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Background Anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1) immunotherapy promotes systemic anti-tumor immunity through expanding neoantigen-specific CD8 + T cells, but it is less effective in patients with liver metastases. Nearly 20% of non-small cell lung cancer (NSCLC) patients develop liver metastases, and these patients are characterized by fewer and less active effector T cells. Preclinical work has shown that liver metastases cause systemic immunosuppression through siphoning neoantigen-specific CD8 + T cells from systemic circulation with subsequent macrophage-mediated intrahepatic death. In preclinical models, liver metastasis-directed radiotherapy can reverse this systemic immunosuppression and sensitize tumors to anti-PD-(L)1 therapy. However, it is unknown whether liver metastasis-directed stereotactic ablative radiotherapy (liver SABR) can sensitize tumors to anti-PD-(L)1 in human NSCLC. Methods The HAMMER-NSCLC trial is a randomized phase II study planned to enroll 68 patients with newly diagnosed metastatic NSCLC – without known targetable EGFR, ALK, BRAF, or ROS1 alterations – involving the liver. Patients will be randomized 1:1 to standard-of-care anti-PD-(L)1-based immunotherapy +/- platinum-based chemotherapy (Arm 1) or standard-of-care treatment plus liver SABR (Arm 2). Patients can be enrolled and randomized up to the start of cycle 3 of immunotherapy. For patients in Arm 2, it is preferred that liver SABR be completed prior to initiating standard-of-care anti-PD-(L)1 therapy. Liver SABR must be completed prior to the third cycle of anti-PD-(L)1 or within 90 days of anti-PD-(L)1 therapy initiation, whichever is sooner. The primary endpoint is progression-free survival (PFS). Secondary endpoints include the safety/tolerability of liver SABR when added to anti-PD-(L)1-based immunotherapy, overall survival, and hepatic progression. The study needs 68 patients combined in the two arms to demonstrate an improvement in PFS with a hazard ratio of 0.6 to provide 80% power with a one-sided alpha of 10%. Discussion The HAMMER-NSCLC trial will determine if adding liver SABR to first-line anti-PD-(L)1-based immunotherapy +/- platinum-based chemotherapy can improve median PFS in patients with NSCLC liver metastases. Trial registration NCT05657873, registered 12/12/2022.

Background Multimodality therapy incorporating a combination of cytoreductive surgery (CRS), intraperitoneal (IP) and systemic therapy continues to evolve for peritoneal carcinomatosis (PC) However, treatment and outcomes vary depending on tumor of origin. Aims To develop Appropriate Use Criteria (AUC) guidelines to facilitate treatment decision‐making for patients with PC based on available evidence. Materials and Methods The American Radium Society (ARS) multidisciplinary expert panel performed a comprehensive systematic review. Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well‐established modified Delphi consensus methodology. Results Treatment of PC is often treated with a combination of CRS and IP ± systemic chemotherapy but specific recommendations exist for different tumor types and outcomes vary. Discussion Treatment of PC is complex and varies depending on origin of primary tumor and extent of disease. These AUC assist in patient and treatment selection for different clinical scenarios. Conclusion A summary of recommendations is outlined to guide practitioners on the management of PC from different tumor origins.

Treatment of advanced and relapsed cervical cancer is frequently ineffective, due in large part to chemoresistance. To examine the pathways responsible, we employed the cervical carcinoma-derived SiHa and CaSki cells as cellular models of resistance and sensitivity, respectively, to treatment with chemotherapeutic agents, doxorubicin, and cisplatin. We compared the proteomic profiles of SiHa and CaSki cells and identified pathways with the potential to contribute to the differential response. We then extended these findings by comparing the expression level of genes involved in reactive oxygen species (ROS) metabolism through the use of a RT-PCR array. The analyses demonstrated that the resistant SiHa cells expressed higher levels of antioxidant enzymes. Decreasing or increasing oxidative stress led to protection or sensitization, respectively, in both cell lines, supporting the idea that cellular levels of oxidative stress affect responsiveness to treatment. Interestingly, doxorubicin and cisplatin induced different profiles of ROS, and these differences appear to contribute to the sensitivity to treatment displayed by cervical cancer cells. Overall, our findings demonstrate that cervical cancer cells display variable profiles with respect to their redox-generating and -adaptive systems, and that these different profiles have the potential to contribute to their responses to treatments with chemotherapy.

Background: Abdominoperineal resection (APR) has been advocated for persistent or recurrent disease after failure of chemoradiation (CRT) for anal squamous cell cancer (SCC). Treatment with salvage APR can potentially achieve a cure. This study aimed to analyze oncological outcomes for salvage APR in a recent time period at a comprehensive cancer center. Methods: A retrospective review of all patients who underwent APR for biopsy-proven persistent or recurrent anal SCC between 1 January 2007 and 31 December 2020 was performed. Patients with stage IV disease at the time of initial diagnosis and patients with missing data were excluded. Univariate analysis was used with a chi-square test for categorical variables, and non-parametric tests were used for continuous variables. Kaplan–Meier survival analysis was performed to evaluate disease-specific (DSS), post-APR local recurrence-free (RFS), and disease-free survival (DFS). Results: A total of 96 patients were included in the analysis: 39 (41%) with persistent disease and 57 (59%) with recurrent SCC after chemoradiation had been completed. The median follow-up was 22 months (IQR 11–47). Forty-nine patients (51%) underwent extended APR and/or pelvic exenteration. Eight (8%) patients developed local recurrence, 30 (31%) developed local and distant recurrences, and 16 (17%) developed distant recurrences alone. The 3-year DSS, post-APR local recurrence-free survival, and disease-free survival were 53.8% (95% CI 43.5–66.5%), 54.5% (95% CI 44.4–66.8%), and 26.8% (95% CI 18.6–38.7%), respectively. In multivariate logistic regression analysis, positive microscopic margin (OR 10.0, 95% CI 2.16–46.12, p = 0.003), positive nodes in the surgical specimen (OR 9.19, 95% CI 1.99–42.52, p = 0.005), and lymphovascular invasion (OR 2.61 95% CI 1.05–6.51, p = 0.04) were associated with recurrence of disease. Gender, indication for APR (recurrent vs. persistent disease), HIV status, extent of surgery, or type of reconstruction did not influence survival outcomes. Twenty patients had targeted tumor-sequencing data available. Nine patients had PIK3CA mutations, seven of whom experienced a recurrence. Conclusions: Salvage APR for anal SCC after failed CRT was associated with poor disease-specific survival and low recurrence-free survival. Anal SCC patients undergoing salvage APR should be counseled that microscopic positive margins, positive lymph nodes, or the presence of lymphovascular invasion in the APR specimen are prognosticators for disease relapse. Our results accentuate the necessity for additional treatment strategies for the ongoing treatment challenge of persistent or recurrent anal SCC after failed CRT.

High risk types of Human Papillomavirus are the causative agents of virtually all cases of cervical cancer, 50-90% of other anogenital cancers and approximately 30% of oral and pharyngeal cancers. The high-risk types encode two viral oncogenes, E6 and E7, which work together to initiate cell transformation. The approximately 50 amino acid product of the E6* transcript is expressed during the early stages of HPV infection. In this study, we found that expression of E6* increased the level of reactive oxygen species (ROS) in both HPV+ and HPV- cells. This increased oxidative stress led to higher levels of DNA damage. The observed increase in ROS may be due to a decrease in cellular anti-oxidant activity, as we found that E6* expression also led to decreased expression of SOD and Gpx, These studies indicate that E6* may play an important role in virus-induced mutagenesis by increasing oxidative stress and DNA damage.

HPV-DNA integration into cellular chromatin is usually a necessary event in the pathogenesis of HPV-related cancer; however, the mechanism of integration has not been clearly defined. Breaks must be created in both the host DNA and in the circular viral episome for integration to occur, and studies have shown that viral integration is indeed increased by the induction of DNA double strand breaks. Inflammation generates reactive oxygen species, which in turn have the potential to create such DNA strand breaks. It is plausible that these breaks enable a greater frequency of HPV-DNA integration, and in this way contribute to carcinogenesis. Consistent with this idea, co-infections with certain sexually transmitted diseases cause cervical inflammation, and have also been identified as cofactors in the progression to cervical cancer. This article examines the idea that inflammation facilitates HPV-DNA integration into cellular chromatin through the generation of reactive oxygen species, thereby contributing to carcinogenesis.

Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status. In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10). This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.

Background Survival following melanoma and chronic lymphocytic leukemia (CLL) have both been individually associated with previous history of non-melanoma skin cancers (specifically keratinocyte carcinomas [KC]). Furthermore, melanoma and CLL have been reported to occur within the same patients. The survival experience of patients with both cancers is understudied, and the role of history of KC is unknown. Additional research is needed to tease apart the independent associations between KC and CLL survival, KC and melanoma survival, and the co-occurrence of all three cancers. Methods A retrospective cohort study was conducted among patients who were diagnosed with melanoma and/or CLL at a comprehensive cancer center between 2008 and 2020. Multivariable Cox regression models were used to examine the association between history of KC and survival following melanoma and/or CLL with careful consideration of calendar year of diagnosis, treatment regimens and other risk factors. A nested case–control study comparing patients with both CLL and melanoma to those with only CLL or only melanoma was conducted to compare blood parameters across the three groups. Results A time-dependent association was observed between history of KC and favorable melanoma survival within 4 years following diagnosis and poorer survival post 7 years after melanoma diagnosis. History of KC was not significantly associated with survival following the diagnosis of CLL, after adjustment for clinical factors including historical/concurrent melanoma. Patients with co-occurring melanoma and CLL tended to be diagnosed with melanoma first and had elevated blood parameters including white blood cell and lymphocyte counts as compared with patients who were diagnosed with only melanoma. Conclusions History of KC was an independent predictor of survival following melanoma but not of CLL. Additional studies are needed to determine if blood parameters obtained at the time of melanoma diagnosis could be used as a cost-effective way to identify those at high risk of asymptomatic CLL for the promotion of earlier CLL diagnosis.

Significant racial disparities in prostate cancer (PCa) outcomes have been reported, with African‐American men (AAM) more likely to endure adverse oncologic outcomes. Despite efforts to dissipate racial disparities in PCa, a survival gap persists and it remains unclear to what extent this disparity can be explained by known clinicodemographic factors. In this study, we leveraged our large institutional database, spanning over 25 years, to investigate whether AAM continued to experience poor PCa outcomes and factors that may contribute to racial disparities in PCa. A total of 7307 patients diagnosed with PCa from 1989 through 2015 were included. Associations of race and clinicodemographic characteristics were analyzed using chi‐square for categorical and Mann–Whitney U‐test for continuous variables. Racial differences in prostate cancer outcomes were analyzed using competing risk analysis methods of Fine and Gray. Median follow‐up time was 106 months. There were 2304 deaths recorded, of which 432 resulted from PCa. AAM were more likely to be diagnosed at an earlier age (median 60 vs. 65 years, P = <0.001) and were more likely to have ≥1 comorbidities (13.6% vs. 7.5%, P < 0.001). In a multivariate competing risk model, adjusted for baseline covariates, AAM experienced significantly higher risk of PCSM compared to NHW men (HR, 1.62, 95% CI, 1.02–2.57, P = 0.03) NHW. Among men diagnosed at an older age (>60 years), racial differences in PCSM were more pronounced, with AAM experiencing higher rates of PCSM (HR, 2.05, 95% CI, 1.26–3.34, P = 0.003). After adjustment of clinicodemographic and potential risk factors, AAM continue to experience an increased risk of mortality from PCa, especially older AAM. Furthermore, AAM are more likely to be diagnosed at an early age and more likely to have higher comorbidity indices. Study will evaluate if AAM continued to experience poor Prostate Cancer (PCa) outcomes and factors that may contribute to racial disparities in PCa.

Purpose History of keratinocyte carcinoma (KC) has been associated with survival following the diagnosis of a second primary malignancy (SPM), with the direction of the association varying by cancer type. Research is needed to elucidate the role of other key factors in this association. Methods A retrospective cohort study was conducted among patients newly diagnosed and/or treated at Moffitt Cancer Center in December 2008–April 2020 with breast cancer, lung cancer, melanoma, colon cancer, prostate cancer, and non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) ( n  = 29,156). History of KC was obtained from new patient intake questionnaires. Age- and stage-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated to estimate the association between history of KC and survival following each cancer, stratified by demographic/clinical characteristics. Results KC history was most prevalent in patients with melanoma (28.7%), CLL (19.8%) and lung cancer (16.1%). KC history was associated with better overall survival following prostate cancer (HR = 0.74, 95% CI = 0.55–0.99) and poorer overall survival following CLL (HR = 1.73, 95% CI = 1.10–2.71). Patients with a history of KC experienced better survival within the first four years of a melanoma diagnosis (HR = 0.79, 95% CI = 0.67–0.92); whereas poorer survival was observed for patients who survived 7 + years after a melanoma diagnosis (HR = 2.18, 95% CI = 1.17–4.05). Stratification by treatment and stage revealed directional differences in the associations between KC history and survival among patients with breast cancer and melanoma. Conclusions KC history may be a predictor of survival following an SPM, possibly serving as a marker of immune function and/or DNA damage repair capacity.