Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer.

BACKGROUND: Treatment outcomes of advanced non-small cell lung cancer (NSCLC) have substantially improved with immune checkpoint inhibitors (ICI), although only approximately 19% of patients respond to immunotherapy alone, increasing to 58% with the addition of chemotherapy. The gut microbiome has been recognized as a modulator of ICI response via its priming effect on the host immune response. Antibiotics as well as chemotherapy reduce gut microbial diversity, hence altering composition and function of the gut microbiome. Since the gut microbiome may modify ICI efficacy, we conducted a retrospective study evaluating the effects of prior antibiotic or chemotherapy use on NSCLC patient response to ICI. METHODS: We retrospectively evaluated 256 NSCLC patients treated between 2011-2017 at Moffitt Cancer Center with ICI ± chemotherapy, examining the associations between prior antibiotic or chemotherapy use, overall response rate and survival. Relative risk regression using a log-link with combinatorial expectation maximization algorithm was performed to analyze differences in response between patients treated with antibiotics or chemotherapy versus patients who didn't receive antibiotics or chemotherapy. Cox proportional hazards models were constructed to evaluate associations between risk factors and overall survival. RESULTS: Only 46 (18% of 256) patients used antibiotics prior to and/or during ICI treatment, and 146 (57%) had prior chemotherapy. Antibiotic users were 8% more likely to have worse overall response rate (RR:1.08; CI:0.93-1.26; p = 0.321), as well as a 35% worse overall survival (HR:1.35; CI:0.91-2.02; p = 0.145), although results were not statistically significant. However, prior use of chemotherapy was significantly associated with poor ICI response (RR:1.24; CI:1.05-1.47; p = 0.013) and worse overall survival (HR:1.47; CI:1.07-2.03; p = 0.018). CONCLUSIONS: Patients receiving antibiotics prior to and/or during ICI therapy might experience worse treatment outcomes and survival than unexposed patients, although these associations were not statistically significant and hence warrant further prospective study. Prior chemotherapy significantly reduced ICI response and overall survival. Antibiotic or chemotherapy exposure may negatively impact ICI response, perhaps through disruption of the eubiotic gut microbiome.

Prostate cancer-specific mortality burden by risk group among men with localized disease: Implications for research and clinical trial priorities.

OBJECTIVE: To estimate contemporary population-based patterns of the relative burden of prostate cancer-specific mortality (PCSM) attributable to each N0M0 prostate cancer risk-group, that may guide prioritization in research, trial design, and clinical practice. METHODS: We categorized 2004-2015 Surveillance, Epidemiology, and End Results database patients by risk group (low, favorable intermediate, unfavorable intermediate, high, and very highrisk). Using the Fine-Gray method, we calculated the relative burden of 10-year PCSM attributable to each risk group. RESULTS: Among N = 337 162 men (6.8-year median follow-up; median age 65 years), the relative proportion of low-, favorable intermediate-, unfavorable intermediate-, high-, and very high-risk diagnoses were 29.9% (N = 100 969), 31.1% (N = 104 696), 17.9% (N = 60 360), 18.1% (N = 61 023), and 3.0% (N = 10 114). Within 10 years of diagnosis, among patients who died of prostate cancer (N = 15 064), 5.0% (N = 746) had low-risk, 13.7% (N = 2060) had favorable intermediate-risk, 16.1% (N = 2429) had unfavorable intermediate-risk, 47.8% (N = 7196) had high-risk, and 17.5% (N = 2633) had very high-risk disease at diagnosis. Patients aged 65 and older accounted for 51.9% of all diagnoses and 72.3% of 10-year PCSM. Although black patients accounted for 15.0% of low-risk diagnoses, they accounted for 20.6% of 10-year PCSM. White patients accounted for 80.3% of low-risk diagnoses and 75.7% of 10-year PCSM. CONCLUSION: Although high-risk and very high-risk disease account for one-fifth of diagnoses, they account for two-thirds of 10-year PCSM. Older patients and black patients with low-risk disease accounted for a disproportionately large proportion of deaths. These findings support targeting research toward high-risk disease and ensuring adequate representation of older and black men in clinical trials.

Validation of a subclassification for high-risk prostate cancer in a prospective cohort.

BACKGROUND: A subgroup of men with favorable high-risk prostate cancer (T1c with either a Gleason score of 4 + 4 = 8 and a prostate-specific antigen [PSA] level <10 ng/mL or a Gleason score of 6 and a PSA level >20 ng/mL) has been associated with improved outcomes in comparison with other standard high-risk patients. This study was designed to validate the prognostic utility of a subclassification for high-risk disease with a prospectively collected data set. METHODS: This study identified 3033 men from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had been diagnosed from 1993 to 2001 with clinically localized prostate cancer-either intermediate-risk disease (clinical stage T2b-c, a Gleason score of 7, or a PSA level of 10 to 20 ng/mL) or high-risk disease (clinical stage T3-T4, a Gleason score of 8-10, or a PSA level >20 ng/mL)-that was managed with radical prostatectomy or radiation therapy. Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) for pathological T3 to T4 or N1 (pT3-T4/pN1) disease. Fine and Gray competing risks regression was used to determine adjusted hazard ratios (aHRs) of prostate cancer-specific mortality (PCSM). RESULTS: The median follow-up was 5.7 years. Patients with favorable high-risk disease had lower 8-year PCSM in comparison with patients with standard high-risk disease (2.2% vs 10.8%; aHR, 0.26; 95% confidence interval [CI], 0.09-0.73; P = .01) but similar PCSM in comparison with patients with intermediate-risk disease (2.2% vs 2.2%; aHR, 0.90; 95% CI, 0.32-2.54; P = .84). Among those who underwent surgery, those with favorable high-risk disease had lower odds of pT3-T4/pN1 disease than those with standard high-risk disease (46.2% vs 63.3%; aOR, 0.50; 95% CI, 0.27-0.94; P = .03). CONCLUSIONS: This study validates the prognostic utility of a subclassification for high-risk disease in a prospectively collected patient cohort. Patients with favorable high-risk disease have PCSM similar to that of patients with intermediate-risk disease and significantly better than that of patients with standard high-risk disease. Future trials are needed to assess possible de-intensification of therapy for favorable high-risk disease.

General and Health-Related Internet Use Among Cancer Survivors in the United States: A 2013-2018 Cross-Sectional Analysis.

BACKGROUND: A significant proportion of cancer survivors endorse ongoing health information needs and may use the internet to access information. We assessed patterns and predictors of general and health-specific internet use among cancer survivors. METHODS: Using data from the National Health Interview Survey (NHIS), which was administered in 2013 through 2018, for adults reporting a cancer diagnosis, sample weight-adjusted estimates defined prevalence and multivariable logistic regressions defined adjusted odds ratios (aORs) of general and health-specific internet use, adjusting for relevant sociodemographic covariates, including healthcare satisfaction as the primary independent variable. The analysis for health-specific internet use was also repeated including a sex (female vs male)*healthcare satisfaction (very satisfied/somewhat satisfied vs somewhat dissatisfied/very dissatisfied) interaction term. RESULTS: Among 12,970 survivors of cancer, general and health-specific internet use increased from 2013 to 2018 (from 63.2% to 70.8% and from 46.8% to 52.2%, respectively; P<.05 for both). Survivors who were very dissatisfied with healthcare were more likely to use the internet for health information compared with those who were very satisfied (59.5% vs 48.0%; aOR, 1.78; 95% CI, 1.20-2.64; P=.004). Younger age, female sex, higher educational attainment, and higher socioeconomic status were all associated with increased reported use of the internet for both general and health-specific purposes (P<.001 for all). There was a significant sex*healthcare satisfaction interaction (P=.009) such that for female survivors, healthcare dissatisfaction was associated with higher odds of health-specific internet use (61.4% vs 52.5%; P<.001; men, P=.97). No association was found between healthcare satisfaction and general internet use (P=.42). CONCLUSIONS: The increasing proportion of survivors of cancer using the internet for health-specific information may be associated with self-reported dissatisfaction with healthcare. Efforts are needed to improve both access to the internet and the quality of cancer-relevant online health information, and to enhance patients' online health literacy.

The Association of Rural Residence With Surgery and Adjuvant Radiation in Medicare Beneficiaries With Rectal Cancer.

Purpose: Radiation therapy and surgery are fundamental site-directed therapies for nonmetastatic rectal cancer. To understand the relationship between rurality and access to specialized care, we characterized the association of rural patient residence with receipt of surgery and radiation therapy among Medicare beneficiaries with rectal cancer. Methods and Materials: We identified fee-for-service Medicare beneficiaries aged 65 years or older diagnosed with nonmetastatic rectal cancer from 2016 to 2018. Beneficiary place of residence was assigned to one of 3 geographic categories (metropolitan, micropolitan, or small town/rural) based on census tract and corresponding rural urban commuting area codes. Multivariable regression models were used to determine associations between levels of rurality and receipt of both radiation and proctectomy within 180 days of diagnosis. In addition, we explored associations between patient rurality and characteristics of surgery and radiation such as minimally invasive surgery (MIS) or intensity modulated radiation therapy (IMRT). Results: Among 13,454 Medicare beneficiaries with nonmetastatic rectal cancer, 3926 (29.2%) underwent proctectomy within 180 days of being diagnosed with rectal cancer, and 1792 (13.3%) received both radiation and proctectomy. Small town/rural residence was associated with an increased likelihood of receiving both radiation and proctectomy within 180 days of diagnosis (adjusted subhazard ratio, 1.15; 95% CI, 1.02-1.30). Furthermore, small town/rural radiation patients were significantly less likely to receive IMRT (adjusted odds ratio, 0.62; 95% CI, 0.48-0.80) or MIS (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97) than metropolitan patients. Conclusions: Although small town/rural Medicare beneficiaries were overall more likely to receive both radiation and proctectomy for their rectal cancer, they were less likely to receive preoperative IMRT or MIS as part of their treatment regimen. Together, these findings clarify that among Medicare beneficiaries, there appeared to be a similar utilization of radiation resources and time to radiation treatment regardless of rural/urban status.

Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non-RA-MIBC are unknown. OBJECTIVE: To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non-RA-MIBC. DESIGN, SETTING, AND PARTICIPANTS: We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non-RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival. RESULTS AND LIMITATIONS: We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non-RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC. CONCLUSIONS: We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC. PATIENT SUMMARY: Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation.

Association Between Travel Distance and Use of Postoperative Radiation Therapy Among Men With Organ-Confined Prostate Cancer: Does Geography Influence Treatment Decisions?

PURPOSE: After radical prostatectomy, men with adverse pathologic features or a persistent postoperative detectable prostate-specific antigen (PSA) are candidates for postoperative radiation therapy (PORT). Previous data have suggested disparities in receipt of adjuvant radiation therapy for adverse pathologic features according to travel distance. Among patients without adverse pathologic features (pT2 disease and negative margins), the main indication for PORT is a persistent postoperative detectable PSA. However, it remains unknown whether the rate of receipt of PORT in this cohort of men with persistently detectable PSA is related to travel distance from the treating facility. METHODS AND MATERIALS: Using the National Cancer Database, we identified 170,379 men with prostate cancer diagnosed from 2004 to 2015 managed with upfront surgery who were found to have pT2 disease with negative surgical margins. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% confidence intervals (CIs) of receiving PORT as the primary dependent variable and distance (<5, 5-10, 10-20, ≥20 miles from the treatment facility) as the primary independent variable. RESULTS: Within our cohort, progressively farther distance from the treatment facility was associated with lower rates of PORT. In patients living <5 miles, 5 to 10 miles, 10 to 20 miles, and >20 miles from the treating facility, rates of PORT of were 1.37% (referent), 1.16% (AOR, 0.90; 95% CI, 0.79-1.04; P = .158), 0.98% (AOR, 0.80; 95% CI, 0.70-0.93; P = .003), and 0.64% (AOR, 0.47; 95% CI, 0.41-0.54; P < .001), respectively. CONCLUSIONS: For men with localized prostate cancer without adverse pathologic features managed with surgery, increasing distance from treatment facility was associated with lower receipt of PORT. Given that the rate of a persistent postoperative detectable PSA is unlikely to depend on the distance to the treatment facility, these findings raise the possibility that the geographic availability of radiation treatment facilities influences the decision to undergo PORT for patients with persistent postoperative detectable PSA.

Clinical characterization of radiation-associated muscle-invasive bladder cancer.

OBJECTIVE: To characterize the presentation, patterns of care, and outcomes of radiation-associated muscle-invasive bladder cancer (RA-MIBC) compared to primary (non-radiation associated) MIBC. RA-MIBC has been suggested to represent a more aggressive disease variant and be more difficult to treat compared to primary (non-radiation associated) MIBC. METHODS: We identified 60,090 patients diagnosed with MIBC between 1988-2015 using the Surveillance, Epidemiology, and End Results database and stratified patients based on whether radiation had been administered to a prior pelvic primary cancer. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC compared to primary MIBC. RESULTS: There were 1,093 patients with RA-MIBC and 58,997 patients with primary MIBC. RA-MIBCs were more likely to be T4 at diagnosis (21.0% vs 17.3%, P < .001), and less likely to be node-positive (10.3% vs 17.1%, P < .001). The rate of 5-year BCSM was significantly higher for patients with RA-MIBC vs primary MIBC (56.1% vs 35.3%, AHR 1.24, P < .001), even after stratification by other tumor, treatment and patient-specific factors. CONCLUSION: RA-MIBCs tended to present with higher grade and T stage disease and were less likely to receive curative treatment. Even when accounting for stage, grade, and receipt of treatment, patients with RA-MIBC had worse survival compared to those with primary MIBC. These findings suggest that RA-MIBC present unique clinical challenges and may also represent a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand the biology of RA-MIBC and develop improved treatment approaches.

Factors Influencing Noncompletion of Radiation Therapy Among Men With Localized Prostate Cancer.

PURPOSE: Treatment noncompletion may occur with radiation therapy (RT), especially with protracted treatment courses such as RT for prostate cancer, and may affect the efficacy of RT. For men with localized prostate cancer managed with primary RT, we evaluated associations between rates of treatment noncompletion and RT fractionation schedules. METHODS AND MATERIALS: The National Cancer Database identified men diagnosed from 2004 to 2014 treated with primary RT. Patients receiving 180 cGy/fraction or 200 cGy/fraction were defined as having completed radiation therapy if they received ≥41 fractions of 180 cGy/fraction or ≥37 fractions of 200 cGy/fraction. Stereotactic body radiation therapy (SBRT) was defined as 5 to 8 fractions of 600 to 800 cGy/fraction. Odds ratios compared rates of treatment noncompletion, adjusting for sociodemographic covariates. A propensity-adjusted multivariable Cox regression assessed the association between treatment completion and overall survival. RESULTS: Of 157,657 patients, 95.7% (n = 150,847) received conventional fractionation and 4.3% (n = 6810) received SBRT. Rates of noncompletion were 12.5% (n = 18,803) among patients who received conventional fractionation and 1.9% (n = 131) among patients who received SBRT (odds ratio [OR] versus conventional, 0.21; 95% confidence interval [CI], 0.18-0.26; P < .001). The rate of noncompletion among 25,727 African American patients was 12.8%, compared with 11.8% among 126,199 white patients (OR, 1.14; 95% CI, 1.09-1.19; P < .001). In a subgroup analysis, the disparity in noncompletion persisted for conventional fractionation (13.2% vs 12.3%, respectively; OR, 1.09; 95% CI, 1.05-1.13; P < .001), but not for SBRT (2.2% vs 1.8%, respectively; OR, 1.26; 95% CI, 0.79-2.00; P = .34). Noncompletion was associated with worse survival in a propensity-adjusted multivariable analysis (hazard ratio, 1.25; 95% CI, 1.22-1.29; P < .001). CONCLUSIONS: SBRT was associated with lower rates of RT noncompletion among men with localized prostate cancer. African American race was associated with greater rates of treatment noncompletion, although the disparity may be decreased among men receiving SBRT.

Is it Time to Say Goodbye to Culture and Sensitivity? The Case for Culture-independent Urology.

Next-generation sequencing has highlighted the limitations of conventional culture methods in the role of urology while discovering the intricate details of the role of microbiota in urologic health and disease. This review article explores: the utility and limitations of conventional culture methods; how culture-independent technologies are revolutionizing medicine; and how the implementation of these technologies may lead to improved patient outcomes. Finally, this article discusses the barriers to widespread adoption of culture-independent technologies, with suggestions for how these hurdles may be overcome.

The human gastrointestinal microbiota and prostate cancer development and treatment.

The human gastrointestinal microbiome contains commensal bacteria and other microbiota that have been gaining increasing attention in the context of cancer development and response to treatment. Microbiota play a role in the maintenance of host barrier surfaces that contribute to both local inflammation and other systemic metabolic functions. In the context of prostate cancer, the gastrointestinal microbiome may play a role through metabolism of estrogen, an increase of which has been linked to the induction of prostatic neoplasia. Specific microbiota such as Bacteroides, Streptococcus, Bacteroides massiliensis, Faecalibacterium prausnitzii, Eubacterium rectalie, and Mycoplasma genitalium have been associated with differing risks of prostate cancer development or extensiveness of prostate cancer disease. In this Review, we discuss gastrointestinal microbiota's effects on prostate cancer development, the ability of the microbiome to regulate chemotherapy for prostate cancer treatment, and the importance of using Next Generation Sequencing to further discern the microbiome's systemic influence on prostate cancer.

Trends, Quality, and Readability of Online Health Resources on Proton Radiation Therapy.

PURPOSE: Many patients weighing cancer treatment options may consider relatively novel options including proton radiation therapy (PRT) and turn to the Internet for online health resources (OHR). However, quality and readability of OHR for radiation oncology therapies has been shown to need improvement. Because the OHR that patients access can influence their treatment decisions, our study sought to understand the patterns of use, quality, and readability of OHR on PRT. METHODS AND MATERIALS: To validate the need to assess OHR on PRT, we assessed search patterns in the United States for the search phrase "proton therapy" using Google Trends. The Google search engine was then queried for websites with PRT information using 10 search phrases. The subsequent websites were analyzed for readability by the Flesch-Kincaid Grade Level and a Composite Grade Level (CGL) metric comprised of 5 readability metrics. Quality was analyzed using the DISCERN instrument. RESULTS: Search volume index for "proton therapy" increased by an average of 2.0% each year for the last 15 years (January 1, 2005 to June 1, 2019, P < .001). States that had a greater number of proton centers tended to have a greater relative search volume in Google (P < .001). Of the 45 unique websites identified, the mean Flesch-Kincaid Grade Level was 12.0 (range, 7.3-18.6) and the mean CGL was 12.4 (range, 7-18). In addition, 80% of PRT pages required greater than 11th grade CGL. The mean DISCERN score of all websites was 39.8 out of 75, which corresponds to "fair" quality OHR. CONCLUSIONS: Despite increasing interest in PRT OHR, in general, PRT websites require reading levels much higher than currently recommended, making PRT OHR less accessible to the average patient. Provision of high-quality PRT OHR at the appropriate reading level may increase comprehension of PRT, improve patient autonomy, and facilitate informed decision-making among radiation oncology patients.

Soluble extracts from carioca beans (Phaseolus vulgaris L.) affect the gut microbiota and iron related brush border membrane protein expression in vivo (Gallus gallus).

The effect of soluble extracts with putative prebiotic ability extracted from various bean varieties on the intestinal brush border membrane (BBM) iron related proteins, and intestinal bacterial populations were evaluated using the Gallus gallus model and by the intra-amniotic administration procedure. Eight treatment groups [(non-injected; 18 MΩ H2O; 40 mg/mL Inulin; 50 mg/mL BRS Perola (carioca standard); 50 mg/mL BRS Cometa (carioca, Fe biofortified); 50 mg/mL BRS Esteio (black, standard); 50 mg/mL SMN 39 (black, Fe biofortified); 50 mg/mL BRS Artico (white, standard)] were utilized. Tested groups reduced the relative abundance of Clostridium and E. coli compared to the Inulin group (positive control) and they did not affect the relative abundance of Bifidobacterium and Lactobacillus compared to the negative control (18MΩ H2O). The relative expression of zinc transporter 1, ferroportin and amino peptidase were up-regulated in the BRS Cometa group (Fe-biofortified carioca beans). Results suggest that soluble extracts from carioca beans may improve the iron bioavailability by affecting intestinal bacterial populations, and BBM functionality.