Hierarchical integration of DNA nanostructures and NanoGold onto a microchip facilitates covalent chemistry-mediated purification of circulating tumor cells in head and neck squamous cell carcinoma.

It is well-established that the combined use of nanostructured substrates and immunoaffinity agents can enhance the cell-capture performance of the substrates, thus offering a practical solution to effectively capture circulating tumor cells (CTCs) in peripheral blood. Developing along this strategy, this study first demonstrated a top-down approach for the fabrication of tetrahedral DNA nanostructure (TDN)-NanoGold substrates through the hierarchical integration of three functional constituents at various length-scales: a macroscale glass slide, sub-microscale self-organized NanoGold, and nanoscale self-assembled TDN. The TDN-NanoGold substrates were then assembled with microfluidic chaotic mixers to give TDN-NanoGold Click Chips. In conjunction with the use of copper (Cu)-catalyzed azide-alkyne cycloaddition (CuAAC)-mediated CTC capture and restriction enzyme-triggered CTC release, TDN-NanoGold Click Chips allow for effective enumeration and purification of CTCs with intact cell morphologies and preserved molecular integrity. To evaluate the clinical utility of TDN-NanoGold Click Chips, we used these devices to isolate and purify CTCs from patients with human papillomavirus (HPV)-positive (+) head and neck squamous cell carcinoma (HNSCC). The purified HPV(+) HNSCC CTCs were then subjected to RT-ddPCR testing, allowing for detection of E6/E7 oncogenes, the characteristic molecular signatures of HPV(+) HNSCC. We found that the resulting HPV(+) HNSCC CTC counts and E6/E7 transcript copy numbers are correlated with the treatment responses in the patients, suggesting the potential clinical utility of TDN-NanoGold Click Chips for non-invasive diagnostic applications of HPV(+) HNSCC.

Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.

PURPOSE: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR). RESULTS: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively. CONCLUSION: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.

Management of Cutaneous Head and Neck Squamous and Basal Cell Carcinomas for Immunocompromised Patients.

The incidence of non-melanoma skin cancer (NMSC) continues to rise, and more than one million cases are diagnosed in the United States each year. The increase in prevalence has been attributed to increased lifespan and improvements in survival for conditions that increase the risk of these malignancies. Patients who are immunocompromised have a higher risk of developing NMSC compared to the general population. In immunosuppressed patients, a combination of prevention, frequent surveillance, and early intervention are necessary to reduce morbidity and mortality. In this review, we collate and summarize current knowledge regarding pathogenesis of head and neck cutaneous SCC and BCC within immunocompromised patients, examine the potential role of the immune response in disease progression, and detail the role of novel immunotherapies in this subset of patients.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Implementing a Tailored Psychosocial Distress Screening Protocol in a Head and Neck Cancer Program.

OBJECTIVES/HYPOTHESIS: Psychosocial distress is common among patients with head and neck cancer (HNC) and is associated with poorer quality of life and clinical outcomes. Despite these risks, distress screening is not widely implemented in HNC care. In this study, we investigated the prevalence of psychosocial distress and its related factors in routine care of patients with HNC. METHODS: Data from medical records between September 2017 and March 2020 were analyzed. Psychosocial distress was measured by the National Comprehensive Cancer Network's Distress Thermometer (DT), and a modified HNC-specific problem list; depression and anxiety were assessed using the Patient Health Questionnaire-4. Descriptive statistics and logistic regression were conducted to report prevalence of distress, depression and anxiety, and factors associated with clinical distress. Implementation outcomes, including rates of referrals and follow-up for distressed patients, are also reported. RESULTS: Two hundred and eighty seven HNC patients completed the questionnaire (age 64.3 ± 14.9 years), with a mean distress score of 4.51 ± 3.35. Of those, 57% (n = 163) reported clinical distress (DT ≥ 4). Pain (odds ratio [OR] = 3.31, 95% CI = 1.75-6.26), fatigue (OR = 2.43, 95% CI = 1.1.7-5.05), anxiety (OR = 1.63, 95% CI = 1.30-2.05), and depression (OR = 1.51, 95% CI = 1.04-2.18) were significantly associated with clinical distress (P < .05). Of patients identified as distressed, 79% received same-day psychosocial evaluation. CONCLUSIONS: Clinical distress was identified in 57% of patients who completed the questionnaire, suggesting that an ultra-brief psychosocial screening protocol can be implemented in routine ambulatory oncology care, and identifies patients whose distress might otherwise go unrecognized. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1600-1608, 2022.

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial.

BACKGROUND: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. METHODS: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. FINDINGS: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. FUNDING: Merck Sharp & Dohme.

Paracrine regulation of normal and malignant hematopoiesis.

PURPOSE OF REVIEW: The paradigm of niche-regulation of hematopoiesis has rapidly and substantially evolved within the last 12 months. Here, we will review the most critical advances in understanding of paracrine regulation of normal and malignant hematopoietic stem cell fate during the past year. RECENT FINDINGS: Several novel paracrine mechanisms have been recently identified, highlighting the function of mesenchymal progenitor cells, osteoprogenitor cells and endothelial cells in regulating hematopoietic stem cell maintenance and regeneration. Similarly, niche-driven inflammatory states, paracrine mechanisms, exosomes, and endocytosis have each been shown to powerfully regulate the maintenance and propagation of leukemic cells. SUMMARY: The elucidation of paracrine mechanisms that regulate normal and malignant hematopoiesis is critical for both fundamental understanding of hematology and for the identification of novel molecular targets for therapeutic translation.