Exploring unmet concerns in home hospice cancer care: Perspectives of patients, informal caregivers, palliative care providers, and family physicians.

OBJECTIVES: The study examines perspectives of patients in home hospice care; their informal caregivers; palliative health-care providers (HCPs); and family physicians, all regarding patients' unmet needs and quality of life (QoL)-related concerns. METHODS: Participants from all 4 groups were approached within 2 months after the patient's admission to the home hospice care unit. Participants completed Edmonton Symptom Assessment Scale (ESAS) and Measure Yourself Concerns and Wellbeing (MYCAW) questionnaires, for patient's QoL-related concerns. Qualitative analysis of short narratives was conducted using ATLAS.ti software for systematic coding. RESULTS: In total, 78 participants completed the study questionnaires: 24 patients, 22 informal caregivers, 22 palliative HCPs, and 11 family physicians. Informal caregivers gave higher scores (i.e., greater severity) than patients for fatigue on ESAS (p = 0.009); and family physicians lower scores than patients for ESAS drowsiness (p = 0.046). Compared with patients, palliative HCPs gave higher scores for patient emotional-spiritual concerns (77.2% vs. 41.7%, p = 0.02); lower scores for gastrointestinal concerns (p = 0.048); and higher scores for overall function (p = 0.049). Qualitative assessment identified a gap between how patients/informal caregivers vs. palliative HCPs/family physicians regard emotional-spiritual themes, including discussing issues related to death and dying. SIGNIFICANCE OF RESULTS: The findings of the present study suggest that exploring a multifaceted cohort of home hospice patients, informal caregivers, palliative HCPs, and family physicians may provide insight on how to reduce communication gaps and address unmet needs of patients, particularly regarding emotional and spiritual concerns. CONCLUSIONS: While the 4 groups were similar in their scoring of patient QoL-related concerns, there were discrepancies for some concerns (e.g., patient fatigue) and expectations regarding the need to discuss emotional and spiritual concerns, including on death and dying. Educational initiatives with programs providing training to all 4 groups may help bridge this gap, creating a more open and collaborative hospice care environment.

Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockade.

While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) - known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.

MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells.

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here, we report that preexposure of melanoma cells to cognate T cells enhanced the chemotaxis of new T cells in vitro. The effect was HLA class I-restricted and IFNγ-dependent, as it was abolished by ß2M-knockdown, MHC-blocking antibodies, JAK1 inhibitors, JAK1-silencing and IFNgR1-blocking antibodies. RNA sequencing (RNA-seq) of 73 melanoma metastases showed a significant correlation between the interferon-inducible p150 isoform of adenosine-deaminase-acting-on-RNA-1 (ADAR1) enzyme and immune infiltration. Consistent with this, cocultures of cognate melanoma/T-cell pairs led to IFNγ-dependent induction of ADAR1-p150 in the melanoma cells, as visualized in situ using dynamic cell blocks, in ovo using fertilized chick eggs, and in vitro with Western blots. ADAR1 staining and RNA-seq in patient-derived biopsies following immunotherapy showed a rise in ADAR1-p150 expression concurrently with CD8+ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNγ-driven enhanced T-cell migration, confirming its mechanistic role. Silencing and overexpression of the constitutive isoform of ADAR1, ADAR1-p110, decreased and increased T-cell migration, respectively. Chemokine arrays showed that ADAR1 controls the secretion of multiple chemokines from melanoma cells, probably through microRNA-mediated regulation. Chemokine receptor blockade eliminated the IFNγ-driven T-cell chemotaxis. We propose that the constitutive ADAR1 downregulation observed in melanoma contributes to immune exclusion, whereas antigen-specific T cells induce ADAR1-p150 by releasing IFNγ, which can drive T-cell infiltration.

Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti­programmed cell death 1 (anti­PD-1)­based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ­positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.

Elective neck dissection versus observation in patients with head and neck cutaneous squamous cell carcinoma.

BACKGROUND: The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. METHODS: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. RESULTS: A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. CONCLUSIONS: Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1ß in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Gut Microbiota and Antitumor Immunity: Potential Mechanisms for Clinical Effect.

Several landmark preclinical studies have shown an association between the gut microbiota and the effectiveness of immunotherapy for cancer. These studies have sparked clinical trials aimed at modulating the gut microbiota in order to improve clinical response rates to immunotherapy. Despite this, the mechanisms through which the gut microbiota influences the effectiveness of immunotherapy are still incompletely characterized. Preclinical and preliminary clinical findings from numerous types of gut microbiota modulation studies, including fecal transplantation, probiotics, consortia, and diet, demonstrate that favorable microbiota modulation is associated with increased intratumoral infiltration of CD8+ effector T cells. This CD8+ T-cell infiltration is often associated with enhanced intratumoral activity of T-helper type 1 cells and dendritic cells and a lower density of immunosuppressive cells. Herein, we discuss how gut microbiota may affect the activity of immune cells by at least three interlacing mechanisms: activation of pattern recognition receptors, molecular mimicry, and impact of metabolites. We also discuss the therapeutic potential and limitations of the different gut microbiota modulation techniques and their putative mechanisms of immune activation.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

Inclusion of extranodal extension in the lymph node classification of cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC. METHODS: This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models. RESULTS: No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195). CONCLUSIONS: The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.

Immune co-culture cell microarray - a feasible tool for high-throughput functional investigation of lymphocyte-cancer interactions.

Omics analyses often result in dozens to hundreds of potential targets, requiring validation for their biological relevance. Current high-throughput functional investigation methods are frequently labor-intensive, expensive, and display low reproducibility. The Immune Co-Culture Cell Microarray (ICCM) is a formalin-fixed paraffin-embedded cell block microarray based on co-cultures of patient-derived tumor-infiltrating lymphocytes and their autologous melanoma cells. Each ICCM slide represents the same experiment and can be stained using standard immunohistochemistry and immunofluorescence techniques. Functional dynamics assessment of both proteins and microRNAs using ICCM stained slides demonstrated similar findings to flow cytometry assays and to previously published patient-derived biopsy reports.

Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls.

PURPOSE OF REVIEW: While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field. RECENT FINDINGS: Knowledge of immunotherapy toxicity has continually evolved, and several major oncologic societies have recently released new or updated guidelines. Keeping up with the evolving field of immunotherapy and related toxicities is crucial, because ICI use, in combination with other agents, will only continue to increase and likely result in new and different patterns of irAEs. Providing clear and concise references for clinicians will help ensure proper irAE evaluation and management going forward. We present one such reference here, covering management of common and/or serious irAEs.

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma.

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence.

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.

Locally advanced rectal adenocarcinoma: Are preoperative short and long course radiotherapy truly equivalent?

In the neoadjuvant treatment of locally advanced rectal adenocarcinoma, long- and short-course radiotherapy are considered to be of equivalent efficacy based upon several randomized trials. The present study assessed the effect of radiotherapy dose on overall survival. Using the National Cancer Database (2006-2013) 458 individuals with clinical stage II/III rectal adenocarcinoma treated were identified, with either short- (25 Gy) or long- (45 or 50.4 Gy) course neoadjuvant radiotherapy followed by surgery, without neoadjuvant or adjuvant chemotherapy. Multivariate COX regression was employed to evaluate differences in overall survival according to radiotherapy regimen. An association with improved overall survival in individuals treated with long- compared with short-course radiotherapy was demonstrated (HR=0.50, 0.34-0.73). The 30- and 90-day post-surgery mortality rates were higher in the short-course group when compared with the long-course group (12.2 vs. 2.4%; and 18.5 vs. 5.4%, respectively). Following the exclusion of patients that succumbed within 90-days post-surgery, overall survival advantage in the long-course group compared with the short-course group was maintained [hazard ratio (HR)=0.62, 0.39-0.99], with a median overall survival of 25.3 months (IQR 16.9-41.6) for the short-course group compared with 43.5 months (IQR 25.6-67.9) for the long-course group. To the best of our knowledge, the present results suggest for the first time that long-course radiotherapy is associated with an improved overall survival compared with short-course radiotherapy in locally advanced rectal adenocarcinoma in the absence of chemotherapy usage. This possible advantage is clinically relevant mainly in patients who cannot tolerate systemic chemotherapy.

Recurrent Pneumonitis in Patients with Melanoma Treated with Immune Checkpoint Inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have changed the oncologic landscape in the past few years. Alongside impressive antitumor responses, new novel immune-related adverse events (irAEs) have emerged; pneumonitis is an irAE that can potentially be fatal and necessitates a proper management. No consensus exists regarding steroid treatment duration or drug rechallenge options. Our study describes the clinical and radiological course of melanoma patients diagnosed with immune-related pneumonitis that has recurred because of rechallenge attempt or despite complete treatment discontinuation (unprovoked). MATERIALS AND METHODS: The study population was composed of patients with metastatic melanoma who were treated with anti-programmed cell death 1 (PD-1) as monotherapy or in combination with anti-cytotoxic T lymphocyte antigen-4 and who were diagnosed with immune-related pneumonitis. For recurrent cases after clinical and radiological resolution, we explored the differences from cases with no recurrence. RESULTS: Nineteen out of 386 (4.8%) patients treated with ICI were diagnosed with pneumonitis. Median age was 66 years, and 53% were male. Compared with single-agent nivolumab, patients treated with ipilimumab-nivolumab combination presented with an earlier onset (27.5 vs. 10.3 weeks, respectively, p = .015) and had higher grades of severity. After complete resolution, rechallenge was attempted in seven patients; three of them had recurrent pneumonitis. Three other patients experienced recurrent pneumonitis despite complete discontinuation of the drug (unprovoked by rechallenge). The latter were characterized with an earlier onset of the first pneumonitis compared with those who did not experience recurrence (median, 12.4 vs. 26.4 weeks) and a shorter course of steroid treatment at first episode (median, 5.1 vs. 10 weeks). Recurrent cases were generally more severe than the first episode. CONCLUSION: Unprovoked recurrent pneumonitis is a new, poorly reported entity that requires further investigation. Our observations suggest that cases of pneumonitis that present early in the course of immunotherapy treatment may recur despite treatment discontinuation, thus necessitating closer monitoring and a longer course of steroid treatment. IMPLICATIONS FOR PRACTICE: This article sheds light on a poorly described immune-related adverse event: recurrent pneumonitis despite complete discontinuation of immunotherapy (unprovoked), in patients with advanced melanoma.

Physiologic colonic fluorine-18-fluorodeoxyglucose uptake may predict response to immunotherapy in patients with metastatic melanoma.

The gut microbiota impacts response to immunotherapy in cancer patients. We sought to evaluate the role of physiologic colonic fluorine-18-fluorodeoxyglucose (F-FDG) uptake, a test that was recently shown to reflect colonic bacterial load, as a possible predictor for response to immunotherapy. We carried out a retrospective study in metastatic melanoma patients who received the immune checkpoint inhibitor ipilimumab as first-line therapy. All patients underwent an F-FDG PET scan before treatment initiation. The primary outcome was defined as response to treatment according to the RECIST criteria. Regions of interest were drawn on each transaxial slice around the outer boundaries of the colon. Uptake was measured using maximum and mean standardized uptake value (SUV). A nonparametric test was used to compare SUV between response groups. The study included 14 melanoma patients, of whom two (14.3%) achieved a complete response (CR) following treatment, eight (57.1%) achieved a partial response (PR), and four (28.6%) developed progressive disease (PD). The mean SUVmax was 1.33±0.04, 2.2±0.46, and 3.33±2.67 for individuals with CR, PR, and PD, respectively. The difference between individuals with CR and those without CR (PR or PD) in total colonic SUVmax was statistically significant (P=0.03). Thus, physiologic colonic F-FDG uptake may predict CR to immunotherapy in metastatic melanoma patients.

Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.

Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.