Publications by authors named "Kristopher Attwood"

153 Publications

A Principal Component of Quality of Life Measures Is Associated with Survival for Head and Neck Cancer Patients Treated with Radiation Therapy.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, 665 Elm Street, Buffalo, NY 14203, USA.

Background: Health-related quality of life (HRQOL) metrics can be associated with survival in head and neck cancer (HNC); however, the impact of HRQOL recovery and the relevant HRQOL domains regarding outcome are unclear.

Methods: Using a single-institution database, we retrospectively reviewed HNC patients treated with definitive or postoperative radiation therapy between 2013 and 2018. The recovery of individual HRQOL domains were determined by the ratio of the post-treatment to baseline scores. Univariate and Multivariate Cox regression were used to analyze survival outcomes. Principal component analysis was used to adjust for multicollinearity of HRQOL domains.

Results: In 218 HNC patients who received radiation therapy, median follow-up was 24.8 months (interquartile range (IQR) 14.5-32.0). Principal component analysis evaluating the recovery of HRQOL domains revealed two independent principal components (PC), PC1 and PC2. PC1, which received contributions from the functional domains; physical (PF), role (RF), emotional (EF), cognitive (CF), and global health status (GQOL) was significantly associated with disease-free (HR = 0.77, 95% CI 0.61-0.98, = 0.034) and overall survival (HR = 0.76, 95% CI 0.65-0.91, = 0.004) on multivariate analysis and PC2, had no correlation with outcome and was mainly represented by social functioning. Unplanned hospitalization was significantly associated with lower PC1 scores (β = -0.997, Std. Error = 0.244, < 0.001).

Conclusion: Our study provides evidence that post-treatment recovery of HRQOL domains were associated with overall survival (OS) in HNC. PC1 is an attractive clinical tool to assess the recovery across multiple different HRQOL and the relationship with survival. Future prospective studies may identify patients who could benefit from additional rehabilitation based on PC1 score.
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http://dx.doi.org/10.3390/cancers13051155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962523PMC
March 2021

Active Surveillance for Risk Stratification of all Small Renal Masses Lacking Predefined Clinical Criteria for Intervention.

J Urol 2021 Mar 29:101097JU0000000000001714. Epub 2021 Mar 29.

Department of Urology, Roswell Park Cancer Institute, Buffalo, New York.

Purpose: Despite general indolence of small renal masses (SRM) and no known adversity from treatment delays, broad usage of active surveillance (AS) as a means to risk-stratify SRM patients for more selective treatment has not been studied. We describe outcomes for a novel approach in which AS was recommended to all SRM patients lacking predefined progression criteria for intervention (PCI).

Materials And Methods: All non-dialysis dependent, nonmetastatic SRM patients seen by one urologist at a comprehensive cancer center during January 2013-September 2017 were managed with AS if standardized PCI were absent, with delayed intervention (DI) recommended only upon PCI development. PCI were defined prospectively as SRM-related symptoms, unfavorable histology, cT3a stage, or either of the following without benign neoplastic biopsy histology: longest tumor diameter (LTD) >4 cm; growth rate>5 mm/year for LTD≤3 cm or>3 mm/year for LTD>3 cm.

Results: 96% (123/128) of SRM patients lacked PCI at presentation and underwent AS. With median/mean 31/34 months follow-up, none developed metastasis, and 30% (37/123) developed PCI, 78% (29/37) of whom underwent DI. One (1%) patient crossed over to DI without PCI. 3-year PCI-free and DI-free rates were 72% and 75%, respectively. DI resections were enriched (62%) for pT3 and/or nuclear grade 3-4 malignant pathology, with no benign resections.

Conclusions: AS using predefined PCI in otherwise unselected SRM patients allows intervention to be focused on at-risk SRMs with common adverse pathology, avoiding treatment for most SRM patients. Long-term DI and oncologic safety require study.
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http://dx.doi.org/10.1097/JU.0000000000001714DOI Listing
March 2021

Impact of a Thoracic Multidisciplinary Conference on Lung Cancer Outcomes.

Ann Thorac Surg 2021 Mar 17. Epub 2021 Mar 17.

Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA; Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, SUNY Buffalo, NY. Electronic address:

Background: With the complexity of cancer treatment rising, the role of multidisciplinary conferences (MDCs) in making diagnostic and treatment decisions has become critical. The aim of this study was to evaluate the impact of a thoracic MDC (T-MDC) on lung cancer care quality and survival.

Methods: Lung cancer cases over 7 years were identified from the Roswell Park cancer registry system. The survival rates and treatment plans of 300 patients presented at the MDC were compared to 300 matched patients. The National Comprehensive Cancer Network (NCCN) guidelines were used to define the standard of care. The compliance of care plans with NCCN guidelines was summarized using counts and percentages, with comparisons made using Fisher's exact test. Survival outcomes were summarized using Kaplan-Meier methods.

Results: There was improvement in median overall survival (36.9 versus 19.3 months; p<0.001) and cancer specific survival (48 versus 28.1 months; p<0.001) for lung cancer patients discussed at the T-MDC compared to controls. These differences were statistically significant in patients with stages III/IV, but not in patients with stages I/II disease. The NCCN guidelines compliance rate of treatment plans improved from 80% to 94% (p<0.001) following MDC discussion. 123 of 300 (41%) patients had treatment plan changes recommended by the MDC.

Conclusions: Our results suggest that lung cancer patients have a survival benefit from MDC discussion compared to controls. Patients with advanced disease (stages III and IV) benefited the most. Further research is necessary to understand the precise mechanisms that drive these results.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.017DOI Listing
March 2021

Porfimer Sodium Versus PS785 for Photodynamic Therapy (PDT) of Lung Cancer Xenografts in Mice (A Novel Agent for Lung Cancer PDT).

J Surg Res 2021 Mar 10;263:245-250. Epub 2021 Mar 10.

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Background: Lung cancer is the greatest cause of cancer mortality in the United States, necessitating ongoing improvements in current treatment techniques. Photodynamic therapy (PDT) involves the interaction between a photosensitizer, light, and oxygen. The resulting release of reactive oxygen species causes tumor necrosis. It has been used as an endoscopic technique for the palliation of lung cancer. Porfimer sodium (Photofrin) is the only Food and Drug Administration-approved photosensitizer for PDT but has limited depth of penetration and produces prolonged skin phototoxicity. Multiple newer photosensitizers are in development, including PS785. The effectiveness of PS785 was compared with porfimer sodium in the treatment of human lung cancer xenografts in mice.

Methods: Human non-small cell lung cancer (NSCLC) xenografts were established in severe combined immunodeficient mice and grouped into small (3-5 mm) and large tumors (6-10 mm). PS785 or porfimer sodium was administered intravenously, and PDT was executed at 24, 48, or 72 h after injection. The primary endpoint was the delay of tumor regrowth after PDT.

Results: Porfimer sodium and PS785 produced statistically similar delays of tumor regrowth after PDT when small tumors were treated at 24 and 48 h. At 72 h, PS785 performed better in small tumors. However, for large tumors, PS785 produced no delay in tumor regrowth at any time point.

Conclusions: PS785 and porfimer sodium were able to effectively treat NSCLC to a depth of ≤5 mm. However, porfimer sodium was more effective in treating NSCLC tumors to a depth of 6-10 mm. Further efforts are required to produce photosensitizers that will facilitate PDT of larger tumors.
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http://dx.doi.org/10.1016/j.jss.2020.12.067DOI Listing
March 2021

T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors.

Nat Commun 2021 03 3;12(1):1402. Epub 2021 Mar 3.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1CD8 T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8 T cells. Furthermore, an increase in the frequency of the CX3CR1 subset in circulating CD8 T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.
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http://dx.doi.org/10.1038/s41467-021-21619-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930182PMC
March 2021

A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis.

Sci Rep 2021 Mar 2;11(1):4946. Epub 2021 Mar 2.

Department of Gastroenterology, Mayo Clinic, Jacksonville, FL, USA.

Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC). During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).
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http://dx.doi.org/10.1038/s41598-021-84430-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925603PMC
March 2021

Art Heals: Randomized Controlled Study Investigating the Effect of a Dedicated In-House Art Gallery on the Recovery of Patients following Major Oncologic Surgery.

Ann Surg 2020 Dec 29. Epub 2020 Dec 29.

*Roswell Park Comprehensive Cancer Center, Buffalo, NY †The Albright-Knox Art Gallery, Buffalo, NY.

Introduction: We sought to investigate the effect of exposure to a dedicated art gallery during the perioperative period on the recovery of patients undergoing major oncologic procedures.

Methods: 80 patients were randomized into 2 arms; standard of care versus exposure to art. All patients completed a survey assessing their baseline art knowledge, and 4 post-study validated questionnaires assessing their pain (Pain Rating Scale), hope (Herth Hope Index), anxiety (State-Trait Anxiety Inventory for Adults), and mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale). A linear model adjusted for baseline scores was run comparing the scores among the 2 study arms. Stepwise multivariate regression analyses were used to identify predictors of improved pain, hope, anxiety, and wellbeing.

Results: Both groups were comparable in terms of demographics, passion and knowledge about art. There was no statistically significant difference in pain scores between the two groups. The exposure to art group experienced higher hope (2.4 points higher vs 0.05, p = 0.004), lower anxiety (8 points lower vs -0.9, p < 0.0001), and higher mental well-being scores (5.23 points higher vs -0.05, p < 0.0001) in comparison to the standard of care group. On multivariate analyses, exposure to art was significantly associated with improved hope, anxiety, and mental well-being after adjusting for patient and disease characteristics.

Conclusion: Dedicated exposure to art was associated with improved hope, anxiety, and mental well-being of patients after major oncologic surgery.
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http://dx.doi.org/10.1097/SLA.0000000000004059DOI Listing
December 2020

Association of significant financial burden with survival for head and neck cancer patients treated with radiation therapy.

Oral Oncol 2021 Apr 10;115:105196. Epub 2021 Feb 10.

Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, 665 Elm Street, Buffalo, NY 14203, USA. Electronic address:

Objective: To assess the association between financial toxicity and survival in patients with head and neck cancer (HNC).

Materials And Methods: Using a single-institution database, we retrospectively reviewed HNC patients treated at Roswell Park Comprehensive Cancer Center treated with definitive or postoperative radiation therapy between 2013 and 2017. Kaplan-Meier method and log-rank tests were used to analyze survival outcomes. Propensity score matching on all clinically relevant baseline characteristics was performed to address selection bias. All statistical tests were two-sided and those less than 0.05 were considered statistically significant.

Results: Of a total of 284 HNC patients (age: median 61 years, IQR 55-67; 220 [77.5%] men), 204 patients (71.8%) received definitive radiation and 80 patients (28.2%) received adjuvant radiation. There were 41 patients (14.4%) who reported high baseline financial toxicity. Chemotherapy was used in 237 patients (83.5%). On multivariable analysis, those with high financial toxicity exhibited worse overall survival (hazards ratio [HR] 1.75, 95% confidence interval [CI] 1.05-2.94, p = 0.03) and cancer specific survival (HR 2.28, 95% CI 1.31-3.96, p = 0.003). On matched pair analysis of 66 patients, high financial toxicity remained associated with worse OS (HR 2.72, 95% CI 1.04-7.09, p = 0.04) and CSS (HR 3.75, 95% CI 1.22-11.5, p = 0.02).

Conclusion: HNC patient reported baseline financial toxicity was significantly correlated with both decreased overall and cancer specific survival. These significant correlations held after match pairing. Further research is warranted to investigate the impact of financial toxicity in HNC and mitigate its risk.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105196DOI Listing
April 2021

Oncologic outcome of radical prostatectomy versus radiotherapy as primary treatment for high and very high risk localized prostate cancer.

Prostate 2021 Mar 20;81(4):223-230. Epub 2021 Jan 20.

Departments of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Objective: To compare the oncologic outcomes of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) ± androgen deprivation therapy for primary treatment of high risk localized prostate cancer (CaP).

Methods: We retrospectively reviewed a prospectively-populated database for cases who underwent primary treatment for high risk localized CaP, had more than 2 years follow-up, and were treated since 2006. A total of 335 cases were studied of whom 291 underwent RP and 44 underwent EBRT. Clinical characteristics, biochemical progression-free survival (BPFS), metastasis-free survival (MFS), cancer-specific survival (CSS) and overall survival (OS) were compared.

Results: EBRT cases were older (p < .01; mean 71 years vs. 61 years) and had longer PSA doubling time (PSADT) (p = .03; median 4.8 years vs. 3.5 years) than RP. Race, pretreatment PSA and biopsy Gleason score were similar. Median follow-up was 5.1 (range: 2.3-12.8) years for RP versus 3.3 (range: 2-12.4) years for EBRT. Three- and 5-year BPFS were 42% and 36% after RP versus 86% and 75% after EBRT (p < .01). The rate of adjuvant/salvage therapy was 58% after RP versus 20% after EBRT (p < .01). Three- and 5-year MFS were 80% and 77% after RP versus 91% and 91% after EBRT (p = .11). Three-year CSS was 98% in both groups and OS was 97% after RP versus 94% after EBRT (p = .73).

Conclusions: RP had higher rates of biochemical failure and adjuvant or salvage treatment versus EBRT in high risk localized CaP. MFS trended toward benefit after EBRT, but CSS and OS remained high in both groups.
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http://dx.doi.org/10.1002/pros.24089DOI Listing
March 2021

Correlation between perioperative outcomes and long-term survival for non-small lung cancer treated at major centers.

J Thorac Cardiovasc Surg 2020 Dec 3. Epub 2020 Dec 3.

Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY; Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY. Electronic address:

Background: The public is placing increased emphasis on specialty specific rankings, thereby affecting patients' choices of clinical care programs. In the spirit of transparency, public reporting initiatives are underway or being considered by various surgical specialties whose databases rank programs based on short-term outcomes. Of concern, short-term risk avoidance excludes important comparative cases from surgical database participation and may adversely affect overall long-term oncologic treatment team results. To assess the validity of comparing short-term perioperative and long-term survival outcomes of all patients treated at major centers, we studied the correlations between these variables.

Methods: The National Cancer Database was queried for patients diagnosed with non-small cell lung carcinoma (NSCLC) between 2008 and 2012, yielding 5-year follow-up data for all patients at centers treating at least 100 patients annually. Mortality (30- and 90-day), unplanned 30-day readmissions, and hospital length of stay were modeled using logistic regression with sex, race, age, Charlson-Deyo combined comorbidity, extent of surgery, income, insurance status, histology, grade, and analytic stage as predictors, all with 2-way interaction terms. The differences between the predicted rates and observed rates were calculated for each short-term outcome, and the average of these was used to create a short-term metric (STM). A similar approach was used to create a long-term metric (LTM) that used overall survival as a single dependent variable. Centers were ranked into deciles based on these metrics. Visual plotting as well as correlation coefficients were used to judge correlation between STM and LTM.

Results: A total of 298,175 patients from 541 centers were included in this analysis, of whom 102,860 underwent surgical resection for NSCLC. The correlation between STM and LTM was negative using parametric estimates (Pearson correlation coefficient = -0.09 [P = .03] and -0.22 [P < .01]) and nonparametric estimates (Spearman rank correlation coefficient = -0.09 [P = .02] and -0.22 [P < .01]) for squamous cell carcinoma and adenocarcinoma, respectively.

Conclusions: Short-term perioperative outcome rankings correlate poorly with long-term survival outcome rankings when cancer treatment centers are compared. Factors explaining this discrepancy merit further study. Rankings based on short-term outcomes alone may be incomplete for public reporting.
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http://dx.doi.org/10.1016/j.jtcvs.2020.11.108DOI Listing
December 2020

Prostate Cancer Screening Patterns Among Sexual and Gender Minority Individuals.

Eur Urol 2021 May 26;79(5):588-592. Epub 2020 Nov 26.

Johns Hopkins Center for Transgender Health, Baltimore, MD, USA. Electronic address:

One in six gay and bisexual men will be diagnosed with prostate cancer in their lifetime. Lesbian, gay, bisexual, and transgender (LGBT) populations are under-represented in cancer research, and guidelines on prostate-specific antigen (PSA) screening are limited. We performed a cross-sectional study to assess patterns of PSA screening and decision-making in this cohort. The Behavioral Risk Factor Surveillance System database was queried for LGBT adults for 2014-2016 and 2018, when PSA questions were asked in the annual survey. Multivariable logistic regression was performed to evaluate the association of LGBT status with PSA screening and informed and shared decision-making. A total of 164 370 participants were eligible for PSA screening, representing a weighted estimate of 1.2 million LGBT individuals. Compared to cisgender (CG) straight individuals, CG gay/bisexual cohorts were more likely to participate in PSA screening (CG gay: odds ratio [OR] 1.07; p < 0.001; CG bisexual: OR 1.06; p < 0.001). CG gay participants were more likely to make informed decisions (OR 1.10; p < 0.001) and engage in shared decision-making (OR 2.55; p < 0.001). Select gay populations were more likely to undergo PSA screening recommended by their clinicians and participate in informed and shared decision-making. PATIENT SUMMARY: This large study of sexual and gender minorities in the USA suggests that gay and bisexual individuals were more likely to undergo prostate cancer screening and that select gay individuals were more likely to make informed and shared decisions. However, transgender individuals were less likely to have prostate cancer screening and make informed decisions.
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http://dx.doi.org/10.1016/j.eururo.2020.11.009DOI Listing
May 2021

Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial.

JAMA Oncol 2021 Jan;7(1):78-85

Department of Gynecologic Oncology, Clinical Sciences Center, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Importance: Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.

Objective: To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Design, Setting, And Participants: This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.

Interventions: Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.

Main Outcomes And Measures: Primary outcomes were objective response rate (ORR) and progression-free survival (PFS).

Results: Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).

Conclusions And Relevance: In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.

Trial Registration: ClinicalTrials.gov Identifier: NCT02853318.
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http://dx.doi.org/10.1001/jamaoncol.2020.5945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677872PMC
January 2021

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

Clin Cancer Res 2021 Jan 30;27(1):87-95. Epub 2020 Oct 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.

Patients And Methods: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months.

Results: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders.

Conclusions: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785669PMC
January 2021

Gastric Cancer Disparities Among Asian American Subpopulations.

Anticancer Res 2020 Nov;40(11):6381-6385

Department of Surgery, Mayo Clinic, Jacksonville, FL, U.S.A.

Background/aim: Asian Americans (AA) are one of the largest and fastest growing minority groups in the United States consisting of 18 million people. This population is an ethnically diverse group that tends to be classified as one cohort resulting in hidden survival disparities among AA subgroups.

Patients And Methods: The National Cancer Data Base was queried for patients of Korean, Japanese or Filipino ancestry with gastric adenocarcinoma or esophageal adenocarcinoma between 2004 and 2013.

Results: A total of 28,213 patients met the inclusion criteria: 1,542 with gastric adenocarcinoma and 26,671 with esophageal adenocarcinoma. The Korean group with gastric cancer (0.42) showed improved 5-year survival over the Japanese (0.31) and Filipino (0.21; p<0.001) groups.

Conclusion: A significant difference in survival exists among AA subgroups signifying a need to acknowledge the heterogeneity of AA in future studies. Thus, individual-specific medicine with respect to race-related outcomes is extremely important.
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http://dx.doi.org/10.21873/anticanres.14659DOI Listing
November 2020

High intratumoral CD8 T-cell infiltration is associated with improved survival in prostate cancer patients undergoing radical prostatectomy.

Prostate 2021 Jan 21;81(1):20-28. Epub 2020 Oct 21.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Background: A high density of CD8 tumor infiltrating lymphocytes (TILs) is associated with improved survival in multiple cancers, but its prognostic role in prostate cancer remains controversial. The aim of our study was to evaluate the prognostic value of CD8 TILs in prostate cancer patients undergoing radical prostatectomy (RP). We hypothesized that elevated density of CD8 TILs in the RP specimen would correlate with improved clinical outcomes. This information may be helpful for future immunotherapy clinical trial design and treatment selection.

Methods: Tumor microarrays constructed from 230 patients with localized prostate cancers who underwent RP from 2006 to 2012 at Roswell Park Comprehensive Cancer Center were analyzed retrospectively using immunohistochemistry. CD8 cell density was evaluated using a computerized scoring system. The cohorts were separated by CD8 TIL density at the 25th percentile (i.e., low 
Results: One hundred and forty-nine (65%) patients had high risk diseases (Gleason >7 or pT3/4). The median follow-up time was 8.4 years. High CD8 TIL density was associated with improved 5-year overall survival (98% vs. 91%, p = .01) and prostate cancer-specific survival (99% vs. 95%, p = .04) compared with patients with low CD8 TIL density. There was a trend toward higher 5-year biochemical recurrence-free survival and metastasis-free survival in the cohort of patients with high CD8 TIL density (52% vs. 38% and 86% vs. 73%, respectively), although the difference did not reach statistical significance (p = .18 and p = .05, respectively). In a multivariate analysis high CD8 TIL density was an independent favorable prognostic factor for overall survival (hazards ratio = 0.38; 95% confidence interval: 0.17-0.87; p = .02). In contrast to the prognostic value of CD8 TIL density, the CD8 cell density in the matched normal prostate tissue was not associated with any clinical outcomes.

Conclusion: Intratumoral CD8 T-cell infiltration in the RP specimen is independently associated with improved survival after RP in this high-risk prostate cancer cohort. Pre-RP immunomodulation that promotes intratumoral CD8 cytotoxic T-cell infiltration may be beneficial for this population.
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http://dx.doi.org/10.1002/pros.24068DOI Listing
January 2021

Sequencing Systemic Therapy Pathways for Advanced Hepatocellular Carcinoma: A Cost Effectiveness Analysis.

Liver Cancer 2020 Sep 12;9(5):549-562. Epub 2020 Aug 12.

GI Division, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Introduction: Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide and carries a poor prognosis. Historically, sorafenib was the only available systemic treatment for advanced HCC. However, in recent years, 6 new treatments have been approved by the US Food and Drug Administration (FDA): regorafenib, lenvatinib, cabozantinib, pembrolizumab, ramucirumab, and nivolumab. Data are lacking regarding the most appropriate sequencing pathway for these agents. Our objective was to conduct a comprehensive cost effectiveness analysis (CEA) of different 1st- and 2nd-line treatment pathways for HCC reflecting all new drug approvals, and then use our data to provide guidance for clinicians on which pathway is the most cost-effective.

Materials And Methods: Markov models were used to evaluate the cost effectiveness of 8 different 1st- and 2nd-line treatment sequences. The model allowed for 9 possible states. Cost effectiveness ratios (CER) and incremental CER (ICER) were calculated to compare costs between different pathways and against a willingness-to-pay (WTP) threshold. Efficacy and toxicity data were extracted from the landmark trials for each agent. All agents except ramucirumab were included. The cost of each agent was based on the wholesale acquisition cost (WAC) in USD as of June 2019. Monte-Carlo methods were used to simulate the experience of 1,000,000 patients per treatment sequence for a 12-month period.

Results: The pathway with the lowest CER was sorafenib, followed by pembrolizumab (USD 227,741.03/quality-adjusted life year [QALY]). ICER analysis supported implementing 2nd-line pembrolizumab-based pathways at a higher WTP threshold of 300,000/quality-adjusted life year. Sensitivity analysis did not substantially change these results.

Conclusions: The most cost-effective strategy was 1st-line tyrosine kinase inhibitor therapy followed by 2nd-line immunotherapy. All pathways exceeded a commonly accepted WTP of USD 100-150,000/QALY. Our preliminary results warrant further studies to best inform real-world practices.
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http://dx.doi.org/10.1159/000508485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548874PMC
September 2020

Prevalence and clinical relevance of tumor-associated tissue eosinophilia (TATE) in breast cancer.

Surgery 2020 Sep 18. Epub 2020 Sep 18.

Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Japan; Department of Breast Surgery and Oncology, Tokyo Medical University, Japan; Department of Breast Surgery, Fukushima Medical University, Japan; Department of Surgery, Yokohama City University, Yokohama, Japan. Electronic address:

Background: Tumor-associated tissue eosinophilia (TATE) has been associated with outcomes in a variety of solid tumors; however, its role in breast cancer is not well defined. We hypothesized that tumor-associated tissue eosinophilia is associated with a high mutation and neoantigen load, and we assessed its correlation with cancer outcomes.

Methods: The Cancer Genome Atlas was analyzed for eosinophil signatures in breast cancer specimens. Descriptive analyses were performed, including the tumor-infiltrating cell composition using CIBERSORT, cytolytic activity score, and gene set enrichment analysis. Overall survival and disease-free survival were calculated using the Kaplan-Meier method.

Results: Out of 1069 cases analyzed, 40 (3.7%) had tissue eosinophils (the tumor-associated tissue eosinophilia group). Tumor-associated tissue eosinophilia was noted in 32.5% luminal, 5% HER2-positive, and 15% triple-negative breast cancer subtypes. The single nucleotide variant-neoantigen load was significantly higher in the tumor-associated tissue eosinophilia group (P = .005), with a higher nonsilent mutation rate (P = .01). The tumor-associated tissue eosinophilia group had lower cytolytic activity (P = .02) but had enriched MYC-targeted (P = .002), E2F-targeted (P = .04), deoxyribonucleic acid repair (P = .03), and unfolded protein response gene sets (P = .05). Tumor-associated tissue eosinophilia was associated with a trend toward improved disease-free survival (P = .06) but presented no differences in overall survival (P = .56).

Conclusion: Tumor-associated tissue eosinophilia was noted in 3.7% of breast cancers and was associated with a higher single nucleotide variant-neoantigen load and nonsilent mutation rate, similar to that of tumor-infiltrating lymphocytes in the triple-negative subtype. However, a lower cytolytic activity score and enriched cell proliferation-related gene sets implicate different roles for tumor-associated tissue eosinophilia than for tumor-infiltrating lymphocytes.
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http://dx.doi.org/10.1016/j.surg.2020.07.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969474PMC
September 2020

Age-Based Trends of Gastric Adenocarcinoma in the United States.

Am Surg 2020 Dec 31;86(12):1721-1727. Epub 2020 Aug 31.

Department of Surgery, Mayo Clinic, Jacksonville, FL, USA.

Background: Recent studies have shown an increase in the incidence of gastric cancer (GC) among young adults in Asia and Latin America. However, it is unknown if a similar trend is happening in the United States (US).

Methods: A retrospective review of the National Cancer Data Base was conducted to identify patients diagnosed with gastric adenocarcinoma between the years of 2004 and 2013.

Results: A total of 93 734 patients were included. The 2 age groups below 40 did not see a change in GC incidence; however, age groups above 40 had increasing incidence. Patients aged 18-25 had the largest proportion of stage 4 disease and a poor survival (median 11.5 months), compared to older patients.

Conclusion: Despite the increasing trend of GC among individuals, the incidence of GC among young adults is not increasing. However, this subpopulation presents at more advanced stages (clinical stage 4) and thus has worse survival.
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http://dx.doi.org/10.1177/0003134820947395DOI Listing
December 2020

Beyond Single Nucleotide Polymorphisms: Composite and Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients.

Front Genet 2020 11;11:889. Epub 2020 Aug 11.

Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, United States.

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both or . Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both and A metabolic composite based upon the polymorphisms: (rs776746), (10264272), ), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: > > > . Finally, a combined analysis using both and polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance ( < 0.001) with 50% lower AUC ( < 0.001) than Poor metabolizers. No differences in C were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The haplotype analysis detected significant associations of the wildtype haplotype to tacrolimus dose ( = 0.03), CL ( = 0.023), CL/LBW ( = 0.022), and AUC ( = 0.078). Finally, analysis combining and genotypes indicated that the presence of the 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite haplotypes. Consideration of multiple alleles using metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.
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http://dx.doi.org/10.3389/fgene.2020.00889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433713PMC
August 2020

Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience.

Ann Hematol 2020 Oct 17;99(10):2323-2328. Epub 2020 Aug 17.

Department of Medicine, Division of Hematology & Oncology, BronxCare Hospital Center, Bronx, NY, USA.

Infection with SARS-CoV-2 (COVID-19) can cause prothrombotic complications. We aim to study the frequency of thrombotic complications and impact of anticoagulation on outcomes in hospitalized patients. We conducted a retrospective chart review of 921 consecutive patients admitted to our hospital with COVID-19. Patients were divided into four groups depending on whether they were on anticoagulation prior to admission, started anticoagulation during the admission, received prophylactic anticoagulation, or did not receive any anticoagulation. At the time of analysis, 325 patients (35.3%) had died, while 544 patients (59%) had been discharged resulting in inpatient mortality of 37.3%. Male sex, age > 65 years, and high D-dimer at admission were associated with higher mortality. Sixteen patients (1.7%) had venous thromboembolism confirmed with imaging, 11 patients had a stroke, and 2 patients developed limb ischemia. Treatment with therapeutic anticoagulation was associated with improved inpatient mortality compared with prophylactic anticoagulation alone (63% vs 86.2%, p < 0.0001) in patients requiring mechanical ventilation. Other outcomes such as rates of liberation from mechanical ventilation and duration of mechanical ventilation were not significantly impacted by the type of anticoagulation.
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http://dx.doi.org/10.1007/s00277-020-04216-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430929PMC
October 2020

Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma.

Sci Rep 2020 08 6;10(1):13245. Epub 2020 Aug 6.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Despite advances in therapy for melanoma, heterogeneous responses with limited durability represent a major gap in treatment outcomes. The purpose of this study was to determine whether alteration in tumor blood flow could augment drug delivery and improve antitumor responses in a regional model of melanoma. This approach to altering tumor blood flow was termed "dynamic control." Dynamic control of tumor vessels in C57BL/6 mice bearing B16 melanoma was performed using volume expansion (saline bolus) followed by phenylephrine. Intravital microscopy (IVM) was used to observe changes directly in real time. Our approach restored blood flow in non-functional tumor vessels. It also resulted in increased chemotherapy (melphalan) activity, as measured by formation of DNA adducts. The combination of dynamic control and melphalan resulted in superior outcomes compared to melphalan alone (median time to event 40.0 vs 25.0 days, respectively, p = 0.041). Moreover, 25% (3/12) of the mice treated with the combination approach showed complete tumor response. Importantly, dynamic control plus melphalan did not result in increased adverse events. In summary, we showed that dynamic control was feasible, directly observable, and augmented antitumor responses in a regional model of melanoma. Early clinical trials to determine the translational feasibility of dynamic control are ongoing.
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http://dx.doi.org/10.1038/s41598-020-70233-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413248PMC
August 2020

Outcome of Everolimus-Based Therapy in Hormone-Receptor-Positive Metastatic Breast Cancer Patients After Progression on Palbociclib.

Breast Cancer (Auckl) 2020 23;14:1178223420944864. Epub 2020 Jul 23.

Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.

Background: Despite the approval of mTOR inhibitor everolimus and CDK4/6 inhibitors in the management of hormone-receptor-positive HER2 non-amplified metastatic breast cancer (HR+ HER2-MBC), the optimal sequence of therapy is unclear. There are no clinical data on efficacy of everolimus in HR+ HER2-MBC after cancer progresses on CDK4/6 inhibitors.

Objective: The objective of this study is to find the efficacy of everolimus in HR+ HER2-MBC after they progress on a CDK4/6 inhibitor palbociclib.

Methods: This is a retrospective, 2-institute review of HR+ HER2-MBC from Jan 2015 to March 2018 treated with everolimus after progression on palbociclib. Primary end point was median progression-free survival (PFS), secondary end points objective response rate (ORR), clinical benefit ratio (CBR), and overall survival (OS).

Results: Out of 41 women with median age 61 years (33, 87) enrolled, 66% had received adjuvant systemic therapy, 61% had visceral disease, and 95% had prior nonsteroidal aromatase inhibitors. About 83% women had 3 or more chemotherapy or hormonal therapies prior to everolimus. Kaplan-Meier estimates showed a median PFS of 4.2 months (95% confidence interval [CI]: 3.2-6.2). The median OS was 18.7 months (95% CI 9.5 to not reached). Objective response rate and CBR were both 17.1%.

Conclusion: Everolimus was associated with modest PFS and ORR in HR+ HER2-MBCs postprogression on palbociclib.
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http://dx.doi.org/10.1177/1178223420944864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378710PMC
July 2020

Utility of bone marrow aspirate and biopsy in staging of patients with T-cell lymphoma in the PET-Era - tissue remains the issue.

Leuk Lymphoma 2020 12 4;61(13):3226-3233. Epub 2020 Aug 4.

Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The role of 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computerized tomography (PET-CT) in evaluation of bone marrow involvement (BMI) in patients with T-cell lymphoma (TCL) is poorly understood. We investigated whether PET-CT could replace bone marrow aspiration and biopsy (BMAB) in TCL. Sixty patients with newly diagnosed TCL who underwent both diagnostic PET-CT and BMAB were identified. BMI was tissue-confirmed in 15 (25%) cases, however only 8 of these 15 showed BMI on PET-CT (sensitivity of 53.3%, specificity of 100%). BMI by BMAB was associated with lower progression-free survival (PFS) ( = 0.038 and overall survival (OS) ( 0.003) while PET-CT BMI was associated only with OS ( 0.02). BMI detected by BMAB in the setting of a negative PET-CT had similar inferior prognosis as BMI identified on PET-CT. Thus, PET-CT in TCL misses BMI in almost half of the cases detected by BMAB and hence cannot substitute BMAB in evaluation of TCL.
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http://dx.doi.org/10.1080/10428194.2020.1798950DOI Listing
December 2020

Prognostic Significance of Complete Pathologic Response Obtained with Chemotherapy Versus Chemoradiotherapy in Gastric Cancer.

Ann Surg Oncol 2021 Feb 31;28(2):766-773. Epub 2020 Jul 31.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Background: Few studies have compared the survival advantage of complete pathologic response (cPR) achieved through neoadjuvant chemotherapy (nCT) versus neoadjuvant chemoradiotherapy (nCRT) in gastric adenocarcinoma. Our study utilizes a large national cancer database to address this question.

Patients And Methods: This is a retrospective review of patients with clinical stage I to III gastric adenocarcinoma from 2004 to 2013 who received nCT or nCRT. Patients who achieved cPR were selected. Associations were evaluated using Mann-Whitney U and Fisher's exact tests. Survival information was summarized using standard Kaplan-Meier methods, where estimates of the median and 5-year survival rates were estimated with 95% confidence intervals.

Results: A total of 413 patients who had cPR were identified. Eighty-four patients received nCT and 329 patients received nCRT. Patients in the nCRT group had higher clinical stage (88.4% vs. 75.0%) and more proximal location of tumors (95.4% vs. 45.2%). The nCT group (n = 84) had a 94% 5-year survival rate, while the nCRT group's (n = 329) rate was 60% (p < 0.001). On Cox regression modeling using a propensity-weighted approach, nCT treatment was an independent predictor of improved overall survival (nCRT vs. nCT; HR 10.44, p < 0.001).

Conclusions: The use of nCT leads to a significant increase in overall survival in patients when compared with nCRT for those who achieved cPR in gastric adenocarcinoma. While this study is limited in identifying the cause for this difference in overall survival, this important finding nonetheless requires further investigation and should be considered in the development of future gastric cancer trials.
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http://dx.doi.org/10.1245/s10434-020-08921-9DOI Listing
February 2021

Age-Based Trends of Gastric Adenocarcinoma in the United States.

Am Surg 2020 May;86(5):407-414

Department of Surgery, Mayo Clinic, Jacksonville, FL, USA.

Background: Recent studies have shown an increase in the incidence of gastric cancer (GC) among young adults in Asia and Latin America. However, it is unknown if a similar trend is happening in the United States.

Methods: A retrospective review of the National Cancer Database was conducted to identify patients diagnosed with gastric adenocarcinoma between the years of 2004 and 2013.

Results: A total of 93 734 patients were included. The two age groups below 40 did not see a change in GC incidence; however, age groups above 40 had increasing incidence. Patients aged 18 to 25 had the largest proportion of stage 4 disease and a poor survival (median 11.5 months), compared to older patients.

Conclusion: Despite the increasing trend of GC among individuals, the incidence of GC among young adults is not increasing. However, this subpopulation presents at more advanced stages (clinical stage 4) and thus has worse survival.
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http://dx.doi.org/10.1177/0003134820918250DOI Listing
May 2020

Development and Cross-Validation of a Nomogram for Chronic Kidney Disease Following Robot-Assisted Radical Cystectomy.

J Endourol 2020 09 14;34(9):946-954. Epub 2020 Aug 14.

A.T.L.A.S (Applied Technology Laboratory for Advanced Surgery) Program, Department of Urologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

We sought to identify the factors associated with deterioration of renal functions after robot-assisted radical cystectomy, and to develop a nomogram to detect the probability of progression to chronic kidney disease (CKD). A retrospective review of our prospectively maintained database. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epidemiology Collaboration creatinine formula utilizing all follow-up creatinine values. CKD was defined as stage 3b (eGFR <45 mL/minute/1.73 m) based on the National Kidney Foundation classification. Kaplan-Meier curves were used to depict CKD-free survival. A multivariate Cox regression model was used to determine predictors for CKD and to build the perioperative nomogram. The data set comprised 442 patients with a median follow-up of 25 months (12-59). Thirty-seven percent developed CKD at a median of 9 months (4-18). CKD-free survival rates at 1, 3, and 5 years were 75%, 58%, and 50%, respectively. CKD was significantly associated with preoperative eGFR (hazards ratio [HR]: 0.96, 95% confidence interval [CI]: 0.95-0.97,  < 0.01), body mass index (HR: 1.03, 95% CI: 1.01-1.05,  = 0.03), Charlson Comorbidity Index ≥3 (HR: 2.20, 95% CI: 1.35-3.58,  < 0.01), diabetes (HR: 1.59, 95% CI: 1.09-2.31,  = 0.02), 90 days postoperative strictures (HR: 4.04, 95% CI: 1.76-9.30,  < 0.01), 90 days postoperative hydronephrosis (HR: 2.26, 95% CI: 1.34-3.79,  < 0.01), 90 days recurrent urinary tract infection (HR: 1.84, 95% CI: 1.08-3.14,  = 0.02), 90 days acute kidney injury (HR: 1.70, 95% CI: 1.19-2.43,  < 0.01), and node positive disease (HR: 1.94, 95% CI: 1.31-2.86,  < 0.01). A 5-year CKD-free survival nomogram was developed. We have developed and cross-validated a nomogram for detecting CKD-free survival. This nomogram may have a role in counseling and follow up of patients. This study was done after the approval of the IRB committee (I-79606).
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http://dx.doi.org/10.1089/end.2020.0451DOI Listing
September 2020

Exploring the role of survivin in neuroendocrine neoplasms.

Oncotarget 2020 Jun 9;11(23):2246-2258. Epub 2020 Jun 9.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Neuroendocrine tumors (NETs) are a heterogenous group of tumors. While most NETs have excellent prognosis, certain subsets have aggressive biology and have limited treatment options. We explored the role of survivin in NET as a prognostic and potentially therapeutic marker. Tissue microarrays of 132 patients were stained for survivin using immunohistochemistry (IHC) and correlated with outcomes. Using genomic database, we then correlated survivin (BIRC5) mRNA expression with radiosensitivity index (RSI) in 52 samples of NET. Finally, we studied the effect of radiation on survivin expression in human cell lines and the impact of knock-down of BIRC5 on cell proliferation and radiation sensitivity. We found that survivin positivity by IHC correlated with a shorter survival (overall survival 8.5 years vs. 18.3 years, < 0.001). There was a positive correlation between BIRC5 expression and RSI (r = 0.234, < 0.0001). Radiation exposure increased BIRC5 gene expression in a human carcinoid cell line. Knockout of BIRC5 using siRNA reduced proliferation of neuroendocrine cells but did not increase radiation sensitivity. We conclude that survivin expression in NET correlates with an inferior survival and survivin expression in human carcinoid cell lines increases after exposure to ionizing radiation.
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http://dx.doi.org/10.18632/oncotarget.27631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289533PMC
June 2020

Multicenter phase 2 trial of nintedanib in advanced nonpancreatic neuroendocrine tumors.

Cancer 2020 Aug 11;126(16):3689-3697. Epub 2020 Jun 11.

Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Background: Antiangiogenic-targeting agents have low response rates in patients with nonpancreatic neuroendocrine tumors (NETs). Nintedanib is an oral antiangiogenic agent that has inhibitory effects on the fibroblast growth factor receptor, which is highly expressed in NETs. The authors hypothesized that nintedanib would be active in patients with nonpancreatic NETs.

Methods: Patients with advanced, grade 1 or 2, nonpancreatic NETs who were receiving a stable dose of somatostatin analogue were enrolled. Nintedanib was administered at a dose of 200 mg twice daily in 28-day cycles. The primary endpoint was progression-free survival (PFS) at 16 weeks.

Results: Thirty-two patients were enrolled, and 30 were evaluable for the primary outcome. Most had radiographic disease progression within 12 months before enrollment. The 16-week PFS rate was 83%, and the median PFS and overall survival were 11.0 months and 32.7 months, respectively. Nintedanib was well tolerated and delayed deterioration in quality of life. The baseline serotonin level had a strong, positive correlation with activated but exhausted T cells.

Conclusions: Nintedanib is active in nonpancreatic NETs. The immunosuppressive effect of serotonin should be targeted in future clinical trials.
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http://dx.doi.org/10.1002/cncr.32994DOI Listing
August 2020

Racial differences in CD8 T cell infiltration in breast tumors from Black and White women.

Breast Cancer Res 2020 06 9;22(1):62. Epub 2020 Jun 9.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Background: African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome.

Methods: We examined the association of CD8 cytotoxic T cells with clinical-pathological variables in the Women's Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8 T cells were scored for each patient tumor sample with digital image analysis.

Results: Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8 T cell density (median 87.6/mm vs. 53.1/mm; p < 0.001). Within the overall population and in the population of Black women only, CD8 T cell density was significantly higher in younger patients and patients with high-grade and ER/PR-negative tumors. No significant associations were observed between CD8 T cell density and overall survival or breast cancer-specific survival in the overall population, or when Black patients were analyzed as a separate group. However, when stratified by subtype, Black women with triple-negative breast cancer and high CD8 T cell density showed a trend towards better overall survival in comparison with patients with low CD8 T cell density (HR = 0.51; 95% CI 0.25-1.04).

Conclusions: Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups.
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http://dx.doi.org/10.1186/s13058-020-01297-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285742PMC
June 2020