The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.

Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and its potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICI). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA sequencing (RNA-seq) was conducted on the formalin-fixed, paraffin-embedded and fresh frozen tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival >24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The age of the 71 patients with metastatic melanoma ranged from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy-responsive versus nonresponsive tumors. Responders showed significant enrichment of bacteriophages in the phylum Uroviricota, and nonresponders showed enrichment of several bacteria, including Campylobacter jejuni. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs. SIGNIFICANCE: We analyzed the tumor microbiome and interactions with genes and pathways in metastatic melanoma treated with immunotherapy and identified several microbes associated with immunotherapy response and immune-related gene expression signatures. Machine learning models that combined microbe abundances and gene expression outperformed models using either dataset alone in predicting immunotherapy responses.

The Tumor Microbiome Reacts to Hypoxia and Can Influence Response to Radiation Treatment in Colorectal Cancer.

Tumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiation's ability to kill cells. We hypothesized that some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. Therefore, we examined the RNA sequencing data from the Oncology Research Information Exchange Network database of patients with colorectal cancer treated with radiotherapy. We identified microbial RNAs for each tumor and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such as Fusobacterium nucleatum. The presence of other microbes, such as Fusobacterium canifelinum, predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To experimentally investigate this concept, we implanted CT26 colorectal cancer cells into immune-competent BALB/c and immune-deficient athymic nude mice. After growth, in which tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed a metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-tropic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Thus, hypoxia gene expression scores seem to associate with different microbial populations and elicit an adaptive transcriptional response in intratumoral microbes, potentially influencing clinical outcomes. SIGNIFICANCE: Tumor hypoxia reduces radiotherapy efficacy. In this study, we explored whether some of the clinical effects of hypoxia could be due to interaction with the tumor microbiome. Hypoxic gene expression scores associated with certain microbes and elicited an adaptive transcriptional response in others that could contribute to poor clinical outcomes.

A Bioinformatics Tool for Identifying Intratumoral Microbes from the ORIEN Dataset.

Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10%-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, microbial graph attention (MEGA), to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of nine cancer centers in the Oncology Research Information Exchange Network. This package has three unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2,704 tumor RNA sequencing samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors. SIGNIFICANCE: Studying the tumor microbiome in high-throughput sequencing data is challenging because of the extremely sparse data matrices, heterogeneity, and high likelihood of contamination. We present a new deep learning tool, MEGA, to refine the organisms that interact with tumors.

A cancer disparities curriculum in a hematology/oncology fellowship program.

BACKGROUND: After George Floyd's murder in 2020, the Center for Disease Control and Prevention (CDC) called systemic racism a public health crisis. This health crisis is connected to the already-documented racial and socioeconomic disparities in cancer care. Ensuring hematologists and oncologists are aware of these disparities through their medical education can help to address these disparities. METHODS: The authors implemented a healthcare disparities-focused curriculum in a Hematology/Oncology fellowship program during the 2020-2021 academic year at The Ohio State University Hematology/Oncology Fellowship Program. They implemented a pre- and post- survey to evaluate the efficacy of the program. RESULTS: Fifteen fellows completed the pre-curriculum survey and 14 completed the post-survey. Before the curriculum, 12 fellows (80%) noted a "Fair" or "Good" understanding of healthcare disparities, and 6 (40%) had a "Fair" understanding of disparities in clinical trials and access to novel therapies. Fourteen fellows (93.3%) had not previously participated in a research project focused on identifying or overcoming healthcare disparities. After the curriculum, 12 (85%) fellows strongly agreed or agreed that the information presented in the curriculum was useful for training as a hematologist/oncologist. Twelve fellows (85%) noted "Agree" or "Strongly Agree" that the information presented was relevant to their practice. Eleven fellows (92%) noted that they plan to incorporate healthcare disparities into a future research or clinical project. The majority of fellows, 11 (79%) recommended that the fellowship program continue to have a formal health disparities curriculum in the future. DISCUSSION/CONCLUSION: There is utility in incorporating cancer disparities education into a hematology/oncology academic curriculum. We recommend further analysis of such curricula to improve fellowship education and patient outcomes with these interventions.

Sorafenib-Induced Capillary Leak Syndrome.

Capillary leak syndrome is a rare life-threatening disorder of acute endothelial hyperpermeability. It consists of initial fluid extravasation resulting in hypotension, hypoalbuminemia, and hemoconcentration, followed by noncardiogenic pulmonary edema from rapid fluid remobilization into intravascular compartment. Drug-induced etiology is an important diagnostic consideration in cancer patients, particularly with use of antimetabolites, immunostimulants, and monoclonal antibodies. Sorafenib-mediated capillary leak syndrome has never been reported. Here, we present the case of a 29-year-old female patient with a desmoid tumor of the thigh, who was admitted for acute hypoxic respiratory failure after recent initiation of sorafenib. She was found to have extensive pulmonary edema, bilateral pleural effusions, and hemoconcentration, all of which stabilized on supportive care with noninvasive mechanical ventilation and intravenous diuresis. Her infectious and cardiac work-up were negative. Given the temporal relationship between sorafenib use and symptom onset as well as a lack of an alternative etiology of her findings, patient was deemed to have sorafenib-induced acute capillary leak syndrome. Importantly, she did not become hypotensive prior to or during this hospitalization. To our knowledge, we reported for the first time an atypical presentation of acute capillary leak syndrome due to sorafenib use without hemodynamic instability.

National Cancer Institute Centers With Environmental Sustainability Plans for Climate Change.

This qualitative study investigates environmental sustainability plans at National Cancer Institute Comprehensive Cancer Centers and affiliated institutions.

The tumor microbiome as a predictor of outcomes in patients with metastatic melanoma treated with immune checkpoint inhibitors.

Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICIs). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA-seq was conducted on the formalin-fixed paraffin-embedded (FFPE) tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival ≥24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The 71 patients with metastatic melanoma ranged in age from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy responsive versus non-responsive tumors. Responders showed significant enrichment of several microbes including Fusobacterium nucleatum, and non-responders showed enrichment of fungi, as well as several bacteria. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs.

A bioinformatics tool for identifying intratumoral microbes from the ORIEN dataset.

Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, MEGA, to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of 9 cancer centers in the Oncology Research Information Exchange Network (ORIEN). This package has 3 unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2704 tumor RNA-seq samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors.

Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

OBJECTIVES: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. MATERIALS AND METHODS: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. RESULTS: Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. CONCLUSION: Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

Clinical markers of immunotherapy outcomes in advanced sarcoma.

BACKGROUND: Despite immunotherapy's promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this study, we explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in advanced sarcoma outcomes. METHODS: Patients in The Ohio State University Sarcoma Clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single-agent ICI or ICI + combination) along with clinical covariates. ICI + combination was further categorized into ICI + medication, ICI + radiation, ICI + surgery, or ICI + multiple (more than 2 modalities). Statistical analysis included log-rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). RESULTS: Of the patients in the database, 135 met inclusion criteria. We demonstrated improved OS in patients treated with ICI + combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Patients with a documented immune-related adverse event (irAE) of dermatitis had improved OS, but only in the ICI + combination cohort (p = 0.021). Patients who received single-agent ICI and whose change in the neutrophil-to-lymphocyte ratio (NLR) was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI + combination therapy (p = 0.441). There were no differences in OS based on age, gender, histology, or subcategories of ICI + combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036) compared with their older counterparts in this dataset. Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048), or dermatitis (p = 0.003), had an improved PFS. There were no differences in PFS based on ICI regimen (or subcategories of ICI + combination), gender, histology, change in NLR, or grade of irAE. CONCLUSIONS: This retrospective study demonstrates that ICI + combination therapy can improve OS in some patients with advanced sarcoma. This is consistent with our prior results of ICI in sarcoma.

The state of cancer research in fragile and conflict-affected settings in the Middle East and North Africa Region: A bibliometric analysis.

Background: Cancer represents a disproportionate burden in LMICs, especially conflict-affected countries in the MENA region. Research output on cancer fails to match the growing burden in the region. This bibliometric study aims to examine the status and trends of cancer research in fragile and conflict-affected settings in the MENA region from 2000 to 2021, while also incorporating economic and demographic indicators as additional factors of analysis. Methods: The Web of Science databases were searched for publications related to cancer research in Iraq, Lebanon, Libya, Palestine, Syria, and Yemen from January 1, 2000, to December 31, 2021. The retrieved publications were screened based on preset eligibility criteria and the final list was analyzed using the Bibliometrix Package in R to generate the annual scientific production and citations, journals, institutions, authors, collaborations, keywords, and title co-occurrence. Each country's annual scientific production was analyzed against its annual GDP per capita. Results: A total of 4,280 documents met the inclusion criteria in this research. The annual number of publications revealed a significant increase over the past 20 years. These publications were mostly published in international journals that had impact factors rated in the 3rd or 4th quartiles. The overall contribution of researchers from Fragile and Conflict-Affected Settings (FCS) to cancer research was 6.5% of the MENA cancer research productivity, despite comprising around 23% of the total MENA region's population. Lebanon had the highest publication productivity at the country level, followed by Iraq and Syria. GDP per capita was not significantly correlated with cancer research across the countries under investigation. At the institutional level, the American University of Beirut was the most prolific institution and had the highest number of collaborations and the widest range of cooperative partners. Most first authors were male researchers. There is an interest in cancer expression, prevalence, diagnosis, and management in terms of commonly researched topics. Conclusion: This study underscores the need for a concerted effort to improve cancer research outcomes in FCS, which can be achieved through targeted research, increased investment in research infrastructure and capacity-building initiatives, and greater regional and global collaboration.

Emerging Trends in Immunotherapy for Adult Sarcomas.

Soft-tissue sarcomas (STS) are a rare and heterogeneous group of malignant tumors that arise from the oncogenic transformation of mesenchymal tissue. There are over 100 distinct STS histological and molecular subtypes with unique clinical, therapeutic, and prognostic features with variable responses to therapy regimens. Given the quality-of-life concerns and limited efficacy with current regimens, including cytotoxic chemotherapy, there is a need for novel therapies and regimens to treat advanced STS. Although immune checkpoint inhibitors have demonstrated significant improvements in survival outcomes in other cancer types, there remains ambiguous data on the impact of immunotherapy in sarcoma. Biomarkers like PD-1/PD-L1 are not always predictive of outcomes. Therefore, researching emerging novel therapies, such as CAR-T and adoptive cell therapies, is critical to understanding STS biology, STS tumor immune microenvironment immunomodulatory strategies that improve immune response, and survival outcomes. We discuss the underlying biology of the STS tumor immune microenvironment, immunomodulatory strategies that augment pre-existing immune responses, and novel approaches to develop sarcoma-specific antigen-based therapies.

Association of medical comorbidities and cardiovascular disease with toxicity and survival among patients receiving checkpoint inhibitor immunotherapy.

BACKGROUND AND OBJECTIVES: Medical comorbidities (MC) are highly prevalent among patients with cancer and predict worse outcomes for traditional therapies. This association is poorly understood for checkpoint inhibitor immunotherapy (IO). We aimed to explore the relationship between common MC including cardiovascular disease (CVD), immune-related adverse events (irAEs), and overall survival (OS) among patients receiving IO for advanced cancer. METHODS: This is a retrospective cohort study of 671 patients with any cancer who received IO at our institution from 2011 to 2018. Clinical data were abstracted via chart review and query of ICD-10 codes and used to calculate modified Charlson comorbidity index (mCCI) scores. The primary outcomes were the association of individual MC with irAEs and OS using bivariate and multivariable analyses. Secondary outcomes included association of mCCI score with irAEs and OS. RESULTS: Among 671 patients, 62.1% had a mCCI score ≥ 1. No individual MC were associated with irAEs or OS. Increased CCI score was associated with decreased OS (p < 0.01) but not with irAEs. Grade ≥ 3 irAEs were associated with increased OS among patients without CVD (HR 0.37 [95% CI: 0.25, 0.55], p < 0.01), but not among patients with CVD. CONCLUSIONS: No specific MC predicted risk of irAEs or OS for patients receiving IO. Increased CCI score did not predict risk of irAEs but was associated with shorter OS. This suggests IO is safe for patients with MC, but MC may limit survival benefits of IO. CVD may predict shorter OS in patients with irAEs and should be evaluated among patients receiving IO.

Immune checkpoint inhibitor-induced hepatitis injury: risk factors, outcomes, and impact on survival.

PURPOSE: Immune checkpoint inhibitors (ICIs) are associated with a unique set of immune-related adverse events (irAEs). Few studies have evaluated the risk factors and outcomes of patients who develop ICI-induced hepatitis (ICIH). METHODS: We utilized an institutional database of patients with advanced cancers treated with ICI to identify patients with ICIH. irAEs were graded using the Common Terminology Criteria for Adverse Events v4. Overall survival (OS) was calculated from the date of ICI to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan-Meier method and stratified by the occurrence of ICIH. RESULTS: We identified 1096 patients treated with ICI. The most common ICIs were PD1/L1 (n = 774) and CTLA-4 inhibitors (n = 195). ICIH occurred among 64 (6%) patients: severity was < grade 3 in 30 and ≥ grade 3 in 24 patients (3.1% overall). Median time to ICIH was 63 days. ICIH was more frequent in women (p = 0.038), in patients treated with combination ICIs (p < 0.001), and when given as first-line therapy (p = 0.018). Occurrence of ICIH was associated with significantly longer OS, median 37.0 months (95% CI 21.4, NR) compared to 11.3 months (95% CI 10, 13, p < 0.001); there was no difference in OS between patients with ≥ grade 3 ICIH vs grade 1-2. CONCLUSIONS: Female sex, combination immunotherapy, and the first line of immunotherapy were associated with ICIH. Patients with ICIH had improved clinical survival compared to those that did not develop ICIH. There is a need for prospective further studies to confirm our findings.

Case report: The power of immunotherapy in advanced cutaneous squamous cell carcinoma.

We describe the case of a neglected cutaneous squamous cell carcinoma with extensive facial involvement. The patient is a male in his late 70s who presented to dermatology with a large destructive facial mass that had increased in size gradually over 3 years and then rapidly proliferated, consuming a large portion of his left maxillofacial region. While the immediate reaction was referral to hospice care, medical oncology recommended treatment with cemiplimab, an immune checkpoint inhibitor. Collaboration with multiple providers facilitated the delivery of a multidisciplinary approach utilizing immunotherapy with QUAD shot radiotherapy. The immunotherapy treatment resulted in a dramatic disease regression, but the large facial anatomical defect caused by the carcinoma remained. The patient is undergoing reconstructive surgeries. This case illustrates the potential for significant response with immune checkpoint inhibitors delivered in combination with cyclical hypofractionated radiation therapy for patients with cutaneous squamous cell carcinoma, even in very advanced disease.

Acute kidney injury in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Emerging drugs for the treatment of adrenocortical carcinoma.

Introduction: Adrenocortical cancer (ACC) is a rare and aggressive disease with a median survival of 14-17 months and 5-year survival of around 20% for advanced disease. Emerging evidence of sub-groups of ACC with specific molecular drivers indicate ACC may be amenable to inhibition of receptor tyrosine kinases involved in growth and angiogenic signaling. A significant subset of patients may also be responsive to immune strategies.Areas covered: This review outlines approaches of targeting upregulated growth pathways including Insulin-like Growth Factor, Vascular Endothelial Growth Factor, Fibroblast Growth Factor and Epidermal Growth Factor Receptor in ACC. Data of immune checkpoint blockade with nivolumab, ipilimumab, pembrolizumab and avelumab is explored in detail. Genomic studies indicate that up to 40% of ACC are driven by dysregulated WNT and glucocorticoid signaling, special focus is placed on emerging drugs in these pathways.Expert opinion: Progress in the treatment of ACC has faced challenges stemming from the rarity of the disease. Given recent advances in the understanding of the molecular pathogenesis of ACC, a window of opportunity has now opened to make significant progress in developing therapeutic options that target key pathways such as excessive glucocorticoid signaling, WNT signaling, cell cycle and immune checkpoints.

Checkpoint inhibitor immunotherapy toxicity and overall survival among older adults with advanced cancer.

OBJECTIVES: Despite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs. MATERIALS AND METHODS: This was a retrospective cohort study of 673 patients with advanced cancer. Patients who received ≥1 dose of IO at our institution from 2011 to 2018 were eligible. The primary outcome was OS from the start of first line of IO treatment, compared between four patient groups stratified by age and ≥ G3 irAEs with adjustment for patient characteristics using a Cox proportional hazards model. RESULTS AND CONCLUSION: Among all 673 patients, 35.4% were ≥ 70y, 39.8% had melanoma, and 45.6% received single-agent nivolumab. Incidence and types of ≥G3 irAEs did not differ by age. Median OS was significantly longer for all patients with ≥G3 irAEs (unadjusted 21.7 vs. 11.9 months, P = 0.007). There was no difference in OS among patients ≥70y with ≥G3 irAEs (HR 0.94, 95% CI 0.61-1.47, P = 0.79) in the multivariable analysis. Patients <70y with ≥G3 irAEs had significantly increased OS (HR 0.33, 95% CI 0.21-0.52, P < 0.001). Younger patients, but not older adults, with high-grade irAEs experience strong survival benefit. This difference may be due to the toll of irAEs themselves or the effects of treatments for irAEs, such as corticosteroids. Factors impacting OS of older adults after irAEs must be determined and optimized.

Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective. METHODS: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models. RESULTS: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009). CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65 years and lung cancers as independent risk factors for CIP.

Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications.

BACKGROUND: The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. METHODS: We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities. RESULTS: Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, ß-lactams showed the strongest association with OS across all tested cancers. CONCLUSIONS: The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.