MRI- and PET-Based Assessment of Radiological and Clinical Factors Associated With Cervical Cancer Response to External Beam Radiation Therapy.

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 (GTVINITIAL) was estimated after contouring on a planning CT scan registered with pre-EBRT PET and MRI. The maximum standardized uptake value (SUV) of GTVINITIAL from each PET scan report was collected. Spearman's rank correlation coefficient (rho) values were calculated to assess the relationships among age, tumor size, and SUV. Tumor radiological response during EBRT prior to BT was calculated by contouring the final primary gross tumor volume (GTVFINAL) using MRI obtained prior to BT. CR rates during EBRT were estimated from GTVINITIAL and GTVFINAL and compared by the level of various factors using Fisher's exact test (two-sided).  Results Forty-eight patients met the inclusion criteria of the study with a median age of 50 years. The median GTVINITIAL was 82 cc. The median SUV was 14.9. A significant correlation was seen between SUV and GTVINITIAL with a larger tumor size associated with a higher SUV. CR rates were numerically higher for patients who were aged <50 years, or with >37.5 Gy radiation dose at or before the second MRI, or with GTVINITIAL <100 cc, or with no nodes involved or with stages IB or IIA. Conclusions Our study identified higher CC primary tumor CR rates during EBRT in younger patients (<50) with smaller tumors (100 cc) without nodal involvements as well as a positive correlation between PET FDG (18F-fluorodeoxyglucose)-SUV and CC primary tumor size.

A Phase 1 study Combining Pexidartinib, Radiation Therapy, and Androgen Deprivation Therapy in Men With Intermediate- and High-Risk Prostate Cancer.

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.

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial.

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.

Should all prostate needle biopsy Gleason score 4 + 4 = 8 prostate cancers be high risk? Implications for shared decision-making and patient counselling.

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.

The use of 3'-deoxy-3'-18F-fluorothymidine (FLT) PET in the assessment of long-term survival in breast cancer patients treated with neoadjuvant chemotherapy.

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. 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. 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.

Perioperative and oncological outcomes of abdominoperineal resection in the prone position vs the classic lithotomy position: A systematic review with meta-analysis.

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.

Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral Cabozantinib Therapy in Metastatic Castrate-Resistant Prostate Cancer.

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-ß-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 <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit. CONCLUSIONS: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

The extrema of circulating miR-17 are identified as biomarkers for aggressive prostate cancer.

MicroRNAs (miRNAs) constitute short non-coding RNAs that can post-transcriptionally modulate the expression of many oncogenes and tumor suppressor genes engaged in key cellular processes. Deregulated serum miRNA signatures have been detected in various solid cancers including prostate cancer, suggesting that circulating miRNAs could function as non-invasive biomarkers of tumor emergence and progression. To determine whether serum miRNA expression levels are different between patients with aggressive and non-aggressive prostate cancer, we analyzed a panel of miRNAs from the blood of African American (AA) prostate cancer patients using a new recursive partitioning method that allows hypothesis testing of each split. We observed that both extrema of circulating miR-17, i.e. upregulation and downregulation, are associated with aggressive prostate cancer. A similar effect was observed in tumor samples from a separate dataset representing a different population of prostate cancer patients and in AA prostate cancer samples from the TCGA. The dual effect is consistent with the contradictory findings on the role of miR-17 in prostate cancer progression, whereby it controls important oncogenic and tumor-suppressive genes.

Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer.

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.

Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

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 AACRSee related commentary by Vogelbaum, p. 3790.

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma.

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.

A Pilot Trial Evaluating Zoledronic Acid Induced Changes in [18F]FMAU-Positron Emission Tomography Imaging of Bone Metastases in Prostate Cancer.

PURPOSE: We conducted a pilot trial utilizing [18F]FMAU [1-(2'-deoxy-2'-[18F]fluoro-ß-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 [18F]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.

Phase II Trial of Dose-dense Pemetrexed, Gemcitabine, and Bevacizumab in Patients With Advanced, Non-Small-cell Lung Cancer.

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/m2), gemcitabine (1200 mg/m2), 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.

The influence of PSA autoantibodies in prostate cancer patients: a prospective clinical study-II.

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.

Outcomes of nonsurgical management of locally advanced carcinomas of the sinonasal cavity.

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.

Positive associations between galectin-3 and PSA levels in prostate cancer patients: a prospective clinical study-I.

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.

Anti-androgenic activity of absorption-enhanced 3, 3'-diindolylmethane in prostatectomy patients.

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3'-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors.

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/m(2) 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/m(2) 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.