CONCLUSIONS: The incidence of second primary lung cancer is lower than that previously reported. Factors associated with good prognosis predict a second primary. Synchronous NSCLCs have an outcome better than a stage IV (M1a) designation. These patients should receive appropriate stage-specific multi-modality therapy suitable for the independent stage of each cancer without considering them unresectable.

Increasing age and treatment modality are predictors for subsequent diagnosis of bladder cancer following prostate cancer diagnosis.

PURPOSE: To determine the effect of prostate cancer therapy (surgery or external beam irradiation, or both or none) on the actuarial incidence of subsequent bladder cancer. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results registry from 1973 to 2005 was analyzed. Treatment was stratified as radiotherapy, surgery, both surgery and adjuvant radiation, and neither modality. Brachytherapy was excluded. RESULTS: In all, 555,337 prostate carcinoma patients were identified; 124,141 patients were irradiated; 235,341 patients were treated surgically; 32,744 patients had both surgery and radiation; and 163,111 patients received neither modality. Bladder cancers were diagnosed in: 1,836 (1.48%) men who were irradiated (mean age, 69.4 years), 2,753 (1.09%) men who were treated surgically (mean age, 66.9 years); 683 (2.09%) men who received both modalities (mean age, 67.4 years), and 1,603 (0.98%) men who were treated with neither modality (mean age, 71.8 years). In each treatment cohort, Kaplan-Meier analyses showed that increasing age (by decade) was a significant predictor of developing bladder cancer (p < 0.0001). Incidence of bladder cancer was significantly different for either radiation or surgery alone versus no treatment, radiation versus surgery alone, and both surgery and radiation versus either modality alone (p < 0.0001). On multivariate analysis, age and irradiation were highly significant predictors of being diagnosed with bladder cancer. CONCLUSIONS: Following prostate cancer, increasing age and irradiation were highly significant predictors of being diagnosed with bladder cancer. While use of radiation increased the risk of bladder cancer compared to surgery alone or no treatment, the overall incidence of subsequent bladder cancer remained low. Routine bladder cancer surveillance is not warranted.

Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer.

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 microg 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 microg 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 microg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC.

KRAS status and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFOX chemotherapy.

BACKGROUND: Two previous first-line studies showed an improved trend in response rate (RR) and progression free survival (PFS) in metastatic colorectal cancer (CRC) patients with KRAS mutation. Others have reported a worsened outlook for metastatic CRC patients with KRAS mutation and a higher likelihood of metastatic disease to the lungs. In this study, we aimed to address the impact of KRAS on the pattern of metastatic disease at presentation and on RR and PFS with first-line 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. METHODS: Patients with CRC who underwent KRAS testing using DxS assay at Roswell Park Cancer Institute (RPCI) were identified. Patients with metastatic CRC treated with first-line FOLFOX +/- bevacizumab were assessed for response and survival using RECIST 1.1 guidelines. A two-sided Fisher's exact test was used to determine the statistical significance. RESULTS: 181 patients with metastatic CRC and KRAS testing were identified. 83/181 patients were treated with FOLFOX (+/- bevacizumab) in the first-line setting at RPCI and were evaluable as per study guidelines. KRAS mutation (MT) occurred in 40.31% cases. There was no difference in organ-metastases distribution, RR (56.60% in KRAS wild-type (WT) and 50% in KRAS mutant) or PFS (9.3 months KRAS WT and 8.7 months in KRAS MT) based on KRAS status. CONCLUSION: In this single institute study, our findings do not support any predictive role for KRAS-MT in terms of response to FOLFOX first-line chemotherapy, or in terms of sites of metastatic disease at mCRC presentation.

Extent of disease burden determined with magnetic resonance imaging of the bone marrow is predictive of survival outcome in patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable cancer. Treatment often is initiated at the time patients experience a progressive increase in tumor burden. The authors of this report investigated magnetic resonance imaging of the bone marrow (BM-MRI) as a novel approach to quantify disease burden and validated a staging system by correlating BM-MRI with common clinical and laboratory parameters. METHODS: The extent of bone marrow involvement was evaluated by BM-MRI. Clinical and laboratory parameters were assessed in patients with active MM, and correlations between variables were assessed statistically. Bone marrow involvement by BM-MRI was defined as stage A (0%), stage B (<10%), stage C (10%-50%), and stage D (>50%). RESULTS: In total, 170 consecutive patients were evaluated (77 women and 93 men), including 144 patients who had active MM. The median age was 61 years (age range, 35-83 years). Advance stage disease (stage >I) based on Durie-Salmon (DS) staging or International Staging System (ISS) criteria was observed in 122 patients (84%) and 77 patients (53%), respectively. Lytic bone disease was noted in 120 patients (83%). There was a significant association between BM-MRI involvement and DS stage (P = .0006), ISS stage (P = .0001), the presence of lytic bone disease (P < .0001) and mean beta-2 microglobulin levels (P < .0001). Among the patients with previously untreated MM, there was a significant association between BM-MRI stage and overall survival (OS) (univariate P = .013; multivariate P = .045). Plasmacytosis on bone marrow biopsy at diagnosis was not predictive of OS (P = .91). CONCLUSIONS: BM-MRI is a novel approach for quantifying disease burden in patients with MM. The current investigation in a large cohort of nontransplantion MM patients demonstrated that the extent of bone marrow involvement determined by BM-MRI correlates accurately with other conventional parameters of disease burden and can independently predict survival in patients with MM at the time of initial diagnosis.