The distribution of esophageal cancer patients enrolled in care at the Uganda Cancer Institute by sub-regions, districts and ethnicity.

Background: There is limited published data regarding the distribution of esophageal cancer patients by sub-regions, districts and ethnicity in Uganda. Objectives: To study the distribution by sub-regions, districts, ethnicity and sub-regions post-care outcomes of esophageal cancer patients in care over ten years at the Uganda Cancer Institute. Methods: Patients' charts with confirmed diagnoses of esophageal cancer for 2009-2019 were identified. Case information, which included demographics, clinical presentation, distribution by sub-regions, districts, ethnicity and sub-regions post-care outcomes, were retrospectively abstracted. Results: Central 671(34.15%), Southwestern 308(15.67%), Elgon 176(8.95%) and East central 163(8.29%) sub-regions had most patients. Mostly from administrative districts of Wakiso 167(8.50%), Mbarara 51(2.59%), Tororo 53(2.70%), Busia 33(1.68). Baganda, Banyakole, Bagisu and Basoga ethnic groups predominate. Patients from neighbouring countries were mainly from Rwanda 56(2.85%), South Sudan 24(1.22%), then Kenya 21(1.07%), and Rwandese, Dinka and Luo by ethnicity, respectively. Central and Southwestern sub-regions had the most post-care outcomes of the patients regarding living, death, and loss to follow-up. Conclusion: Patients are commonly from the administrative districts of Central, Southwestern, Elgon and East Central sub-regions and neighbouring countries of Rwanda, South Sudan and Kenya. Baganda, Banyakole, Bagisu and Basoga are the main ethnic groups. Central and Southwestern sub-regions are with most post-care outcomes.

Gastroesophageal Adenocarcinomas With Defective Mismatch Repair: Current Knowledge and Clinical Management.

Esophageal, gastroesophageal junction, and gastric adenocarcinomas, referred to collectively as gastroesophageal adenocarcinomas (GEAs), are a major cause of global cancer-related mortality. Our increasing molecular understanding has led to the addition of biomarker-directed approaches to defined subgroups and has improved survival in selected patients, such as those with HER2 and Claudin18.2 overexpression. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, including GEA, but biomarkers beyond PD-L1 expression are lacking. Mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI-H) is observed in 8% to 22% of nonmetastatic GEA, and 3% to 5% of patients with metastatic disease. dMMR/MSI-H tumors are associated with more favorable prognosis and significant benefit from ICIs, although some heterogeneity exists. The activity of ICIs in advanced dMMR/MSI-H cancer is seen across lines of therapy and should be recommended in the frontline setting. In patients with nonmetastatic dMMR/MSI-H cancer, increasing evidence suggests that perioperative and adjuvant chemotherapy may not provide benefit to the dMMR/MSI-H subgroup. The activity of perioperative chemotherapy-free immune checkpoint regimens in patients with nonmetastatic dMMR/MSI-H cancer is highly promising and underscores the need to identify this unique subgroup. We recommend MMR/MSI testing for all patients with GEA at diagnosis, and review the key rationale and clinical management implications for patient with dMMR/MSI-H tumors across disease stages.

An Ailment with Which I Will Contend: A Narrative Review of 5000 Years of Esophagogastric Cancers and Their Treatments, with Special Emphasis on Recent Advances in Immunotherapeutics.

Esophagogastric cancers are among the most common and deadly cancers worldwide. This review traces their chronology from 3000 BCE to the present. The first several thousand years were devoted to palliation, before advances in operative technique and technology led to the first curative surgery in 1913. Systemic therapies were introduced in 1910, and radiotherapy shortly thereafter. Operative technique improved massively over the 20th century, with operative mortality rates reducing from over 50% in 1933 to less than 5% by 1981. In addition to important roles in palliation, endoscopy became a key nonsurgical curative option for patients with limited-stage disease by the 1990s. The first nonrandomized studies on combination therapies (chemotherapy ± radiation ± surgery) were reported in the early 1980s, with survival benefit only for subsets of patients. Randomized trials over the next decades had similar overall results, with increasing nuance. Disparate conclusions led to regional variation in global practice. Starting with the first FDA approval in 2017, multiple immunotherapies now encompass more indications and earlier lines of therapy. As standards of care incorporate these effective yet expensive therapies, care must be given to disparities and methods for increasing access.

Dyspnea-Related Ticagrelor Discontinuation After Percutaneous Coronary Intervention.

BACKGROUND: Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. OBJECTIVES: The authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI). METHODS: In the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables. RESULTS: The incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566). CONCLUSIONS: In the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.

Esophageal Cancer: Overview, Risk Factors, and Reasons for the Rise.

PURPOSE OF REVIEW: Esophageal cancer (EC) is a common cancer affecting many regions of the world and carries significant morbidity and mortality. In this article, we review the key risk factors and their associated impact on the changing incidence and prevalence of EC subtypes within different global regions. We also highlight potential reasons for the ever-changing epidemiology of this prevalent cancer type. RECENT FINDINGS: There has been a shift in incidence of Esophageal Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) within certain populations primarily due to an increase prevalence of primary risk factors. In Western nations, more often the United States, there has been a shift from SCC predominance to the majority of new cases of EC being adenocarcinoma. This shift within the United States has largely correlated with a rise in obesity. The prevalence of AC in Asia is also starting to rise as more countries adopt a western diet. The pathophysiology, associated risk factors, and presentation of ESCC and AC are different. This difference is seen in varying lifestyles, population health, and certain genetic risks. With further development closer analysis of primary risk factors and implementation of policies and programs that promote public health literacy, there is a potential to decrease esophageal cancer's global disease burden.

Eosinophils Exert Antitumorigenic Effects in the Development of Esophageal Squamous Cell Carcinoma.

BACKGROUND AND AIMS: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), as their role in ESCC is unknown. METHODS: Eosinophils were enumerated in tissues from 2 ESCC cohorts. Mice were treated with 4-NQO for 8 weeks to induce precancer or 16 weeks to induce carcinoma. The eosinophil number was modified by a monoclonal antibody to interleukin-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11-/-). Esophageal tissue and eosinophil-specific RNA sequencing was performed to understand eosinophil function. Three-dimensional coculturing of eosinophils with precancer or cancer cells was done to ascertain direct effects of eosinophils. RESULTS: Activated eosinophils are present in higher numbers in early-stage vs late-stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in precancer vs cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with precancer. Eosinophil depletion using 3 mouse models (Ccl11-/- mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against precancer and carcinoma. Tissue and eosinophil RNA sequencing revealed eosinophils drive oxidative stress in precancer. In vitro coculturing of eosinophils with precancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with NAC, a reactive oxygen species scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 protumorigenic pathways. CONCLUSION: Eosinophils likely protect against ESCC through reactive oxygen species release during degranulation and suppression of IL-17.

Clinicopathological characteristics and treatment outcomes of oesophageal cancer patients in Uganda.

Background: Oesophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death worldwide, and its incidence varies globally. In Uganda, the incidence and trend are on the increase. However, there is a paucity of published data regarding this population's oesophageal cancer clinicopathologic characterisation and treatment outcomes. Objectives: To study the patients' clinicopathologic characteristics and treatment outcomes of oesophageal cancer over 10 years at the Uganda Cancer Institute. Methods: Patients' charts with histologically confirmed diagnoses of oesophageal cancer for 2009-2019 were identified. Case information, which included patient demographics, history of alcohol use or smoking, tumour location, histological type, tumour grade, clinical TNM (Tumour, Node, Metastasis) staging treatment exposure and treatment outcomes, was evaluated retrospectively. The median survival time was estimated with the Kaplan-Meier method and the median follow-up period was estimated using the reverse Kaplan-Meier. Results: 1,965 oesophageal cancer patients were identified; 1,380(70.23%) were males and 585(29.77 %) females, their mean age was 60.20 years (±12.66). Most males had a history of both alcohol consumption and smoking 640(46.38%). The lower third of the oesophagus was the most common anatomical location 771(39.24%). The majority had squamous cell carcinoma histological type 1,783(90.74%) followed by adenocarcinomas 182(9.26%) in the distal oesophagus. Poorly differentiated tumour grade 743(37.81%) was predominant. The majority of the patients were in stage IVB, 733(37.30%), and most patients were planned for the best supportive care, 731(37.20%). Radiation alone was offered to 621(31.60%) and feeding gastrostomy to 249(12.70%). Treatment outcomes: at the time of the current analysis, 58.68% had died, 1.48% were alive and 39.84% were lost to follow-up. The median follow-up period was 65 months (IQR:35.83-83.30) with a median survival time of 4.47 months (95% CI: 4.17-4.80). Conclusion: Treatment outcomes of Ugandan oesophageal cancer patients seeking care are poor as most patients present with advanced disease. There is a significant loss of follow-up after treatment initiation. Therefore, reduction in exposure to known modifiable risk factors, early detection and timely referral for treatment strategies are needed to improve outcomes of these patients in our population. Designing interventions to improve treatment adherence is necessary.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. METHODS: This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). RESULTS: Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). CONCLUSIONS: Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma.

Background/Aims: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), since their role in ESCC is unknown. Methods: Eosinophils were enumerated in tissues from two ESCC cohorts. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks to induce pre-cancer or 16 weeks to induce carcinoma. Eosinophil number was modified by monoclonal antibody to IL-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 ( Ccl11 -/- ). Esophageal tissue and eosinophil specific RNA-sequencing was performed to understand eosinophil function. 3-D co-culturing of eosinophils with pre-cancer or cancer cells was done to ascertain direct effects of eosinophils. Results: Activated eosinophils are present in higher numbers in early stage versus late stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in pre-cancer versus cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models ( Ccl11 -/- mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against pre-cancer and carcinoma. Tissue and eosinophil RNA-sequencing revealed eosinophils drive oxidative stress in pre-cancer. In vitro co-culturing of eosinophils with pre-cancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with N-acetylcysteine, a reactive oxygen species (ROS) scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways. Conclusion: Eosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration.

The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.

Association of PD-L1 Expression and Other Variables With Benefit From Immune Checkpoint Inhibition in Advanced Gastroesophageal Cancer: Systematic Review and Meta-analysis of 17 Phase 3 Randomized Clinical Trials.

Importance: Approval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses. Objective: To systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability. Data Sources: MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022). Study Selection, Data Extraction, and Synthesis: Randomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti-PD-1 or PD-L1-containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis. Main Outcomes and Measures: The prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable. Results: In all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs ≤16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs ≤12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results. Conclusions and Relevance: Tissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.

Approach to Localized Squamous Cell Cancer of the Esophagus.

OPINION STATEMENT: Esophageal cancer is a leading cause of cancer deaths worldwide, with an increasing incidence in recent decades. The majority of esophageal cancers are squamous cell carcinoma. The 5-year survival rate of esophageal squamous cell carcinoma (ESCC) is poor, and there remains globally a pressing need for novel treatments that improve patient outcomes and quality of life. In this review, we discuss management of localized ESCC with an update on relevant newly published literature, including targeted therapy and novel biomarkers. The standard treatment approach for locally advanced, resectable ESCC is currently chemoradiation with or without surgery. Here we discuss different approaches to endoscopic resection, surgery, and radiation therapy. Although the typical chemotherapy regimen is a combination of a platinum with a fluoropyrimidine or paclitaxel, different regimens are being evaluated. With the landscape of immunotherapy rapidly evolving, at the forefront of new treatments for ESCC is immunotherapy and other targeted agents. Ultimately, the treatment approach should be individualized to each patient.

Variation in Treatment Patterns of Patients with Early-Onset Gastric Cancer.

Background: Early-onset gastric cancer (EOGC), or gastric cancer in patients younger than 45 years old, is poorly understood and relatively uncommon. Similar to other gastrointestinal malignancies, the incidence of EOGC is rising in Western countries. It is unclear which populations experience a disproportionate burden of EOGC and what factors influence how patients with EOGC are treated. Methods: We conducted a retrospective, population-based study of patients diagnosed with gastric cancer from 2004 to 2018 using the National Cancer Database (NCDB). In addition to identifying unique demographic characteristics of patients with EOGC, we evaluated (using multivariable logistic regression controlling for year of diagnoses, primary site, and stage) how gender/sex, race/ethnicity, treatment facility type, payor status, and location of residence influenced the receipt of surgery, chemotherapy, and radiation. Results: Compared to patients 45−70 and >70 years of age with gastric cancer, patients with EOGC were more likely to be female, Asian/Pacific Islander (PI), African American (AA), Hispanic, uninsured, and present with stage IV disease. On multivariable analysis, several differences among subsets of patients with EOGC were identified. Female patients with EOGC were less likely to receive surgery and chemotherapy than male patients with EOGC. Asian/Pacific Islander patients with EOGC were more likely to receive chemotherapy and less likely to receive radiation than Caucasian patients with EOGC. African American patients were more likely to receive chemotherapy than Caucasian patients with EOGC. Hispanic patients were more likely to receive surgery and chemotherapy and less likely to receive radiation than Caucasian patients with EOGC. Patients with EOGC treated at community cancer centers were more likely to receive surgery and less likely to receive chemotherapy than patients with EOGC treated at academic centers. Uninsured patients with EOGC were more likely to receive surgery and less likely to receive chemotherapy than privately insured patients with EOGC. Patients with EOGC living in locations not adjacent to metropolitan areas were less likely to receive surgery compared to patients with EOGC who resided in metropolitan areas, Conclusions: Patients with EOGC are a demographically distinct population. Treatment of these patients varies significantly based on several demographic factors. Additional analysis is needed to elucidate why particular groups are more affected by EOGC and how treatment decisions are made for, and by, these patients.

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer.

In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.

Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer.

PURPOSE: Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment. EXPERIMENTAL DESIGN: We performed high-dimensional single-cell RNA sequencing (scRNA-seq) on four patient tumors pretreatment and posttreatment from a neoadjuvant trial of patients with advanced-stage head and neck squamous cell carcinoma that were treated with the αPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes. RESULTS: Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFß-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells. CONCLUSIONS: Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. In addition, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma.

PURPOSE: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis. RESULTS: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery. CONCLUSIONS: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.

Data Set for Reporting Carcinoma of the Stomach in Gastrectomy.

CONTEXT.­: A standardized detailed surgical pathology report is the cornerstone of gastric cancer management. OBJECTIVE.­: To guide management and prognostication for patients with gastric carcinomas globally, the International Collaboration on Cancer Reporting aimed to produce an evidence-based international pathology reporting data set with a panel of globally recognized expert pathologists and clinicians. DESIGN.­: Based on published guidelines/data sets for gastric carcinomas, a working draft was developed by the chair of the expert panel of pathologists and clinicians. The draft was then circulated to the panel and discussed in a series of teleconferences and email communications until consensus was achieved. The draft data set was uploaded on the International Collaboration on Cancer Reporting Web site for public comment. The data set was reviewed in consideration of the feedback, and a final version was approved by the panel. RESULTS.­: This data set was developed for gastrectomy specimens for primary gastric carcinomas, including neuroendocrine carcinomas and mixed neuroendocrine-nonneuroendocrine neoplasms. Well-differentiated neuroendocrine tumors, nonepithelial malignancies, and secondary tumors were excluded from this data set. The final data set contains 15 core (required) elements and 8 noncore (recommended) elements. A commentary is provided for each element. CONCLUSIONS.­: The International Collaboration on Cancer Reporting has published freely available, evidence-based data sets for gastric cancer reporting. Standardized reporting has been shown to improve patient care and facilitates data exchange and analysis for quality assurance, cancer epidemiology, and clinical and basic research.

Quality of life and mental health of patients with vascular malformations in a single specialist center in the United Kingdom.

OBJECTIVE: Patients with vascular malformations suffer from chronic debilitating symptoms that have been shown to contribute negatively to their quality of life (QoL) and mental health. Despite this, the current literature evaluating the QoL and mental health of patients with vascular malformations remains scarce. Our aim was to evaluate the QoL and mental health of patients with vascular malformations. METHODS: We prospectively analyzed the validated health-related QoL (HRQoL) questionnaires: the RAND Health Care 36-Item Short Form Survey (SF-36), Hospital Anxiety and Depression Scale (HADS), and visual analogue score for pain reported by 253 patients with vascular malformations in a specialist center of vascular anomalies in the UK over 2 years. RESULTS: Patients with vascular malformations reported significantly poorer SF-36 scores in all domains compared with the UK general population. Patients with low-flow vascular malformations and arteriovenous malformations reported little variations in SF-36, HADS, and visual analogue score for pain scores. No significant association was found between age and any of the health-related QoL scores, other than the physical functioning in SF-36. Female patients reported significantly lower physical and social functioning of SF-36 and worse HADS-Depression than their male counterparts. Patients with syndromic vascular malformations reported significantly lower SF-36 scores in role-physical, role-emotional and bodily pain than nonsyndromic vascular malformations. CONCLUSIONS: This study concluded that patients with vascular malformations reported worse QoL than the UK general population. Therefore, the assessment and management of QoL and mental health should be incorporated into the overall treatment strategies of patients with vascular malformations.