The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment.

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.

Response to Neoadjuvant Targeted Therapy in Operable Head and Neck Cancer Confers Survival Benefit.

PURPOSE: Neoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: A pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. RESULTS: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7-100] compared with those with no stage change (58%; 95% CI, 46.2-69.8) or upstage (40%; 95% CI, 9.6-70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078). CONCLUSIONS: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.

Racial Diversity Among American Cardiologists: Implications for the Past, Present, and Future.

In the United States, race-based disparities in cardiovascular disease care have proven to be pervasive, deadly, and expensive. African American/Black, Hispanic/Latinx, and Native/Indigenous American individuals are at an increased risk of cardiovascular disease and are less likely to receive high-quality, evidence-based medical care as compared with their White American counterparts. Although the United States population is diverse, the cardiovascular workforce that provides its much-needed care lacks diversity. The available data show that care provided by physicians from racially diverse backgrounds is associated with better quality, both for minoritized patients and for majority patients. Not only is cardiovascular workforce diversity associated with improvements in health care quality, but racial diversity among academic teams and research scientists is linked with research quality. We outline documented barriers to achieving workforce diversity and suggest evidence-based strategies to overcome these barriers. Key strategies to enhance racial diversity in cardiology include improving recruitment and retention of racially diverse members of the cardiology workforce and focusing on cardiovascular health equity for patients. This review draws attention to academic institutions, but the implications should be considered relevant for nonacademic and community settings as well.

Molecular (SNP) analyses of overlapping hemizygous deletions of 10q25.3 to 10qter in four patients: evidence for HMX2 and HMX3 as candidate genes in hearing and vestibular function.

We report on the analyses of four unrelated patients with de novo, overlapping, hemizygous deletions of the long arm of chromosome 10. These include two small terminal deletions (10q26.2 to 10qter), a larger terminal deletion (10q26.12 to 10qter), and an interstitial deletion (10q25.3q26.13). Single nucleotide polymorphism (SNP) studies (Illumina 550 K) established that these deletions resulted in the hemizygous loss of approximately 6.1, approximately 6.1, approximately 12.5, and approximately 7.0 Mb respectively. Additionally, these data establish that Patients 1, 2, and 3 share common, distal, hemizygous deleted regions of 6.09 Mb containing 37 RefSeq genes. Patients 3 and 4 share a 2.52 Mb deleted region corresponding to the proximal deleted region of Patient 3 and the distal deleted region of Patient 4. This common, hemizygous region contains 20 RefSeq genes including two H6 family homeobox genes (HMX2 and HMX3). Based on previous reports that Hmx2/Hmx3 knockout mice have vestibular anomalies, we propose that hemizygous deletions of HMX2 and HMX3 are responsible for the inner ear malformations observed from CT images, vestibular dysfunction, and congenital sensorineural hearing loss found in Patients 3 and 4.

Characteristics of participants in a free oral, head and neck cancer screening program.

OBJECTIVE: Early detection of head and neck cancer is associated with improved survival. It is unclear if screening programs successfully target high-risk populations. We sought to determine the characteristics of participants presenting for a free oral, head and neck cancer screening. MATERIALS AND METHODS: Prospective analysis of 89 participants in a one-day, free oral, head, and neck cancer screening. RESULTS: The majority of participants were female (57%) and not tobacco users (71%) with a mean age of 56 years (range, 23-83). Symptoms associated with head and neck cancer were reported by 59 participants (66%), but only 31 (35%) were aware of an association between symptoms and head and neck cancer. There was no correlation between symptom prevalence and exam findings (r = 0.1161). Ten participants (11%) had findings concerning for neoplasia and were referred for immediate consultation. Demographically, 64 (72%) of participants had attended college and 51 (57%) earned an annual income greater then $30,000. The majority of participants (85%) believed that screening increased their awareness and knowledge of oral and head and neck cancer. CONCLUSIONS: Free oral, head and neck cancer screenings increase awareness of oral and head and neck cancer and identify a subset of individuals requiring further evaluation. However, participants do not share characteristics of the population at greatest risk for the development of head and neck cancer based on risk factors and socioeconomic status. These findings suggest that early detection efforts need to be designed to target high-risk populations.

Treatment and survival outcomes based on histologic grading in patients with head and neck mucoepidermoid carcinoma.

BACKGROUND: Histopathologic grade of mucoepidermoid carcinoma (MEC) is an established predictor of prognosis and affects treatment protocol. Tumor behavior is more aggressive in high-grade than in low-grade MEC, leading to a more intensive treatment protocol. Outcomes for patients with intermediate-grade MEC are less clear; therefore, the optimal treatment protocol for this group is not well defined. The treatment protocol and survival outcomes of patients treated for MEC of the head and neck was investigated. METHODS: A retrospective clinical review and prospective review of histopathologic grading were undertaken using the most recently established grading system of 50 patients with MEC of the head and neck from 1983 through 2004. RESULTS: As histologic grade increased from low to intermediate to high, overall survival (P < .0001) and disease-free survival (P < .001) were significantly decreased. Overall and disease-free survival were significantly better for patients with intermediate-grade MEC than those with high-grade disease. Overall and disease-free survival were similar for patients with low-grade and intermediate-grade MEC. There was a low rate of disease recurrence in patients with intermediate-grade MEC, but this did not lead to death from disease. Although no patients with low-grade or intermediate-grade MEC died of disease, 52% of patients with high-grade MEC died of disease. Multivariate analysis revealed that histologic grade, age, and surgical margin status significantly predicted prognosis. CONCLUSIONS: These findings suggest that, under the current histopathologic classification system, the behavior of intermediate-grade MEC is comparable to that of low-grade MEC and different from high-grade MEC, allowing for the establishment of an evidence-based treatment protocol.