To Revise or Not Revise? Isolated Margin Positivity in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

Patient Navigation in Cancer Treatment: A Systematic Review.

PURPOSE OF REVIEW: Patient navigation promotes access to timely treatment of chronic diseases by eliminating barriers to care. Patient navigation programs have been well-established in improving screening rates and diagnostic resolution. This systematic review aimed to characterize the multifaceted role of patient navigators within the realm of cancer treatment. RECENT FINDINGS: A comprehensive electronic literature review of PubMed and Embase databases was conducted to identify relevant studies investigating the role of patient navigators in cancer treatment from August 1, 2009 to March 27, 2023. Fifty-nine articles were included in this review. Amongst studies focused on cancer treatment initiation, 70% found a significant improvement in treatment initiation amongst patients who were enrolled in patient navigation programs, 71% of studies focused on treatment adherence demonstrated significant improvements in treatment adherence, 87% of studies investigating patient satisfaction showed significant benefits, and 81% of studies reported a positive impact of patient navigators on quality care indicators. Three palliative care studies found beneficial effects of patient navigation. Thirty-seven studies investigated disadvantaged populations, with 76% of them concluded that patient navigators made a positive impact during treatment. This systematic review provides compelling evidence supporting the value of patient navigation programs in cancer treatment. The findings suggest that patient navigation plays a crucial role in improving access to care and optimizing treatment outcomes, especially for disadvantaged cancer patients. Incorporating patient navigation into standard oncology practice can reduce disparities and improve the overall quality of cancer care.

Out-of-Pocket Cost Modeling of Adjuvant Antiestrogen and Radiation Therapy After Lumpectomy for Early-Stage Breast Cancer Across Medicaid and Medicare Plans.

PURPOSE: The optimal adjuvant therapy (antiestrogen therapy [ET] + radiation therapy or ET alone, or in some reports radiation therapy alone) in older women with early-stage breast cancer has been highly debated. However, granular details on the role of insurance in the out-of-pocket cost for patients receiving ET with or without radiation therapy are lacking. This project disaggregates out-of-pocket costs by insurance plans to increase treatment cost transparency. METHODS AND MATERIALS: Several radiation therapy schedules are accepted standards as per the National Comprehensive Cancer Network guidelines. For our financial estimate model, we used the 5-fraction and 15-fraction radiation therapy and ET prescribed over a 5-year duration. The total aggregate out-of-pocket costs were determined from the sum of treatment costs, deductibles, and copays/coinsurance based on Medicaid, Original Medicare, Medigap Plan G, and Medicare Part D Rx plans. The model assumes a Medicare- and/or Medicaid-eligible patient ≥70 years of age with node-negative, early-stage estrogen-receptor-positive breast cancer. Patient out-of-pocket costs were estimated from publicly available insurance data from plan-specific benefit coverage materials using a 5-year time horizon. RESULTS: Original Medicare beneficiaries face a total out-of-pocket treatment charge of $2738.52 for ET alone, $2221.26 for 5-fraction radiation therapy alone, $2573.92 for 15-fraction radiation therapy alone, $3361.26 for combined ET+ 5-fraction radiation therapy, and $3713.92 for combined ET + 15-fraction radiation therapy. Medigap Plan G beneficiaries have an out-of-pocket charge of $1130.00 with radiation therapy alone and face an out-of-pocket of $2270.00 for ET alone and combined ET+ radiation therapy. For Medicaid beneficiaries, all treatments approved by Medicaid are covered without limit, resulting in no out-of-pocket expense for either adjuvant treatment option. CONCLUSIONS: This model (based on actual cost estimates per insurance plan rather than claims data), by estimating expenses within Medicare and Medicaid plans, provides a level of transparency to patient cost. With knowledge of the costs borne by patients themselves, treatment decisions informed by patients' individual priorities and preferences may be further enhanced.

Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. OBJECTIVE: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). METHODS: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). RESULTS: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. CONCLUSIONS: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Financial Toxicity in Radiation Oncology: Impact for Our Patients and for Practicing Radiation Oncologists.

With rising costs of diagnosis, treatment, and survivorship, financial burdens on patients with cancer and negative effects from high costs, called financial toxicity (FT), are growing. Research suggests that FT may be experienced by more than half of working-age cancer survivors and a similar proportion may incur debt or avoid recommended prescription medications due to treatment costs. As FT can lead to worse physical, psychological, financial, and survival outcomes, there is a discrete need to identify research gaps around this issue that constrain the development and implementation of effective screening and innovative care delivery interventions. Prior research, including within a radiation oncology-specific context, has sought to identify the scope of FT among patients with cancer, develop assessment tools to evaluate patient risk, quantify financial sacrifices, and qualify care compromises that occur when cancer care is unaffordable. FT is a multifactorial problem and potential solutions should be pursued at all levels of the health care system (patient-provider, institutional, and systemic) with specific regard for patients' individual/local contexts. Solutions may include selecting alternative treatment schedules, discussing financial concerns with patients, providing financial navigation services, low-cost transportation options, and system-wide health policy shifts. This review summarizes existing FT research, describes tools developed to measure FT, and suggests areas for intervention and study to help improve FT and outcomes for radiation oncology patients.

Toward chronopharmaceutical drug delivery patches and biomaterial coatings for the facilitation of wound healing.

Implantation of a biomaterial entails a form of injury where the integration of the implant into the host tissue greatly depends on the proper healing of the wound. Wound healing, itself, consists of a number of physiological processes, each occurring within a characteristic time window. A composite, multilayered polymeric drug delivery carrier for adhesion to the wound site and its supply with molecules released at precise time windows at which the stages in the healing process that they target occur is conceptualized here. We also present a simplified version of one such multilayered composite fabricated by a combination of solvent casting and dip coating, comprising the base poly(ε-caprolactone) layer reinforced with hydroxyapatite nanoparticles, poly(glutamic acid) mesolayer and poly-l-lysine surface layer, each loaded with specific small molecules and released at moderately distinct timescales, partially matching the chronology of wound healing. To that end, the base layer proved suitable for the delivery of an anti-inflammatory molecule or an angiogenic agent, the mesolayer appeared appropriate for the delivery of an epithelialization promoter or a granulation factor, and the adhesive surface layer interfacing directly with the site of injury showed promise as a carrier of a vasodilator. The drug release mechanisms were diffusion-driven, suggesting that the drug/carrier interaction is a key determinant of the release kinetics, as important as the nature of the polymer and its hydrolytic degradation rate in the aqueous medium. Morphological and phase composition analyses were performed, along with the cell compatibility ones, demonstrating solid adhesion and proliferation of both transformed and primary fibroblasts on both surfaces of the composite films. The design of the multilayered composite drug delivery carriers presented here is prospective, but requires further upgrades to achieve the ideal of a perfect timing of the sequential drug release kinetics and a perfect resonance with the physiological processes defining the chronology of wound healing.

Association between socioeconomic deprivation and presentation with a ruptured abdominal aortic aneurysm.

OBJECTIVE: Given the ongoing nature of research in the social determinants space and urges to improve United States Preventive Services Task Force screening efforts for abdominal aortic aneurysms (AAAs), this project aims to characterize the association between the level of socioeconomic deprivation, rurality, and ruptured AAA (rAAA) presentation across the United States. METHODS: We queried the Vascular Quality Initiative registry (2010-2019) for patients with AAAs. The area deprivation index (ADI) is an index from 1 to 100 used to capture socioeconomic status. ADI was grouped into quintiles, with the most deprived regions being quintile 5 and having the highest ADI index. Multivariable logistic regression assessed the association between ADI, rurality, and rAAA presentation overall and before age 65. RESULTS: Of the 82,909 patients included, 11,458 patients (14%) resided in the most socioeconomically deprived regions, and 18,083 patients (22%) lived in rural regions. Overall, 6831 patients (8.2%) experienced an rAAA, with 4696 patients (69%) residing in the three most deprived quintiles. Most patients underwent endovascular repair (n = 67,933; 82%), followed by open repair (n = 14,976; 18%). On multivariable analysis, residence in the most socioeconomically deprived region was associated with a near 1.5-fold increased odds of presenting with an rAAA compared with a residence in the least deprived regions (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.31-1.63; P < .001), whereas urban residence was associated with a decreased odds to present with an rAAA compared with rural residence (OR, 0.84; 95% CI, 0.79-0.89; P < .001). When stratifying the study population by the United States Preventive Services Task Force recommended age for AAA screening (65 years old), 14,147 patients (17%) were under 65. Of those under 65, 1381 patients (9.8%) experienced a rAAA, and 9955 patients (71%) resided in the three most deprived quintiles. Residence in the most socioeconomically deprived region was associated with an increased odds of presenting with an rAAA compared with residence in the least deprived region (OR, 1.31; 95% CI, 1.01-1.69; P = .042). However, there were no significant associations between rural residence and increased rAAA presentation among individuals under 65 (OR, 1.07; 95% CI, 0.93-1.23; P = .36). CONCLUSIONS: Among all patients in this study, patients residing in highly socioeconomically deprived or rural regions were more likely to present with an rAAA, but among those under 65, only residence in a socioeconomically deprived area was associated with increased odds of rAAA presentation. Understanding the effects of socioeconomic deprivation on rAAA presentation can identify at-risk populations for early AAA screening before rupture.

Surgical management of 1- to 2-cm neuroendocrine tumors of the appendix: Appendectomy or right hemicolectomy?

BACKGROUND: The surgical management of 1- to 2-cm neuroendocrine tumors of the appendix is an area of debate. We analyzed the clinical outcomes of appendectomy and compared them to right hemicolectomy. METHODS: We queried the National Cancer Database to identify patients treated for 1- to 2-cm ANETs from 2004 to 2018. Patients were stratified by surgical approach (appendectomy vs. hemicolectomy). Multivariable models were used to identify factors associated with the choice of surgical approach and the association between surgical approach and overall survival. RESULTS: Of the 3,189 patients we included, 1,573 (49.3%) underwent right hemicolectomy and 1,616 (50.7%) appendectomy. The appendectomy rate increased from 37.7% in 2004 to 58.9% in 2018. On multivariable analysis, patients with grade 2 and 3 tumors were less likely to undergo appendectomy alone (odds ratio = 0.41, 95% confidence interval = 0.26-0.66). Longer travel distance was associated with a higher likelihood of undergoing appendectomy (odds ratio = 2.52, 95% confidence interval = 1.15-5.51). After adjusting for tumor grade, appendectomy alone had similar survival to hemicolectomy (hazard ratio = 1.03, 95% confidence interval = 0.67-1.59). CONCLUSION: In this updated analysis of the National Cancer Database, right hemicolectomy was not associated with improved overall survival compared to appendectomy alone for 1- to 2-cm neuroendocrine tumors of the appendix. Although patients with grade 2 or 3 tumors are more likely to undergo right hemicolectomy, this procedure may not improve their treatment or overall outcome.

Out-of-Pocket Cost Modeling of Adjuvant Radiation Therapy Duration in Standard-of-Care Early Stage Breast Cancer Treatment Across Medicaid and Medicare Plans.

PURPOSE: For early stage breast cancer (BC), the choice of radiation therapy duration (1 vs 3 weeks) is highly debated. Cost and financial toxicity are major concerns that patients with BC face. Nonetheless, there remain limited discussions providing granular details of the role of insurance in the aggregate cost of 1 week versus 3 weeks of radiation therapy for patients. This project aims to disaggregate costs by plan to increase transparency of out-of-pocket (OOP) cost estimates in radiation therapy. METHODS AND MATERIALS: Treatment procedures were determined through the National Comprehensive Cancer Network guidelines. OOP treatment costs, deductibles, and copays/coinsurance were calculated by using Medicaid, Original Medicare, Medigap Plan G, and Medicare Part D prescription plans. The medicare.gov, medicaid.oh.gov, aarpmedicareplans.com, and the physician fee schedule from cms.gov were used to determine costs by treatment. Price estimates reflect actual costs per insurance plan rather than costs estimated from claims data. All procedures were considered to be performed in an Ohio hospital setting. One-week radiation therapy was defined as 5 fractions without boost, and 3-week radiation therapy was defined as 15 fractions without boost. RESULTS: Medicare beneficiaries with Original Medicare coverage face an OOP treatment charge of $649.24 for 1 week of radiation therapy and $1006.20 for 3 weeks of radiation therapy. Assuming the deductible is met postlumpectomy, Medigap Plan G beneficiaries are faced with no additional charges for both lengths of radiation therapy. Similarly for Medicaid beneficiaries (assuming treatment is approved by Medicaid), all expenses are covered without limit, resulting in no OOP expense. CONCLUSIONS: Considerations of 1 and 3 weeks of radiation therapy for postlumpectomy early-stage BC are often dependent on cancer characteristics and patient preferences. This model (based on actual cost estimates per insurance plan rather than claims data) compares OOP costs across Medicaid and Medicare plans, which more holistically informs providers and patients in radiation therapy duration decision making.

On-DNA hydroalkylation of N-vinyl heterocycles via photoinduced EDA-complex activation.

The emergence of DNA-encoded library (DEL) technology has provided a considerable advantage to the pharmaceutical industry in the pursuit of discovering novel therapeutic candidates for their drug development initiatives. This combinatorial technique not only offers a more economical, spatially efficient, and time-saving alternative to the existing ligand discovery methods, but also enables the exploration of additional chemical space by utilizing novel DNA-compatible synthetic transformations to leverage multifunctional building blocks from readily available substructures. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated N-vinyl heterocycles enabled by single-electron transfer (SET) and subsequent hydrogen atom transfer through electron-donor/electron-acceptor (EDA) complex activation is detailed. The simplicity and robustness of this method permits inclusion of a broad array of alkyl radical precursors and DNA-tethered nitrogenous heterocyles to generate medicinally relevant substituted heterocycles with pendant functional groups. Moreover, a successful telescoped route provides the opportunity to access a broad range of intricate structural scaffolds by employing basic carboxylic acid feedstocks.

Do discussions of financial burdens decrease long-term financial toxicity in adolescent and young adult cancer survivors?

PURPOSE: This study aims to evaluate the associations between patient-provider cost discussions with patient-reported out-of-pocket (OOP) spending and long-term financial toxicity (FT) among adolescent and young adult (AYA; 15-39 years old) cancer survivors. METHODS: Using a cross-sectional survey, we assessed the themes and quality of patient discussions with providers about financial needs and general survivorship preparation, quantified patients' levels of FT, and evaluated patient-reported OOP spending. We determined the association between cancer treatment cost discussion and FT using multivariable analysis. In a subset of survivors (n = 18), we conducted qualitative interviews and used thematic analysis to characterize responses. RESULTS: Two hundred forty-seven AYA survivors completed the survey at a mean of 7 years post treatment and with a median COST score of 13. 70% of AYA survivors did not recall having any cost discussion about their cancer treatment with a provider. Having any cost discussion with a provider was associated with decreased FT (ß = 3.00; p = 0.02) but not associated with reduced OOP spending (χ2 = 3.77; p = 0.44). In a second adjusted model, with OOP spending included as a covariate, OOP spending was a significant predictor of FT (ß = - 1.40; p = 0.002). Key qualitative themes included survivors' frustration about the lack of communication related to financial issues throughout treatment and in survivorship, feeling unprepared, and reluctance to seek help. CONCLUSION: AYA patients are not fully informed about the costs of cancer care and FT; the dearth of cost discussions between patients and providers may represent a missed opportunity to reduce costs.

Rural Communities in the United States Face Persistent Disparities in Access to Orthopaedic Surgical Care.

Background: Access to orthopaedic care across the United States (U.S.) remains an important issue, however, no recent study has examined disparities in rural access to orthopaedic care. The goals of the present study were to (1) investigate trends in the proportion of rural orthopaedic surgeons from 2013 to 2018 as well as the proportion of rural U.S. counties with access to such surgeons and (2) analyze characteristics associated with choice of a rural practice setting. Methods: The study analyzed the Centers for Medicare and Medicaid Services (CMS) Physician Compare National Downloadable File (PC-NDF) for all active orthopaedic surgeons from 2013 to 2018. Rural practice settings were defined using Rural-Urban Commuting Area (RUCA) codes. Linear regression analysis investigated trends in rural orthopaedic surgeon volume. Multivariable logistic regression evaluated the association of surgeon characteristics with rural practice setting. Results: The total number of orthopaedic surgeons increased 1.9%, from 21,045 (2013) to 21,456 (2018). Meanwhile, the proportion of rural orthopaedic surgeons decreased by roughly 0.9%, from 578 (2013) to 559 (2018). From a per capita perspective, the number of orthopaedic surgeons practicing in a rural setting per 100,000 population ranged from 4.55 orthopaedic surgeons per 100,000 in 2013 and 4.47 per 100,000 in 2018. Meanwhile, the number of orthopaedic surgeons practicing in an urban setting ranged from 6.63 per 100,000 in 2013 and 6.35 per 100,000 in 2018. The surgeon characteristics most associated with decreased odds of practicing orthopaedic surgery in a rural setting included earlier career-stage (OR: 0.80, 95% CI: [0.70-0.91]; p < 0.001) and sub-specialization status (OR: 0.40, 95% CI: [0.36-0.45]; p < 0.001). Conclusion: Existing rural-urban disparities in musculoskeletal healthcare access have persisted over the past decade and could worsen. Future research should investigate the effects of orthopaedic workforce shortages on travel times, patient cost burden, and disease specific outcomes. Level of Evidence: IV.

Adjuvant Chemotherapy Is Associated with Improved Survival for Stage III Colon Cancer When Initiated Beyond 8 Weeks.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemotherapy (AC) within 6-8 weeks of surgical resection for patients with stage III colon cancer. However, postoperative complications or prolonged surgical recovery may affect the receipt of AC. The aim of this study was to assess the utility of AC for patients with prolonged postoperative recovery. METHODS: We queried the National Cancer Database (2010-2018) for patients with resected stage III colon cancer. Patients were categorized as having either normal or prolonged length of stay (PLOS: >7 days, 75th percentile). Multivariable Cox proportional hazard regression and logistic regressions were used to identify factors associated with overall survival and receipt of AC. RESULTS: Of the 113,387 patients included, 30,196 (26.6%) experienced PLOS. Of the 88,115 (77.7%) patients who received AC, 22,707 (25.8%) initiated AC more than 8 weeks after surgery. Patients with PLOS were less likely to receive AC (71.5% vs. 80.0%, OR: 0.72, 95%CI=0.70-0.75) and displayed inferior survival (75 vs. 116 months, HR: 1.39, 95%CI=1.36-1.43). Receipt of AC was also associated with patient factors such as high socioeconomic status, private insurance, and White race (p<0.05 for all). AC within and after 8 weeks of surgery was associated with improved survival for patients with both normal LOS and PLOS (normal LOS: <8 weeks HR: 0.56, 95% CI: 0.54-0.59, >8 weeks HR: 0.68, 95% CI: 0.65-0.71; PLOS: <8 weeks HR: 0.51, 95% CI: 0.48-0.54, >8 weeks HR: 0.63, 95% CI 0.60-0.67). AC was associated with significantly improved survival if initiated up to 15 weeks postoperatively (normal LOS: HR: 0.72, 95%CI=0.61-0.85; PLOS: HR: 0.75, 95%CI=0.62-0.90), and very few patients (<3.0%) initiated AC beyond this time. CONCLUSION: Receipt of AC for stage III colon cancer may be affected by surgical complications or otherwise prolonged recovery. Timely and even delayed AC (>8 weeks) are both associated with improved overall survival. These findings highlight the importance of delivering guideline-based systemic therapies, even after complicated surgical recovery.

The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure.

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, ß1AR and ß2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs-DREADD to activate CD8-restricted Gαs signaling and show that a Gαs-PKA signaling axis promotes CD8+ T cell dysfunction and immunotherapy failure. These data indicate that Gαs-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.

Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Comparative Genomic Insights into Bacterial Induction of Larval Settlement and Metamorphosis in the Upside-Down Jellyfish Cassiopea.

Bacteria are important mediators of the larval transition from pelagic to benthic environments for marine organisms. Bacteria can therefore dictate species distribution and success of an individual. Despite the importance of marine bacteria to animal ecology, the identity of inductive microbes for many invertebrates are unknown. Here, we report the first successful isolation of bacteria from natural substrates capable of inducing settlement and metamorphosis of the planula larvae stage of a true jellyfish, the upside-down jellyfish Cassiopea xamachana. Inductive bacteria belonged to multiple phyla, with various capacity to induce settlement and metamorphosis. The most inductive isolates belonged to the genus Pseudoalteromonas, a marine bacterium known to induce the pelago-benthic transition in other marine invertebrates. In sequencing the genome of the isolated Pseudoalteromonas and a semiinductive Vibrio, we found biosynthetic pathways previously implicated in larval settlement were absent in Cassiopea inducing taxa. We instead identified other candidate biosynthetic gene clusters involved in larval metamorphosis. These findings could provide hints to the ecological success of C. xamachana compared to sympatric congeneric species within mangrove environments and provide avenues to investigate the evolution of animal-microbe interactions. IMPORTANCE The pelagic to benthic transition for the larvae of many marine invertebrate species are thought to be triggered by microbial cues. The microbial species and exact cue that initiates this transition remains unknown for many animals. Here, we identify two bacterial species, a Pseudoalteromonas and a Vibrio, isolated from natural substrate that induce settlement and metamorphosis of the upside-down jellyfish Cassiopea xamachana. Genomic sequencing revealed both isolates lacked genes known to induce the life history transition in other marine invertebrates. Instead, we identified other gene clusters that may be important for jellyfish settlement and metamorphosis. This study is the first step to identifying the bacterial cue for C. xamachana, an ecologically important species to coastal ecosystems and an emerging model system. Understanding the bacterial cues provides insight into marine invertebrate ecology and evolution of animal-microbe interactions.

Discordance Between Conventional and Detailed Lymph Node Analysis in Resected, Node-negative Pancreatic or Ampullary Adenocarcinomas and Association With Adverse Survival Outcomes: A Single-institution Analysis.

OBJECTIVE: To assess the frequency of occult metastases (OM) in patients with resected pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) discovered on detailed pathologic examination on lymph nodes (LNs) previously considered negative by conventional analysis and to examine the association between OM and overall survival (OS). BACKGROUND: Poor prognosis of patients with no pathologic evidence of LN metastases may be due to OM that is not detected on conventional LN analysis. METHODS: Patients with LN-negative resected PDAC or AA (2010-2020) were identified from our institutional database. Original hematoxylin and eosin ( H and E ) slides were reanalyzed. In addition, selected LN were analyzed by H and E (3 sections/LN) and pan-cytokeratin (AE1-AE3/PCK26) immunohistochemistry. RESULTS: A total of 598 LNs from 74 LN-negative patients were reexamined. Nineteen patients (25.7%) had OM; 9 (47.4%) were found with immunohistochemistry but not on H and E . The number of positive LNs ranged from 1 to 3. No clinicodemographic, pathologic, or treatment-related factors were associated with OM. On conventional LN analysis, 3/19 patients (15.8%) had stage IA, 9/34 (26.5%) had stage IB, and 7/19 (36.8%) had stage IIA. On detailed LN analysis, 11/19 patients (57.9%) were upstaged to IIB, whereas 8/19 (42.1%) had isolated tumor cells only (N0i+). OM was associated with shorter OS (median OS: 22.3 vs 50.5 months; hazard ratio=3.95, 95% CI: 1.58-9.86). CONCLUSIONS: There is a 26% discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with shorter OS.

Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer.

OBJECTIVE: To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS: Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS: Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (ß = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS: Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.