Nutritional impairment, psychological health and quality of life among older adults with advanced cancer: A secondary analysis of a randomized clinical trial.

BACKGROUND: Nutritional impairment is associated with treatment toxicity and worse overall survival in patients with cancer. We aimed to (1) evaluate the association of nutritional impairment with psychological health and quality of life (QOL) and (2) examine which measures of nutrition had the strongest association with psychological health and QOL among older adults receiving cancer treatment with palliative intent. METHODS: This secondary analysis was performed on baseline data from a nationwide cluster randomized clinical trial (ClinicalTrials.gov identifier: NCT02107443; PI: Mohile). Adults age ≥70 with advanced cancer and ≥1 geriatric assessment (GA) impairment were enrolled from 2014 to 2017. In line with geriatric oncology standards, we defined nutritional impairment as Mini Nutritional Assessment Short Form (MNA-SF) ≤11, body mass index (BMI) <21 kg/m2, or >10% involuntary weight loss in the past 6 months. We conducted multivariable linear regressions to evaluate the association of nutritional impairment with each measure of psychological health and QOL: Geriatric Depression Scale (GDS-15, range 0-15), Generalized Anxiety Disorder-7 (GAD-7, range 0-21), NCCN Distress Thermometer (NCCN DT, range 0-10), and Functional Assessment of Cancer Therapy-General (FACT-G, range 0-108). Analyses were adjusted for patient demographics, clinical characteristics, and GA. RESULTS: Among 541 patients, the mean age was 77 (range 70-96) and 60% had nutritional impairment. Mean baseline scores: GDS-15 3.1 (SD 2.7), GAD-7 2.9 (SD 4.0), NCCN DT 2.9 (SD 2.7), and FACT-G 80 (SD 15). In the adjusted model, compared to those with no nutritional impairment, older adults with nutritional impairment had greater depression (ß = 0.79, 95% CI 0.36-1.23) and anxiety severity (ß = 0.86, 95% CI 0.19-1.53), and worse QOL (ß = -6.31, 95% CI -8.62 to -4.00). Of the measures of nutrition, MNA-SF ≤11 demonstrated the strongest associations with depression, anxiety, distress, and QOL. CONCLUSION: Nutritional impairment is associated with impaired psychological health and worse QOL. Clinicians should use the MNA-SF to screen older adults for nutritional impairment and offer tailored supportive interventions.

Mortality burden of pre-treatment weight loss in patients with non-small-cell lung cancer: A systematic literature review and meta-analysis.

Cachexia, with weight loss (WL) as a major component, is highly prevalent in patients with cancer and indicates a poor prognosis. The primary objective of this study was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia (using established WL criteria prior to treatment initiation) in patients with non-small-cell lung cancer (NSCLC) in studies identified through a systematic literature review. The review was conducted according to PRISMA guidelines. Embase® and PubMed were searched to identify articles on survival outcomes in adult patients with NSCLC (any stage) and cachexia published in English between 1 January 2016 and 10 October 2021. Two independent reviewers screened titles, abstracts and full texts of identified records against predefined inclusion/exclusion criteria. Following a feasibility assessment, a meta-analysis evaluating the impact of cachexia, defined per the international consensus criteria (ICC), or of pre-treatment WL ≥ 5% without a specified time interval, on overall survival in patients with NSCLC was conducted using a random-effects model that included the identified studies as the base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. The standard measures of statistical heterogeneity were calculated. Of the 40 NSCLC publications identified in the review, 20 studies that used the ICC for cachexia or reported WL ≥ 5% and that performed multivariate analyses with hazard ratios (HRs) or Kaplan-Meier curves were included in the feasibility assessment. Of these, 16 studies (80%; n = 6225 patients; published 2016-2021) met the criteria for inclusion in the meta-analysis: 11 studies (69%) used the ICC and 5 studies (31%) used WL ≥ 5%. Combined criteria (ICC plus WL ≥ 5%) were associated with an 82% higher mortality risk versus no cachexia or WL < 5% (pooled HR [95% confidence interval, CI]: 1.82 [1.47, 2.25]). Although statistical heterogeneity was high (I2 = 88%), individual study HRs were directionally aligned with the pooled estimate, and there was considerable overlap in CIs across included studies. A subgroup analysis of studies using the ICC (HR [95% CI]: 2.26 [1.80, 2.83]) or WL ≥ 5% (HR [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Assessments of methodological, clinical and statistical heterogeneity indicated that the meta-analysis was robust. Overall, this analysis found that ICC-defined cachexia or WL ≥ 5% was associated with inferior survival in patients with NSCLC. Routine assessment of both weight and weight changes in the oncology clinic may help identify patients with NSCLC at risk for worse survival, better inform clinical decision-making and assess eligibility for cachexia clinical trials.

Pilot trial testing the effects of exercise on chemotherapy-induced peripheral neurotoxicity (CIPN) and the interoceptive brain system.

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a prevalent, dose-limiting, tough-to-treat toxicity involving numbness, tingling, and pain in the extremities with enigmatic pathophysiology. This randomized controlled pilot study explored the feasibility and preliminary efficacy of exercise during chemotherapy on CIPN and the role of the interoceptive brain system, which processes bodily sensations. Methods: Nineteen patients (65±11 years old, 52% women; cancer type: breast, gastrointestinal, multiple myeloma) starting neurotoxic chemotherapy were randomized to 12 weeks of exercise (home-based, individually tailored, moderate intensity, progressive walking and resistance training) or active control (nutrition education). At pre-, mid-, and post-intervention, we assessed CIPN symptoms (primary clinical outcome: CIPN-20), CIPN signs (tactile sensitivity using monofilaments), and physical function (leg strength). At pre- and post-intervention, we used task-free ("resting") fMRI to assess functional connectivity in the interoceptive brain system, involving the salience and default mode networks. Results: The study was feasible (74-89% complete data across measures) and acceptable (95% retention). We observed moderate/large beneficial effects of exercise on CIPN symptoms (CIPN-20, 0-100 scale: -7.9±5.7, effect size [ES]=-0.9 at mid-intervention; -4.8±7.3, -ES=0.5 at post-intervention), CIPN signs (ES=-1.0 and -0.1), and physical function (ES=0.4 and 0.3). Patients with worse CIPN after neurotoxic chemotherapy had lower functional connectivity within the default mode network (R2=40-60%) and higher functional connectivity within the salience network (R2=20-40%). Exercise tended to increase hypoconnectivity and decrease hyperconnectivity seen in CIPN (R2 = 12%). Conclusion: Exercise during neurotoxic chemotherapy is feasible and may attenuate CIPN symptoms and signs, perhaps via changes in interoceptive brain circuitry. Future work should test for replication with larger samples. ClinicalTrials.gov identifier NCT03021174.

Prognostic implications of tumor histology and microenvironment in surgically resected intrahepatic cholangiocarcinoma: a single institutional experience.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant neoplasm. Certain histologic features and the tumor microenvironment may impact disease progression. We aim to characterize the clinicopathologic features of ICC to identify prognostic factors. A total of 50 surgically resected ICC (partial or transplant) cases were analyzed. The cohort included 26 men and 24 women with a median age of 62 years. Eighteen (36%) cases were multifocal ICC with a mean largest tumor size of 6.5 cm. Neoadjuvant and adjuvant chemotherapy was done in eight (16%) and 33 (66%) patients, respectively. Histologically, 42 (84%) were small duct type, seven (14%) large duct type, and one mixed (2%). Thirty (60%) cases showed lymphovascular invasion (LVI) and 11 (22%) with perineural invasion (PNI). Twenty-eight (56%) cases demonstrated dense intratumoral hyaline fibrosis and 18 (36%) with tumor necrosis, each ≥ 10% tumor volume. On follow-up, 35 (70%) patients died of disease after a median disease-specific survival (DSS) of 21 months. Univariate analysis revealed that hyaline fibrosis and adjuvant chemotherapy were associated with better DSS, while tumor size, multifocality, necrosis, and peritumoral neutrophil to lymphocyte ratio were associated with worse DSS. In contrast, age, sex, small vs. large duct types, LVI, and individual inflammatory cell counts were not significant prognostic factors. In summary, ICC is a heterogeneous malignancy with variable clinical courses associated with tumor burden, histology, and microenvironment. Targeting specific components within the tumor microenvironments may be a promising approach for treatment in the future.

SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma: Clinicopathologic and immunohistochemical study.

The SWItch/Sucrose Non-Fermentable (SWI/SNF) complex is a multimeric protein involved in transcription regulation and DNA damage repair. SWI/SNF complex abnormalities are observed in approximately 14-34 % of pancreatic ductal adenocarcinomas (PDACs). Herein, we evaluated the immunohistochemical expression of a subset of the SWI/SNF complex proteins (ARID1A, SMARCA4/BRG1, SMARCA2/BRM, and SMARCB1/INI1) within our PDAC tissue microarray to determine whether SWI/SNF loss is associated with any clinicopathologic features or patient survival in PDAC. In our cohort, 13 of 353 (3.7 %) PDACs showed deficient SWI/SNF complex expression, which included 11 (3.1 %) with ARID1A loss, 1 (0.3 %) with SMARCA4/BRG1 loss, and 1 (0.3 %) with SMARCA2/BRM loss. All cases were SMARCB1/INI1 proficient. The SWI/SNF-deficient PDACs were more frequently identified in older patients with a mean age of 71.6 years (SD = 7.78) compared to the SWI/SNF-proficient PDACs which occurred at a mean age of 65.2 years (SD = 10.95) (P = 0.013). The SWI/SNF-deficient PDACs were associated with higher histologic grade, compared to the SWI/SNF-proficient PDACs (P = 0.029). No other significant clinicopathologic differences were noted between SWI/SNF-deficient and SWI/SNF-proficient PDACs. On follow-up, no significant differences were seen for overall survival and progression-free survival between SWI/SNF-deficient and SWI/SNF-proficient PDACs (both with P > 0.05). In summary, SWI/SNF-deficient PDACs most frequently demonstrate ARID1A loss. SWI/SNF-deficient PDACs are associated with older age and higher histologic grade. No other significant associations among other clinicopathologic parameters were seen in SWI/SNF-deficient PDACs including survival.

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Cachexia: A systemic consequence of progressive, unresolved disease.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

Effect of Yoga and Mediational Influence of Fatigue on Walking, Physical Activity, and Quality of Life Among Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) negatively affects survivors' walking, engagement in physical activity (PA), and quality of life (QoL). Yoga is an effective therapy for treating CRF; however, evidence from large clinical trials regarding how reducing CRF through yoga influences CRF's interference with survivors' walking, engagement in PA, and QoL is not available. We examined the effects of yoga and the mediational influence of CRF on CRF's interference with walking, PA, and QoL among cancer survivors in a multicenter phase III randomized controlled trial. PATIENTS AND METHODS: Cancer survivors (n=410) with insomnia 2 to 24 months posttreatment were randomized to a 4-week yoga intervention-Yoga for Cancer Survivors (YOCAS)-or standard care. A symptom inventory was used to assess how much CRF interfered with survivors' walking, PA, and QoL. The Multidimensional Fatigue Symptom Inventory-Short Form was used to assess CRF. Two-tailed t tests and analyses of covariance were used to examine within-group and between-group differences. Path analysis was used to evaluate mediational relationships between CRF and changes in CRF's interference with walking, PA, and QoL among survivors. RESULTS: Compared with standard care controls, YOCAS participants reported significant improvements in CRF's interference with walking, PA, and QoL at postintervention (all effect size = -0.33; all P≤.05). Improvements in CRF resulting from yoga accounted for significant proportions of the improvements in walking (44%), PA (53%), and QoL (45%; all P≤.05). CONCLUSIONS: A significant proportion (44%-53%) of the YOCAS effect on CRF's interference with walking, PA, and QoL was due to improvements in CRF among cancer survivors. Yoga should be introduced and included as a treatment option for survivors experiencing fatigue. By reducing fatigue, survivors further improve their walking, engagement in PA, and QoL.

A Novel Use for Pelvic MRI Scans to Estimate Lean Body Mass and Screen for Sarcopenia in Patients With Rectal Cancer.

BACKGROUND: Sarcopenia, the combination of low lean body mass and decreased muscle strength, is associated with significant morbidity and mortality among patients with colorectal cancer. Standard methods for assessing lean body mass and muscle strength, such as bioelectric impedance analysis and handgrip dynamometry, are rarely obtained clinically. Per National Cancer Center Network recommendations, pelvic MRI is routinely collected for staging and surveillance among patients with rectal cancer. However, there are no data assessing the relationship of pelvic MRI lean body mass measurements at the fifth lumbar vertebrae with bioelectric impedance analysis, handgrip strength, or abdominal CT in patients with rectal cancer. Therefore, we aimed to assess whether pelvic MRI lean body mass correlates with a standard for lean body mass measurement (bioelectric impedance analysis), muscle function (handgrip strength), and an imaging modality frequently used in the literature to identify sarcopenia (abdominal CT at the third lumbar vertebrae). IMPACT OF INNOVATION: Lean body mass measurements from routinely collected pelvic MRI at the fifth lumbar vertebrae accurately and reproducibly estimate lean body mass and modestly correlate with handgrip strength. Rectal cancer pelvic MRI may be repurposed for identifying sarcopenia without increasing inconvenience, ionizing radiation exposure, or expenditure to patients with rectal cancer. TECHNOLOGY, MATERIALS, AND METHODS: Patients with locally advanced rectal cancer with pretreatment bioelectric impedance analysis and handgrip strength measurements within 3 months of their staging pelvic MRI were eligible. Axial skeletal muscle areas were segmented using T1-weighted series pelvic MRI at the fifth lumbar vertebrae and abdominal CT at the third lumbar vertebrae using Slice-O-Matic (Tomovision, Montreal, Canada). Lean body mass (kilograms) was derived from skeletal muscle area with standard equations. Handgrip strength (kilograms) was the maximum of 3 dominant hand attempts in the standing anatomical position. The primary outcome was the agreement between lean body mass measured by pelvic MRI (at the fifth lumbar vertebrae) and bioelectric impedance analysis. Secondary outcomes included the concordance of pelvic MRI lean body mass (at the fifth lumbar vertebrae) with abdominal CT (at the third lumbar vertebrae) and handgrip strength. Additionally, the intra- and interobserver validity, internal consistency, and the mean difference (bias) between lean body mass measurements by pelvic MRI and bioelectric impedance analysis were evaluated. PRELIMINARY RESULTS: Sixteen patients were eligible. The average lean body mass was similar and consistent across 2 observers between bioelectric impedance analysis and pelvic MRI. There was a strong correlation between lean body mass measured on pelvic MRI, bioelectric impedance analysis, and abdominal CT. The reliability of 2 pelvic MRI lean body mass measurements (2 weeks apart by blinded observers) and the correlation of lean body mass between pelvic MRI and bioelectric impedance analysis was strong. Inter- and intraobserver correlation, reliability, and internal consistency were strong for the entire cohort. There was a moderate correlation between pelvic MRI lean body mass and handgrip strength. CONCLUSIONS: Lean body mass measured at the fifth lumbar vertebrae on pelvic MRI is reproducible and correlates strongly with measurements from bioelectric impedance analysis (standard) and abdominal CT at the third lumbar vertebrae and modestly with handgrip strength. These data suggest that MRI lean body mass measurements may be a method to screen patients with rectal cancer for sarcopenia. FUTURE DIRECTIONS: Future studies may evaluate changes in lean body mass on serial pelvic MRI studies among patients with rectal cancer.

Low Preoperative Serum Creatinine is Common and Associated With Poor Outcomes After Nonemergent Inpatient Surgery.

OBJECTIVE: To assess the association between low preoperative serum creatinine and postoperative outcomes. BACKGROUND: The association between low creatinine and poor surgical outcomes is not well understood. METHODS: We identified patients with creatinine in the 7 days preceding nonemergent inpatient surgery in the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2020. Multivariable logistic regression was used to examine the association between creatinine and 30-day mortality and major complications. RESULTS: Of 1,809,576 patients, 27.8% of males and 23.5% of females had low preoperative serum creatinine, 14.6% experienced complications, and 1.2% died. For males, compared with the reference creatinine of 0.85 to 1.04, those with serum creatinine ≤0.44 had 55% increased odds of mortality [ adjusted odds ratio (aOR), 1.55; 95% CI, 1.29-1.86] and 82% increased odds of major complications (aOR, 1.82; 95% CI, 1.69-1.97). Similarly, for females, compared with the reference range of 0.65 to 0.84, those with serum creatinine ≤0.44 had 49% increased odds of mortality (aOR, 1.49; 95% CI, 1.32-1.67) and 76% increased odds of major complications (aOR, 1.76; 95% CI, 1.70-1.83). These associations persisted for the total cohort, among those with mildly low albumin, and for those with creatinine values measured 8 to 30 days preoperatively. CONCLUSIONS: A low preoperative creatinine is common and associated with poor outcomes after nonemergent inpatient surgery. A low creatinine may help identify high-risk patients who may benefit from further evaluation and optimization.

Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. SIGNIFICANCE: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.

The Interplay Among Pancreatic Cancer, Cachexia, Body Composition, and Diabetes.

Pancreatic ductal adenocarcinoma (PDAC) is associated with complex changes in body composition. Visceral obesity and type 2 diabetes mellitus are established risk factors for developing PDAC; however, clinical and metabolic features of PDAC commonly lead to cancer cachexia, a hypermetabolic syndrome characterized by weight loss secondary to muscle and adipose tissue wasting. Reduction in muscle mass in patients with PDAC is associated with poorer survival in patients undergoing surgical resection and increased chemotherapy toxicity. Although no standardized treatment exists, a multidisciplinary, tailored, symptom-based approach is recommended to improve outcomes and quality of life for patients with PDAC and cachexia.

Time-restricted Eating to Address Cancer-related Fatigue among Cancer Survivors: A Single-arm Pilot Study.

Purpose: Cancer-related fatigue is a prevalent, debilitating condition that can persist for months or years after treatment. In a single-arm clinical trial, the feasibility and safety of a time-restricted eating (TRE) intervention were evaluated among cancer survivors, and initial estimates of within-person change in cancer-related fatigue were obtained. Methods: Participants were 4-60 months post-cancer treatment, were experiencing fatigue (≥ 3 on a scale 0-10), and were not following TRE. TRE entailed limiting all food and beverages to a self-selected 10-h window for 14 days. Participants reported their eating window in a daily diary and completed the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Brief Fatigue Inventory (BFI), and symptom inventory pre- and post-intervention. This study was pre-registered at clinicaltrials.gov in January 2020 (NCT04243512). Results: Participants (n=39) were 61.5 ± 12.4 years old and 1.8 ± 1.3 years post-treatment; 89.7% had had breast cancer. The intervention was feasible in that 36/39 (92.3%) of participants completed all questionnaires and daily diaries. It was also safe with no severe adverse events or rapid weight loss (average loss of 1.1 ± 2.3 pounds, p=0.008). Most adhered to TRE; 86.1% ate within a 10-h window at least 80% of the days, and the average eating window was 9.33 ± 1.05 h. Fatigue scores improved 5.3 ± 8.1 points on the FACIT-F fatigue subscale (p<0.001, effect size [ES]=0.55), 30.6 ± 35.9 points for the FACIT-F total score (p<0.001, ES=0.50), and -1.0 ± 1.7 points on the BFI (p<0.001, ES=-0.58). Conclusion: A 10-h TRE intervention was feasible and safe among survivors, and fatigue improved with a moderate effect size after two weeks. Limitations: This was a single-arm study, so it is possible that expectation effects were present for fatigue outcomes, independent of effects of TRE per se. However, this feasibility trial supports evaluation of TRE in randomized controlled trials to address persistent cancer-related fatigue.

Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer.

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. RESULTS: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. CONCLUSIONS: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.

Communication About Fall Risk in Community Oncology Practice: The Role of Geriatric Assessment.

PURPOSE: Falls are a modifiable source of morbidity for older adults with cancer, yet are underassessed in oncology practice. In this secondary analysis of a nationwide cluster-randomized controlled trial, we examined characteristics associated with patient-oncologist conversations about falls, and whether oncologist knowledge of geriatric assessment (GA) resulted in more conversations. METHODS: Eligible patients (ClinicalTrials.gov identifier: NCT02107443) were age ≥ 70 years, had stage III/IV solid tumor or lymphoma, were being treated with noncurative treatment intent, and ≥ 1 GA domain impairment. Patients in both arms underwent GA. At practices randomly assigned to the intervention arm, oncologists were provided a GA summary with management recommendations. In both arms, patients had one clinical encounter audio-recorded, transcribed, and coded to categorize whether a conversation about falls occurred. Generalized linear mixed models adjusted for arm, practice site, and other important covariates were used to generate proportions and odds ratios (ORs) from the full sample. RESULTS: Of 541 patients (intervention N = 293 and usual care N = 248, mean age: 77 years, standard deviation: 5.3), 528 had evaluable audio recordings. More patients had conversations about falls in the intervention versus usual care arm (61.3% v 10.3%, P < .001). Controlling for the intervention and practice site, history of falls (OR, 2.1; 95% CI, 1.3 to 3.6; P = .005) and impaired physical performance (OR, 4.7; 95% CI, 1.7 to 12.8; P = .002) were significantly associated with patient-oncologist conversations about falls. CONCLUSION: GA intervention increased conversations about falls. History of falls and impaired physical performance were associated with patient-oncologist conversations about falls in community oncology practice.

Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot.

The rising incidence and persistent dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for new effective systemic therapies. Immunotherapy has shown significant benefits in solid organ tumors, but has thus far been disappointing in the treatment of PDAC. There have been several promising preclinical studies, but translation into the clinic has proved to be challenging. This is likely a result of PDAC's complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Here, we summarize the mechanisms of immunosuppression within the PDAC tumor microenvironment and provide an up-to-date review of completed and ongoing clinical trials using various immunotherapy strategies.

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy.

PURPOSE: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

Association of Oncologist-Patient Communication With Functional Status and Physical Performance in Older Adults: A Secondary Analysis of a Cluster Randomized Clinical Trial.

Importance: The functional status and physical performance of older adults with cancer are underassessed and undertreated despite the high prevalence of impaired functional status and physical performance in this population and their associations with chemotherapy-induced toxic effects and mortality. Objective: To examine the association between providing oncologists with a geriatric assessment (GA) summary with recommendations and having oncologist-patient conversations about functional and physical performance. Design, Setting, and Participants: Data for this secondary analysis were collected from October 29, 2014, to April 28, 2017, for a national cluster randomized clinical trial conducted by the University of Rochester Cancer Center National Cancer Institute Community Oncology Research Program evaluating the effect of a GA intervention on patient satisfaction with communication about aging-related concerns. There were 17 practice clusters in the intervention group and 14 in the usual care group. All 541 participants underwent a GA including standardized functional and physical performance measures and had 1 clinical encounter audio-recorded, transcribed, and blindly coded to categorize conversations by GA domain. Participants were aged 70 years or older, with a stage III or IV solid tumor or lymphoma with palliative treatment intent, and impairment in 1 or more GA domain. Statistical analysis was performed from August 18, 2020, to January 10, 2022. Interventions: Oncologist practices randomized to the intervention received a GA summary and validated recommendations for each patient prior to the audio-recorded clinical encounter. Main Outcomes and Measures: The primary analysis of this clinical trial assessed the effect of the intervention on patient satisfaction with oncologist communication about aging-related concerns. This secondary analysis assessed the post hoc hypothesis that the intervention would be associated with an increase in the proportion of patients having conversations with their oncologists and receiving oncologist recommendations specific to functional and physical performance concerns. Results: A total of 541 patients (276 men [51%]; mean [SD] age, 77.5 [5.2] years [range, 70-96 years]) were analyzed at baseline. Excluding 13 patients without audio recordings, 86% of patients (95% CI, 78%-91%) in the intervention group vs 59% of patients (95% CI, 47%-69%; P < .001) receiving usual care had conversations about functional or physical performance. Conversations were more frequently initiated by oncologists in the intervention group (84%; 95% CI, 77%-90%) than oncologists in the usual care group (58%; 95% CI, 45%-70%; P < .001). Oncologists in the intervention group were more likely to address patients' concerns (43%; 95% CI, 33%-53%) than oncologists in the usual care group (17%; 95% CI, 10%-26%; P < .001). Conclusions and Relevance: In this secondary analysis of a cluster randomized clinical trial, providing oncologists with a GA summary was associated with an increase in the number of oncologist-patient conversations about functional and physical performance-related concerns with recommendations to address these concerns. These findings support the use of the GA summary and recommendations as important tools in caring for older adults with advanced cancer and functional or physical impairments. Trial Registration: ClinicalTrials.gov Identifier: NCT02107443.

Using Geriatric Assessment to Guide Conversations Regarding Comorbidities Among Older Patients With Advanced Cancer.

PURPOSE: Older patients with advanced cancer often have comorbidities that can worsen their cancer and treatment outcomes. We assessed how a geriatric assessment (GA)-guided intervention can guide conversations about comorbidities among patients, oncologists, and caregivers. METHODS: This secondary analysis arose from a nationwide, multisite cluster-randomized trial (ClinicalTrials.gov identifier: NCT02107443). Eligible patients were ≥ 70 years, had advanced cancer (solid tumors or lymphoma), and had impairment in at least one GA domain (not including polypharmacy). Oncology practices (n = 30) were randomly assigned to usual care or intervention. All patients completed a GA; in the intervention arm, a GA summary with recommendations was provided to their oncologist. Patients completed an Older Americans Resources and Services Comorbidity questionnaire at screening. The clinical encounter following GA was audio-recorded, transcribed, and coded for topics related to comorbidities. Linear mixed models examined the effect of the intervention on the outcomes adjusting for practice site as a random effect. RESULTS: Patients (N = 541) were 76.6 ± 5.2 years old; 94.6% of patients had at least one comorbidity with an average of 3.2 ± 1.9. The intervention increased the average number of conversations regarding comorbidities per patient from 0.52 to 0.99 (P < .01). Moreover, there were a greater number of concerns acknowledged (0.52 v 0.32; P = .03) and there was a 2.4-times higher odds of having comorbidity concerns addressed via referral, handout, or other modes (95% CI, 1.3 to 4.3; P = .004). Most oncologists in the intervention arm (76%) discussed comorbidities in light of the treatment plan, and 41% tailored treatment plans. CONCLUSION: Providing oncologists with a GA-guided intervention enhanced communication regarding comorbidities.