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Supplementary Figure Legends - PDF file 86K, Description of supplementary figures

CXCR4 is a chemokine receptor that mediates invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive prostate cancer phenotypes. Previously, we and others have shown that the transcription factor ERG regulates CXCR4 expression in prostate cancer cells and that androgens modulate CXCR4 expression via increasing ERG expression. Herein, the molecular mechanisms of ERG-mediated CXCR4 promoter activation, phosphorylation of ERG by intracellular kinases and subsequent CXCR4 expression, as well as the status of ERG and CXCR4 in human prostate cancer specimens were investigated. Using multiple molecular strategies, it was demonstrated that (i) ERG expressed in TMPRSS2-ERG fusion positive VCaP cells selectively binds to specific ERG/Ets bindings sites in the CXCR4 promoter; (ii) distal binding sites mediate promoter activation; (iii) exogenously expressed ERG promotes CXCR4 expression; (iv) ERG is phosphorylated at Serine-81 and -215, by both IKK and Akt kinases, and Akt mediates CXCR4 expression; (v) ERG-induced CXCR4 drives CXCL12-dependent adhesion to fibronectin; and (vi) ERG and CXCR4 were coexpressed in human prostate cancer tissue, consistent with ERG-mediated transcriptional activation of CXCR4. These data demonstrate that ERG activates CXCR4 expression by binding to specific ERG/Ets responsive elements and via intracellular kinases that phosphorylate ERG at discrete serine residues.Implications: These findings provide a mechanistic link between TMPRSS2-ERG translocations and intracellular kinase-mediated phosphorylation of ERG on enhanced metastasis of tumor cells via CXCR4 expression and function in prostate cancer cells. Mol Cancer Res; 11(11); 1349–61. ©2013 AACR.

Supplementary Data - PDF file 589K, S1. Mutations in putative Ets/ERG binding sites in CXCR4 promoter oigos diminishes oligo binding with either VCaP cell nuclear extracts or in vitro translated ERG protein. S2. ERG ChIP seq analysis of VCaP cells. S3. N-terminus deletion of ERG regulates CXCR4 promoter activation similar to full length ERG protein. S4. LNCaP cells were transfected with ARR2Pb-LUC as a vector control and ARR2Pb-ERG-LUC plasmid. S5. MS3 spectrum of trypsin-digested, TiO2 eluted ERG peptides from VCaP cells

Supplementary Table 1 Pharmacokinetic parametersa of veliparib and its main metabolite (A- 925088) when veliparib was given orally alone on cycle 2 day -1 or in combination with irinotecan on cycle 2 day 8

Purpose:Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0–2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured.Results:Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of −56% (range, −85 to −5%, n = 11) and −41% (range, −60 to −25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or Conclusions:Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

Supplementary Figure Legends

Table S1. Baseline patient characteristics Table S2 Rank Correlations of Percent Change in Imaging with Percent Change in Bone Markers

Supplementary Figure S2. Dose-exposure relationships.

Supplementary Methods, including numbered supplementary methods figures and figure legends

Supplementary Table 2 Pharmacokinetic parametersa of irinotecan and its main active metabolite SN-38 when irinotecan was administered as a 1.5-h intravenous infusion (100 mg/m2) alone on cycle 1 day 1 or in combination with veliparib on cycle 2 day 8

Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor–mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan.Experimental Design: Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10–50 mg) occurred on days 3 to 14 (cycle 1) and days −1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1).Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone.Conclusions: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227–37. ©2016 AACR.

Supplementary Figures and Tables

Supplementary Figure Legends

Supplementary Figure S4. Assessment of pNBS1 in the exploratory multiplex immunofluorescence assay.

Supplementary Figure S3. pNBS1 staining post-combination treatment is limited to tumor cells.

Introduction In the era of MRI-guided external beam radiation therapy (EBRT), complete radiological response (CR) is often seen in cervical cancer (CC) with 4-6 weeks of chemotherapy and EBRT. The clinical and radiological factors associated with this observation were investigated in this study. Materials and methods One hundred and twenty-four CC patients treated with concurrent chemotherapy, EBRT, and brachytherapy (BT) from January 2008 to July 2015 were retrospectively screened. Initial primary gross tumor volume (GTV

Purpose This study aimed to evaluate a combination of radiation therapy (RT), androgen deprivation therapy (ADT), and pexidartinib (colony-stimulating factor 1 receptor [CSF1R]) inhibitor in men with intermediate- and high-risk prostate cancer. CSF1R signaling promotes tumor infiltration and survival of tumor-associated macrophages, which in turn promote progression and resistance. Counteracting protumorigenic actions of tumor-associated macrophages via CSF1R inhibition may enhance therapeutic efficacy of RT and ADT for prostate cancer. Methods and Materials In this phase 1 study, the treatment regimen consisted of pexidartinib (800 mg, administered as a split-dose twice daily) and ADT (both for a total of 6 months), and RT that was initiated at the start of month 3. RT volumes included the prostate and proximal seminal vesicles. The delivered dose was 7920 cGy (180 cGy per fraction) using intensity modulated RT with daily image guidance for prostate localization. The primary objective was to identify the maximum tolerated dose based on dose-limiting toxicities. Results All 4 enrolled patients who were eligible to receive RT had T1 stage prostate cancer, 2 were intermediate risk, and 2 were high risk. The median age was 62.5 years, and the prostate-specific antigen levels were in the range 6.4 to 10.7 ng/mL. The patients’ individual Gleason scores were 3 + 3, 4 + 3, 4 + 4, and 4 + 5. All 4 patients reported ≥1 adverse events before RT. Grade 1 hypopigmentation was observed in 1 patient, and grade 3 pulmonary embolus in another. One patient experienced fatigue and joint pain, and another elevated amylase and pruritus (all grade 3 toxicities). Five of the 6 adverse events noted in 3 patients were all grade 3 toxicities attributable to pexidartinib, qualifying as dose-limiting toxicities and ultimately resulting in the study closure. Conclusions The combination was not well tolerated and does not warrant further investigation in men with intermediate- and high-risk prostate cancer.

To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUVmean was derived using an isocontour ROI drawn approximately half way between the SUVmax and background on three planes for each scan. The change in mean standardized uptake value (SUVmean) for the primary tumor between these two scans was then calculated, and patients were stratified into “responder” and “non-responder” groups based on a cut-off of 20% arithmetic decrease in SUVmean between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them “responders”. The remaining nine patients were “non-responders” to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

BACKGROUND AND OBJECTIVES: This study is a systematic review with meta-analysis designed to compare the perioperative and oncological outcomes of the abdominoperineal resection (APR) carried out in the prone jack-knife position (P-APR) vs the classic lithotomy position (C-APR). METHODS: We conducted an electronic search through PubMed utilizing the PRISMA guidelines. We included all randomized and nonrandomized studies which allowed for comparative analysis between the two groups. Research that focused on and analyzed the extralevator abdominal excision were excluded. Pooled variables and number of events were analyzed using the random-effect model. RESULTS: The final analysis included seven nonrandomized retrospective cohorts encompassing 1663 patients. P-APR was associated with decreased operative time (OT) (DM, −43.8 minutes; P < 0.01) and estimated blood loss (EBL) (DM, 86.9 mL; P < 0.01). There were no observed differences regarding perineal wound infections (PWI) (odds ratio [OR], 0.36; P = 0.18), intraoperative perforation of rectum (IOP) (OR, 0.98; P = 0.97), circumferential resection margin (CRM) positivity (OR, 1.02; P = 0.98) or 5-year LR (OR, 1.00; P = 0.99). CONCLUSION: The prone approach for APR is associated with decreased EBL and OT, although not with any change in the incidence of PWI or IOP. Moreover, surgical positioning per se does not appear to affect the CRM positivity rates or LR rate.

Key Points Question Is enzalutamide combined with androgen deprivation therapy associated with better outcomes than treatment with bicalutamide in Black men with metastatic hormone-sensitive prostate cancer (mHSPC)? Findings In a randomized clinical trial of 71 men with mHSPC, the 7-month prostate-specific antigen response rate was significantly improved with enzalutamide vs bicalutamide among Black patients but not among non-Black patients. Meaning These findings suggest that treatment with enzalutamide is associated with improved outcomes vs bicalutamide in Black men with mHSPC, and incorporation of enzalutamide in the mHSPC treatment plan should be strongly considered., This randomized clinical trial examines the efficacy of enzalutamide vs bicalutamide in combination with androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer., Importance Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration ClinicalTrials.gov Identifier: NCT02058706

Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood–brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma. Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue. Results: The AZD1775 plasma concentration–time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G2 arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study. Conclusions: In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. Clin Cancer Res; 24(16); 3820–8. ©2018 AACR. See related commentary by Vogelbaum, p. 3790

Background Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. Patients and Methods Chemotherapy naive mCRPC patients received docetaxel 75 mg/m2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. Results Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells Conclusion The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen.

Prostate cancer is one of the most common cancers in men worldwide. Currently available diagnostic and prognostic tools for this disease, such as prostate specific antigen, suffer from lack of specificity and sensitivity, resulting in over- and misdiagnosis. Hence, there is an urgent need for clinically relevant biomarkers capable of distinguishing between aggressive and nonaggressive forms of prostate cancer to aid in stratification, management and therapeutic decisions. To address this unmet need, we investigated the patterns of expression of a panel of 68 plasma-derived microRNAs (miRNAs) in a cohort of African American (AA) and European American (EA) prostate cancer patients (n = 114). miRNA qPCR results were analyzed using in-depth statistical methods, and a bioinformatics analysis was conducted to identify potential targets of the differentially expressed miRNAs. Our data demonstrate that a new previously unreported circulating miRNA signature consisting of a combination of interacting miRNAs (miR-17/miR-192) and an independent miRNA (miR-181a) are capable of segregating aggressive and nonaggressive prostate cancer in both AA and EA patients. The interacting miRNAs outperformed independent miRNAs in identifying aggressiveness. Our results suggest that these circulating miRNAs may constitute novel biomarkers of prostate cancer aggressiveness in both races and warrant further investigation.

// Priscila H. Goncalves 1 , Lance K. Heilbrun 1 , Michael T. Barrett 2 , Shivaani Kummar 4, 8 , Aaron R. Hansen 3 , Lillian L. Siu 3 , Richard L. Piekarz 4 , Ammar W. Sukari 1 , Joseph Chao 5 , Mary Jo Pilat 1, 6 , Daryn W. Smith 1 , Lindsay Casetta 1 , Scott A. Boerner 1, 7 , Alice Chen 4 , Elizabeth Lenkiewicz 2 , Smriti Malasi 2 , Patricia M. LoRusso 1, 7 1 Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA 2 Mayo Clinic Arizona, Scottsdale, AZ, USA 3 Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada 4 Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA 5 Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA 6 Eugene Applebaum College of Pharmacy and Health Sciences, Physician Assistant Studies, Wayne State University, Detroit, MI, USA 7 Current address: Yale Cancer Center, New Haven, CT, USA 8 Current address: Stanford University, Palo Alto, CA, USA Correspondence to: Priscila H. Goncalves, email: priscila.goncalves@nih.gov Keywords: adenoid cystic, salivary gland tumor, vorinostat, suberoylanilide hydroxamic acid, SAHA Received: February 09, 2017 Accepted: March 14, 2017 Published: March 22, 2017 ABSTRACT Purpose: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial. Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients. Results: Thirty patients were enrolled. Median age of patients was 53 years (range 21–73). Median number of cycles was 5 (range 1-66). Lymphopenia ( n = 5), hypertension ( n = 3), oral pain ( n = 2), thromboembolic events ( n = 2) and fatigue ( n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC. Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

PURPOSE: We conducted a pilot trial utilizing [(18)F]FMAU [1-(2′-deoxy-2′-[(18)F]fluoro-β-d-arabinofuranosyl thymine] as a tumor tracer in positron emission tomography (PET) and evaluated its reproducibility, and changes in maximum and peak standardized uptake value (SUVmax and SUVpeak) with zoledronic acid treatment in castrate resistant prostate cancer (CRPC) patients with bone metastases (BM). PROCEDURES: Eligible patients had CRPC with radiographic evidence of BM and creatinine clearance >30 ml/min. Two baseline [(18)F]FMAU-PET scans (about 1 week apart, range 2–12 days) were obtained for testing reproducibility. Zoledronic acid 4 mg was infused over 15 min within 1 week after second scan and a third PET scan was obtained 7 days later. The bony lesion with the highest uptake on the first scan was compared with later scans. Bone turnover markers and prostate-specific antigen (PSA) were obtained pre- and post-therapy. PET response was defined as decline in SUVmean of ≥15 % after zoledronic acid. RESULTS: Eleven patients were evaluated, median age was 65 years, five were African-American and six were Caucasian, and median PSA level was 36.3 ng/ml (range 1.0–1209.3). Notably, the range of absolute percent SUVmax changes varied between 0.77 and 54.7, and only nine measurements were greater than one (1.09–2.19). Zoledronic acid did not appreciably change FMAU uptake. No clinical response was noted. Urine N-telopeptide (NTx) was markedly decreased in all patients after zoledronic acid and serum bone-specific alkaline phosphatase (BSAP) registered a modest change. Urine NTx correlated more closely with SUV max than serum BSAP. CONCLUSIONS: FMAU tracer was able to detect bone metastases in CRPC patients but uptake was highly variable in bony lesions. Zoledronic acid did not produce an appreciable change in scans. Future investigations of FMAU tracer as a marker of early response in CRPC is recommended.

Objective To determine the outcome of definitive concurrent chemoradiation with platinum for locally advanced sinonasal carcinomas. Study Design Retrospective cohort. Methods Twenty-three nonsurgically and definitively treated patients diagnosed between July 1998 and February 2009 were analyzed. Patients with adenoid cystic carcinoma or adenocarcinoma were treated with photons and neutrons; the other histologies received photons alone. The vast majority received chemotherapy. Descriptive statistics were utilized, and Kaplan-Meier estimates were computed. Results Female (57%) and Caucasian (74%) preponderance were observed. Eighty-seven percent were unresectable; the maxillary and nasoethmoid sites were equally prevalent. Intensity-modulated radiation therapy (IMRT) and photons alone were utilized in 74% and 70%, respectively. Platinum agents were given in 95% of chemotherapy patients. Complete response was observed in 64% of patients. Median progression-free survival (PFS) and overall survival (OS) were 28.8 and 65.3 months, respectively. Three-year PFS and OS rates were 44% and 72%, respectively; 5-year PFS and OS rates were 30% and 60%, respectively. Intensity-modulated radiation therapy and a maxillary site of origin showed a trend toward superior PFS; higher-dose regimens were associated with somewhat shorter PFS. Relapse was observed in 59% of patients, predominantly local. There were few unanticipated adverse effects, and no grade IV/V events were reported. Conclusion Advanced sinonasal carcinomas are chemoradiosensitive tumors, albeit with a high propensity for local relapse. There is a definite indication for IMRT and a potential curative role of platinum-based chemoradiation regimens. Level of Evidence 4. Laryngoscope, 127:855–861, 2017

// Kosei Nakajima 1,2,* , Lance K. Heilbrun 1,3,* , Victor Hogan 1,2 , Daryn Smith 1,3 , Elisabeth Heath 1 and Avraham Raz 1,2 1 Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA 2 Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA 3 Biostatistics Core, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA * Authors share equal credit Correspondence to: Avraham Raz, email: // Elisabeth Heath, email: // Keywords : galectin-3, PSA, autoantibody, diagnostic biomarker, prostate cancer Received : August 17, 2016 Accepted : September 20, 2016 Published : October 12, 2016 Abstract Galectin-3 (Gal-3), an oncogenic pro-inflammatory protein, has been suggested as a possible complementary diagnostic candidate to prostate specific antigen (PSA) blood test for prostate cancer patients. The presence of the proteins in the circulation (biomarkers) may elicit an intrinsic humoral immune reaction by generating autoantibodies, which consequently could alter the detection levels. Here, we report the associations of the two prostate cancer biomarkers, Gal-3 and PSA in patients at different clinical states of prostate cancer while taking into account the autoantibody levels. A blind, prospective, single institution, pilot study was conducted. A total of 95 men were classified into 5 groups: healthy controls (Group1), newly diagnosed patients (Group2), no recurrence after local therapy (Group3), rising PSA after local therapy (Group4), and metastatic patients (Group5). Gal-3 and PSA level were divided by their respective autoantibodies, which yielded relative PSA and relative Gal-3 levels. After the adjustments, Spearman’s rank correlations and linear regression modeling revealed the positive associations between relative Gal-3 and relative PSA levels among all 95 men combined (rho = 0.446, P < 0.0001; fitted slope 0.448, P < 0.0001), in Group2 (rho = 0.616, P = 0.0050; fitted slope 0.438, P =0.0011), and Group3 (rho = 0.484, P = 0.0360; fitted slope 0.470, P = 0.0187). The data show positive associations of relative Gal-3 and relative PSA levels in prostate cancer patients, notably at early clinical time course. Allowing for the influence of autoantibodies, Gal-3 level might be considered as a potential biomarker since it is positively associated with PSA level.

// Kosei Nakajima 1,2,* , Lance K. Heilbrun 1,3,* , Daryn Smith 1,3 , Victor Hogan 1,2 , Avraham Raz 1,2 and Elisabeth Heath 1 1 Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA 2 Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA 3 Biostatistics Core, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA * Authors share equal credit Correspondence to: Elisabeth Heath, email: // Avraham Raz, email: // Keywords : PSA autoantibody, PSA test, false-results, prostate cancer, Galectin-3 Received : August 17, 2016 Accepted : October 07, 2016 Published : October 12, 2016 Abstract The U.S. Preventive Services Task Force (USPSTF) has recommended against PSA-based screening for prostate cancer due to potential possibilities of false-results. Since no alternative test is available to replace it, we have initiated a trial with the purpose of establishing whether Galectin-3 (Gal-3) serum level and/or the patients’ immune response to PSA and Gal-3 antigens could complement the PSA test as diagnostic tools for prostate cancer patients. A blind, prospective, single institution, pilot study was conducted. A total of 95 men were recruited and classified into 5 different groups: healthy controls (Group1), newly diagnosed patients (Group2), no recurrence after local therapy (Group3), rising PSA after local therapy (Group4), and metastatic patients (Group5). The primary endpoints were the levels of serum PSA, PSA autoantibodies (AAPSA), Gal-3, and Gal-3 autoantibodies (AAGal-3). Data were analyzed by Spearman’s rank correlation (rho) and least squares linear regression modeling. The expression levels of PSA, AAPSA, Gal-3, and AAGal-3 were determined in both healthy controls and prostate cancer patients. Negative correlations were observed between PSA and AAPSA levels among all 95 men combined (rho = -0.321, P = 0.0021; fitted slope -0.288, P = 0.0048), and in metastatic patients (rho = -0.472, P = 0.0413; fitted slope -1.145, P = 0.0061). We suggest an association between PSA and AAPSA, whereby the AAPSA may alter PSA levels. It provides a novel outlook for prostate cancer diagnosis, and should serve as a basis for an all-inclusive diagnostic trial centering on patients with metastasis.

OBJECTIVE: To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. METHODS: This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUV(mean) was derived using an isocontour ROI drawn approximately half way between the SUV(max) and background on three planes for each scan. The change in mean standardized uptake value (SUV(mean)) for the primary tumor between these two scans was then calculated, and patients were stratified into “responder” and “non-responder” groups based on a cut-off of 20% arithmetic decrease in SUV(mean) between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. RESULTS: 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them “responders”. The remaining nine patients were “non-responders” to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. CONCLUSION: Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

Background/aim Podocalyxin, a member of the CD34 family of cell surface sialomucins, is overexpressed in human embryonal carcinoma cell lines, as well as in several cancer types, and is associated with poor prognosis. Podocalyxin variants are associated with an increased risk and aggressiveness of prostate cancer. Herein podocalyxin protein expression in prostate cancer was characterized. Materials and methods Expression of podocalyxin as well as of TRA-1-60 and TRA-1-81 antigens was assessed immunohistochemically in 84 radical prostatectomy specimens and in adjacent normal tissues. Results Podocalyxin expression and H-scores were considerably higher in prostate tumors compared to normal tissues. High TRA-1-60 and TRA-1-81 staining was detected, however, in a much smaller percentage of prostate tumors, while their expression and H-scores were low in normal tissues. Similar trends for all three proteins were observed in prostatic intraepithelial neoplasia. Conclusion Overexpression of podocalyxin in prostate cancer renders the protein a putative immunohistochemical marker of prostate cancer that may contribute to stratification of patients for optimal treatment.

INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In pre-clinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising pre-clinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

OBJECTIVES: To estimate the probability of downgrading to Gleason score ≤7 at radical prostatectomy for men with a prostate needle biopsy demonstrating Gleason score 8 (4 + 4). METHODS: This is a retrospective review of men with Gleason score 8 (4 + 4) prostate cancer on needle biopsy who then underwent a radical prostatectomy at the Karmanos Cancer Institute or the University of Michigan. Men with any pattern 5 on the diagnostic biopsy were excluded. The objective was to estimate the proportion of patients whose tumors were downgraded to Gleason score ≤7 at radical prostatectomy and to identify clinical and biopsy parameters associated with downgrading. RESULTS: Median age of our cohort was 63 years (IQR: 59, 67.5) and median follow-up was 15 months (IQR: 7, 37). Of the 105 men that met inclusion criteria, 59% (62/105) were downgraded to Gleason score ≤7 at radical prostatectomy. Having ≤2 cores demonstrating Gleason score 8, ≤50% maximal tumor involvement of any individual core positive for Gleason score 8, or the presence of Gleason pattern 3 (such as 3 + 4, 4 + 3, or 3 + 3) in other biopsy cores were all independently associated with downgrading in our multivariable model. Depending on the absence, presence, or combination of these 3 factors, patients had an estimated 6% to 82% probability of having their tumor downgraded at radical prostatectomy. CONCLUSIONS: Men with low volume Gleason 8 (4 + 4) and/or the presence Gleason pattern 3 on prostate needle biopsy often have their tumors downgraded at radical prostatectomy. The presence of these preoperative biopsy parameters could affect pretreatment counseling and impact patient management. Published by Elsevier Inc.

Purpose: Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib. Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0–2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured. Results: Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of −56% (range, −85 to −5%, n = 11) and −41% (range, −60 to −25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or Conclusions: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

Purpose: We conducted a Phase II, clinical trial to evaluate the efficacy and safety of a biweekly gemcitabine and paclitaxel (GEMTAX) regimen as second-line treatment in patients with recurrent or metastatic unresectable, squamous cell carcinoma of the head and neck (SCCHN). The primary endpoint was response rate. Patients and Methods: Patients with recurrent unresectable or metastatic platinum refractory SCCHN, who had performance status ≤2 and adequate organ function, were eligible. Gemcitabine (3000 mg/m 2 intravenous) and paclitaxel (150 mg/m 2 intravenous) was given on days 1 and 15of 4 weeks cycle, until patients had disease progression or unacceptable toxicity. Results: Disease control (partial response [PR] + complete response [CR] + stable disease [SD]) was noted in 19 patients (54%) and overall response (CR + PR) was noted in 8 patients (23%). However, the most frequent response outcomes were progressive disease in 16 patients (46%) and SD in 11 patients (31%). The most frequent Grade 3-4 adverse events were lymphopenia in 38 patients (75%), anemia in 20 patients (39%), and infection in 16 patients (31%). Median progression-free survival was 3.6 months; median overall survival was 6.3 months. Conclusion: The biweekly GEMTAX regimen has statistically significant grade 3 and 4 adverse events and has meaningful clinical activity as a second-line treatment in patients with recurrent or metastatic SCCHN who have received prior chemotherapy. This regimen may particularly be a useful treatment option in patients who progressed in

Background The clinical utility of fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan in predicting the outcome of patients with metastatic colorectal cancer (mCRC) has not been well studied. We hypothesized that standardized uptake value (SUV) in FDG-PET scans after treatment predicts outcomes among patients with mCRC. Patients and Methods We retrospectively reviewed mCRC patients who had FDG-PET scans before their treatment and measured their SUV on follow-up imaging at the Karmanos Cancer Institute. Primary end points of time to progression (TTP) and overall survival (OS) were compared in 2 groups: follow-up (posttreatment) SUV of 0 versus > 0. Results The study population consisted of 44 patients (median age of 58.1 years). Forty (91%) of the patients were treated first-line, 34 (77%) received an oxaliplatin-based regimen, and 7 (16%) received an irinotecan-based regimen. Thirty-four (77%) patients received concurrent bevacizumab. Median pretreatment SUV was 9.2 (range, 1.7-46.3), and median posttreatment SUV (in n = 41) was 4.0 (range, 0-14). The median percent change in SUV was −68.5% (range, −9.2% to −100%). The median time interval between scans was 2.6 months. There was no statistically significant difference noted between metabolic responders and nonresponders with regard to TTP and OS. However, patients with a posttreatment SUV of 0 had significantly longer OS than those with posttreatment SUV of > 0 (median, 42 vs. 25.2 months, respectively), and slightly longer TTP (median, 8.2 vs. 6.9 months, respectively). Conclusion Systemic therapy significantly decreased SUV on follow-up PET scans in advanced colorectal cancer patients. Absence of FDG uptake on follow-up PET scans was associated with markedly longer OS and slightly longer TTP.

Background: There is continuing controversy about prostate cancer testing and the recent American Urological Association guidelines. We hypothesize that the reduction and elimination of racial survival disparity among African American men (AAM; high-risk group) compared with European American men (EAM; intermediate-risk group) during the PSA testing era compared with the pre-PSA era strongly supports the use of PSA testing in AAM. Methods: We used Surveillance, Epidemiology, and End Results (SEER) data to investigate relative survival disparities between AAM and EAM. To evaluate pre-PSA testing era, we selected malignant first primary prostate cancer in AAM and EAM, all stages, diagnosed during 1973–1994. To evaluate relative survival disparities in the current PSA testing era, we selected malignant first primary local, regional, and distant stage prostate cancers diagnosed during 1998–2005 to calculate 5-year relative survival rates. Results: Age-adjusted 5-year relative survival of prostate cancer diagnosed during 1973–1994 in the national SEER data revealed significantly shorter survival for AAM compared with EAM (P < 0.0001). The SEER-based survival analysis from 1995 to 2005 indicated no statistical difference in relative survival rates between AAM and EAM by year of diagnosis of local, regional, or distant stage prostate cancer. Conclusion: We conclude that the elimination of prostate cancer racial disparity of local, regional, and metastatic prostate cancer relative survival in the current PSA testing era compared with pre-PSA era as an endpoint to test PSA efficacy as a marker for prostate cancer diagnosis is evidence for aggressive testing of AAM. Impact: Evidence for screening AAM. Cancer Epidemiol Biomarkers Prev; 23(8); 1505–11. ©2014 AACR.

We investigated the novel combination of dose-dense pemetrexed, gemcitabine and bevacizumab as frontline treatment for advanced non–small cell lung cancer. Thirty-nine patients received pemetrexed (400 mg/m(2)), gemcitabine (1200 mg/m(2)), and bevacizumab (10 mg/kg), given every 14 days. Median progression-free survival was 6.1 months (95% confidence interval [CI], 4.2–7.9) and median overall survival was 18.4 months (95% CI, 13.1–29.5). Treatment met the primary endpoint and represents a reasonable therapeutic option. INTRODUCTION: Platinum-based chemotherapy is standard for untreated, advanced non-small-cell lung cancer (NSCLC). We investigated the activity and tolerability of the novel combination of dose-dense pemetrexed, gemcitabine, and bevacizumab in patients with advanced NSCLC. METHODS: This multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (400 mg/m(2)), gemcitabine (1200 mg/m(2)), and bevacizumab (10 mg/kg), given every 14 days in patients with untreated, advanced NSCLC. The primary endpoint was progression-free survival with secondary endpoints of response rate and overall survival. RESULTS: Thirty-nine patients were enrolled. Treatment was well tolerated; the most common grade 3–4 toxicities were neutropenia and fatigue. Of the 38 patients evaluable for tumor response, 1 (3%) had complete response, 15 (39%) had partial response, 12 (31%) had stable disease, and 10 (26%) had progressive disease. Median progression-free survival was 6.1 months (95% confidence interval [CI], 4.2–7.9) and median overall survival was 18.4 months (95% CI, 13.1–29.5). The 1-year overall survival rate was 64% (95% CI, 51%−81%) and the 2-year overall survival rate was 41% (95% CI, 28%−60%). CONCLUSIONS: Treatment with dose-dense pemetrexed, gemcitabine, and bevacizumab met the primary endpoint with promising efficacy and a manageable safety profile in patients with untreated advanced NSCLC. This regimen represents a reasonable therapeutic option.

Lessons Learned The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

Purpose. To assess feasibility, complications, local tumor recurrences, overall survival (OS) and estimates of cost-effectiveness for multi-site cryoablation (MCA) of oligo-metastatic colorectal cancer (mCRC) in a prospective study. Materials and Methods. 111 CT and/or US-guided percutaneous MCA procedures were performed on 151 tumors in 59 oligo mCRC patients. Mean patient age was 63 years (range 21–92 years), consisting of 29 males and 30 females. Tumor location was grouped according to common metastatic sites. Median OS was determined using the Kaplan-Meier. Estimates of MCA costs per LYG were compared to historical values for systemic therapies. Results. A mean 1.9 MCAs per patient were performed with a median clinical follow-up of 12 months. Major complication and local recurrence rates were 8% (9/111) and 12% (18/151), respectively. Median overall-survival (OS) was 23.6 months with an estimated 3-year survival rate of ~30%. Cryoablation remained cost effective with or without the presence of systemic therapies, with an adjunctive cost-effectiveness ratio (ACER) of $39,661–$85,580 per LYG. Conclusions. Multi-site cryoablation had very low complication and local recurrence rates, and was able to provide local control even for diverse soft tissue locations. Even as an adjunct to systemic therapies, MCA appeared cost-effective, with apparent increased survival.

To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC).A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies.Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost-effectiveness ratio of $28,312-$59,554 per LYG.MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC.

Purpose To assess feasibility, complications, local tumor recurrences, overall survival (OS), and estimates of cost effectiveness for multisite cryoablation (MCA) of oligometastatic non–small-cell lung cancer (NSCLC). Materials and Methods A total of 49 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 60 tumors in 31 patients (19 women and 12 men) with oligometastatic NSCLC. Average patient age was 65 years. Tumor location was grouped according to common metastatic sites. Median OS was determined by Kaplan–Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. Results Total numbers of tumors and cryoablation procedures for each anatomic site were as follows: lung, 20 and 18; liver, nine and seven; superficial, 12 and 11; adrenal, seven and seven; paraaortic/isolated, two and two; and bone, 10 and seven. A mean of 1.6 procedures per patient were performed, with a median clinical follow-up of 11 months. Major complication and local recurrence rates were 8% (four of 49) and 8% (five of 60), respectively. Median OS for MCA was 1.33 years, with an estimated 1-year survival rate of approximately 53%. MCA appeared cost-effective even when added to the cost of best supportive care or systemic regimens, with an adjunctive cost-effectiveness ratio of $49,008–$87,074. Conclusions MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, and possibly increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic NSCLC.

Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and the efficacy of these agents in patients with renal insufficiency (RI). This is clinically relevant, especially as about one-third of patients with mRCC have renal dysfunction. The primary objective was to assess the safety and efficacy of targeted agents in patients with mRCC with RI. Medical records of patients with mRCC at Wayne State University, started on sunitinib, temsirolimus, everolimus, or bevacizumab, were reviewed. Patients with a calculated creatinine clearance of less than or equal to 60 ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function. RI was observed in 33% of our patients with mRCC. The incidence of toxicities, responses, time to progression, and overall survival were not significantly different in patients with RI compared with patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with mammalian target of rapamycin inhibitors, than did patients with normal renal function. In conclusion, RI was commonly observed in our patients with mRCC. Molecularly targeted agents are well tolerated, and efficacy seems to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for patients receiving sunitinib and bevacizumab.

Chopra T, Chandrasekar P, Salimnia H, Heilbrun LK, Smith D, Alangaden GJ. Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation. Clin Transplant 2011: 25: E82–E87. © 2010 John Wiley & Sons A/S. Abstract: Given the limited information on Clostridium difficile infection (CDI) during hematopoietic stem cell transplantation (HSCT), we examined the recent epidemiology of CDI in HSCT recipients at our institution. During the two-yr retrospective study period (2005–2006), 361 transplants were performed: 60% allogeneic and 40% autologous. Among all hospitalized patients in a non-outbreak setting, CDI rates in HSCT recipients were ninefold higher than those in general patients and 1.4-fold higher than those in patients with cancer (24.0 vs. 2.6 vs. 16.8/10 000 patient-days respectively). Sixty-two episodes of CDI occurred in 51 (14%) HSCT recipients: 39 (18%) allogeneic vs. 12 (8%) autologous (p = 0.01). Almost half of CDI episodes occurred within 30 d post-HSCT and 22% before HSCT. Clostridium difficile toxin assay was initially positive in 28% of the first, 31% of the second and 27% of the third stool samples tested. All but one patient responded to therapy with metronidazole or vancomycin. Severe CDI occurred in one patient and recurrent CDI in two patients. CDI is common during HSCT especially in allogeneic transplants during the peri-HSCT period. Prospective studies to better define the epidemiology and identify unique risk factors for CDI and more accurate tests to confirm the diagnosis in this population are needed.