Selective Personalized RadioImmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial (SPRINT).

PURPOSE: Standard therapy for locally advanced non-small-cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. For biomarker-selected patients with LA-NSCLC, we hypothesized that sequential pembrolizumab and risk-adapted radiotherapy, without chemotherapy, would be well-tolerated and effective. METHODS: Patients with stage III NSCLC or unresectable stage II NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible for this trial. Patients with a PD-L1 tumor proportion score (TPS) of ≥50% received three cycles of induction pembrolizumab (200 mg, once every 21 days), followed by a 20-fraction course of risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic volume exceeding 20 cc, 48 Gy delivered to smaller lesions), followed by consolidation pembrolizumab to complete a 1-year treatment course. The primary study end point was 1-year progression-free survival (PFS). Secondary end points included response rates after induction pembrolizumab, overall survival (OS), and adverse events. RESULTS: Twenty-five patients with a PD-L1 TPS of ≥50% were enrolled. The median age was 71, most patients (88%) had stage IIIA or IIIB disease, and the median PD-L1 TPS was 75%. Two patients developed disease progression during induction pembrolizumab, and two patients discontinued pembrolizumab after one infusion because of immune-related adverse events. Using RECIST criteria, 12 patients (48%) exhibited a partial or complete response after induction pembrolizumab. Twenty-four patients (96%) received definitive thoracic radiotherapy. The 1-year PFS rate is 76%, satisfying our efficacy objective. One- and 2-year OS rates are 92% and 76%, respectively. The most common grade 3 adverse events were colitis (n = 2, 8%) and esophagitis (n = 2, 8%), and no higher-grade treatment-related adverse events have occurred. CONCLUSION: Pembrolizumab and risk-adapted radiotherapy, without chemotherapy, are a promising treatment approach for patients with LA-NSCLC with a PD-L1 TPS of ≥50%.

HIV Associated Lung Cancer: Unique Clinicopathologic Features and Immune Biomarkers Impacting Lung Cancer Screening and Management.

OBJECTIVES: Lung cancer contributes significantly to morbidity and mortality in people with HIV (PWH). We study the clinicopathologic characteristics and immune microenvironment in HIV associated lung cancer. MATERIAL AND METHODS: Clinicopathological characteristics including immunotherapy outcomes were collected for 174 PWH diagnosed with lung cancer. Immunohistochemical staining for PD-L1, CD4, and CD8 was performed. RESULTS: At diagnosis, patients with HIV associated lung cancer were significantly younger (56.9 vs. 69 years, P < .0001) and more frequently had advanced disease (70% vs. 53%, P = .01). The majority were African American (60% vs. 42%, P < .0001) and were smoking at the time of diagnosis or smoked in the past (98% vs. 86%, P = .0001). Only 10% of HIV associated lung cancer was diagnosed through the screening program. The median CD4+ lymphocyte count was 334 cells/µL, 31% had a CD4 ≤200 cells/µL and 63% of the cohort was virally suppressed. HIV associated non-small-cell lung cancer(NSCLC) was characterized by limited PD-L1 expression compared to the HIV negative cohort, 64% vs. 31% had TPS <1%, and 20% vs. 34% had TPS≥50%, respectively (P = .04). Higher CD8+ TILs were detected in PD-L1-high tumors (P < .0001). 50% of patients achieved disease control in the metastatic setting with the use of immunotherapy, and there were no new safety signals in 19 PWH treated with immunotherapy. CONCLUSION: Lung cancer in PWH demonstrates unique features highlighting the need for a specialized screening program. Despite low PD-L1 expression, immunotherapy is well tolerated with reasonable disease control. Altered immune system in lung cancer pathogenesis in PWH should be further investigated.

Predictive Factors for Cancer Treatment Delay in a Racially Diverse and Socioeconomically Disadvantaged Urban Population.

PURPOSE: Incremental delays in time to treatment initiation (TTI) have been shown to cause a proportional, increased independent risk of disease-specific mortality for breast cancer, colorectal cancer (CRC), head and neck cancer (HNC), non-small-cell lung cancer (NSCLC), and pancreatic cancer. Studies suggest that delays are associated with racial and socioeconomic disparities. We evaluated associations between patient factors and TTI to identify those associated with delay. MATERIALS AND METHODS: This is a retrospective cohort study at an urban community-based academic center of patients diagnosed with or referred for curative-intent treatment of breast cancer, CRC, HNC, NSCLC, and pancreatic cancer from January 2019 to December 2021. Variables of interest included Charlson Comorbidity Index (CCI) score, insurance type, language preference, and inpatient admission 30 days before diagnosis. Factors associated with TTI delay, defined as TTI ≥ 30 days, were assessed using multivariable logistic regression. RESULTS: Among 2,543 patients (69% female), the mean age was 63.4 years and the median TTI was 25 days (IQR, 6-44). Within multivariable models, patients treated as outpatient and not admitted 30 days before diagnosis experienced statistically significant greater delay for CRC (odds ratio [OR], 2.82; 95% CI, 1.71 to 4.66) and NSCLC (OR, 2.11; 95% CI, 1.31 to 3.39). Higher CCI score was associated with delay for HNC (OR, 2.63; 95% CI, 1.04 to 6.66) and NSCLC (OR, 1.75; 95% CI, 1.14 to 2.71). For breast cancer, uninsured and Spanish-speaking patients (OR, 1.79; 95% CI, 1.21 to 2.67) experienced increased TTI. CONCLUSION: Care coordination/compliance (eg, inpatient 30 days before diagnosis), clinical (eg, medical comorbidities), and socioeconomic (eg, uninsured status) predictors for delayed TTI were identified and may inform delay minimizing interventions. Our data support evidence that TTI delays are associated with demographic and socioeconomic disparities. Existing disparities are likely exacerbated by delays that disproportionately affect patients with care coordination/compliance issues, multiple comorbidities, and lower socioeconomic status.

Survival analysis of patients with advanced hypopharyngeal cancer comparing patients who received primary surgery to those who received chemoradiation: An analysis of the NCDB.

INTRODUCTION: The objective of this study was to use the American College of Surgeons' National Cancer Database (NCDB) to examine the association between primary treatment and overall survival (OS) among patients with locoregionally advanced hypopharyngeal cancer. METHODS: 6,055 adult patients diagnosed between 2004 and 2015 with stage III or IV, M0, hypopharyngeal squamous cell carcinoma were identified within the NCDB. Patients who received primary chemoradiation (CRT) were compared to those that received surgery with adjuvant radiation or chemoradiation (S + Adj). OS was compared between treatment groups using Kaplan-Meier analyses, propensity score adjustment, and Cox regression analyses. RESULTS: The median survival was 22.7 months (IQR 11.0-49.0). The S + Adj group had a significantly higher comorbidity score, higher grade disease, and more advanced stage disease than the CRT group. S + Adj was associated with significantly improved survival when compared to CRT (p < 0.0001). A propensity score adjusting for facility type, facility location, care at multiple facilities, histology, and T stage was developed. S + Adj was associated with longer survival (HR: 0.72, 95% CI: 0.64-0.80) when compared to CRT in a multivariable Cox regression analysis (adjusting for age, race and ethnicity, insurance status, a comorbidity index, diagnosis year, treatment delay, N stage, and the propensity score). S + Adj was associated with significantly improved survival among those with T2 disease (p = 0.02), T3 disease (p = 0.02), and T4 disease (p < 0.0001) in sensitivity analyses examining these subcohorts independently. CONCLUSIONS: Among patients with advanced hypopharyngeal cancer reported in NCDB, treatment with S + Adj was associated with longer survival compared to those treated with primary CRT.

INI-1 (SMARCB1)-Deficient Undifferentiated Sinonasal Carcinoma: Novel Paradigm of Molecular Testing in the Diagnosis and Management of Sinonasal Malignancies.

Sinonasal tumors consist of a group of rare heterogeneous malignancies, accounting for 3%-5% of all head and neck cancers. Although squamous cell carcinomas make up a significant portion of cancers arising in the sinonasal tract, there are a variety of aggressive tumor types that can present with a poorly differentiated morphology and continue to pose diagnostic challenges. Accurate classification of these unique malignancies has treatment implications for patients. Recent discoveries have allowed more detailed molecular characterization of subsets of these tumor types, and may lead to individualized treatments. INI-1 (SMARCB1)-deficient sinonasal carcinoma is a recently identified subtype of sinonasal malignancy, which is characterized by deletion of the INI-1 tumor suppressor gene. Loss of INI-1 expression has emerged as an important diagnostic feature in several human malignancies including a subset of sinonasal carcinomas. In this article, we present a case of INI-1 (SMARCB1)-deficient sinonasal carcinoma, provide an overview of recent advances in histological and molecular classification of sinonasal malignancies, and discuss challenges of caring for patients with these rare malignancies, as well as potential treatment implications. KEY POINTS: Clinicians and pathologists should recognize that a variety of sinonasal tumors can present with a poorly differentiated morphology that warrants further workup and molecular classification. Routine workup of poorly or undifferentiated sinonasal tumors should include testing for INI-1/SMARCB1, SMARCA4, and NUT. Patients with these molecularly defined subsets of tumors may benefit from clinical trials that seek to exploit these molecular alterations. The EZH2 inhibitor, tazemetostat, has demonstrated some antitumor activity in INI-1-deficient tumors, and is currently under investigation.

Treatment sequence and survival in locoregionally advanced hypopharyngeal cancer: A surveillance, epidemiology, and end results-based study.

OBJECTIVES/HYPOTHESIS: The objective of this study was to examine the association between modality of primary treatment and survival among patients with locoregionally advanced hypopharyngeal cancer. STUDY DESIGN: Retrospective cohort. METHODS: There were 2,328 adult patients diagnosed with stage III or IV, M0, hypopharyngeal squamous cell carcinoma identified within the Surveillance, Epidemiology and End Results (SEER) registry (years 2004-2015). Patients who received primary chemoradiation (CRT) were compared to those who received surgery with either adjuvant radiation therapy (S + RT), or surgery with adjuvant CRT (S + CRT). The latter primary surgery group (S + Adj) was also analyzed collectively. Overall survival (OS) and disease-specific survival (DSS) were assessed using Kaplan-Meier analyses and Cox regression models using a propensity score to adjust for factors associated with treatment allocation. RESULTS: Median survival was 20 months (interquartile range [IQR] = 10-45) with CRT and 25 months (IQR = 10-47) with S + Adj (P < .001). S + Adj had higher-grade cancers and more advanced T staging (P < .001). S + CRT was associated with longer OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.59-0.84) and DSS (HR = 0.66, 95% CI: 0.54-0.82) after adjusting for age, gender, race, subsite, grade, and stage. S + RT was associated with longer DSS than CRT (HR = 0.75, 95% CI: 0.57-0.99) but not OS (HR = 0.82, 95% CI: 0.66-1.04). S + Adj was associated with longer DSS in T1/T2 disease (P = .04) and T4 disease (P = .0003), but did not reach significance among patients with T3 disease (P = .06). CONCLUSIONS: Among patients with advanced hypopharyngeal cancer reported in the SEER database, treatment with S + Adj was associated with longer DSS and OS compared to those treated with primary CRT. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:2611-2621, 2020.

DNA Polymerase ɛ Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity.

Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase ɛ have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in POLE lead to impaired proofreading intrinsic to Pol ɛ during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol ɛ have been found most frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germline mutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these POLE mutations could be overlooked unless appropriate algorithms are in place. We present two cases of metastatic CRC with a POLE mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in POLE deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here. The Oncologist 2017;22:497-502 KEY POINTS: Clinicians should recognize that tumors with high tumor mutation burden and that are microsatellite stable may harbor a POLE mutation, which is associated with an ultramutated phenotype.Work-up for POLE deficiency should indeed become part of the routine molecular testing paradigm for patients with colorectal cancer.This subset of patients may benefit from clinical trials where the higher number of mutation-associated neoantigens and defect in DNA repair may be exploited therapeutically.

Clinical significance of cell population data (CPD) on Sysmex XN-9000 in septic patients with our without liver impairment.

BACKGROUND: This study evaluated the clinical significance of cell population data (CPD) parameters obtained on Sysmex XN-9000 in septic patients admitted to intensive care unit (ICU) and stratified according to liver function. METHODS: The study population consisted in 84 patients, 44 of whom did not develop sepsis (NS), whereas the remaining 40 developed sepsis (SE) (n=24) or septic shock (SS) (n=16). Two hundred ostensibly healthy blood donors [healthy subjects (HS)], undergoing routine blood testing before a regular blood donation, were studied. RESULTS: Except for neutrophils and lymphocytes cell size (NE-FCS and LY-Z), all other CPD values were significantly different in ICU patients compared to HS. Neutrophils and monocytes fluorescence intensity (NE-SFL and MO-X) values were significantly higher in SS compared to sepsis and not develop sepsis patients. The value of many parameters was also different according to liver function. Overall, MO-X and neutrophils fluorescence intensity (NE-SFL) exhibited the best performance for diagnosing sepsis in all patients (AUC, 0.75 and 0.72), as well as in those with (AUC, 0.95 and 0.89) or without (AUC, 0.72 for both) liver impairment. These parameters were also significantly correlated with Sequential Organ Failure Assessment (SOFA) score. CONCLUSIONS: This study suggested that some novel CPD parameters (namely NE-SFL and MO-X) may provide useful information for diagnosis and management of sepsis.

Extended leukocyte differential count and C-reactive protein in septic patients with liver impairment: diagnostic approach to evaluate sepsis in intensive care unit.

BACKGROUND: Sepsis is still a major cause of death in intensive care units (ICUs) worldwide. Patients with liver impairment express an imbalanced cytokine response which alters common sepsis biphasic nature. Cytokines measurement is expensive, often unavailable, whereas leukocytes (WBC) evaluation performed through hematology analyzers can provide a practical strategy for monitoring inflammatory response. METHODS: A total of 200 healthy subjects (HS) and 84 patients (18 with, 66 without liver impairment) admitted to ICU, were assessed for International Sepsis Definitions, Sequential Organ Failure Assessment (SOFA) and Model for End-Stage Liver Disease (MELD) scores. We tested 1,022 peripheral blood samples using Sysmex XN-9000, estimating diagnostic accuracy of leukocyte differential count and nontraditional parameters through receiver operating characteristics (ROC) curves analysis compared to clinical classification. RESULTS: Median value of all-leukocyte parameters was different in ICU patients compared to HS. Leukocytes, neutrophils (NE) and immature granulocytes (IGs) in sepsis and septic shock (SS) were higher than no sepsis (NS), with an area under the curve: 0.81, 0.82 and 0.78 respectively. Lymphocytes (LY) and monocytes (MO) were significantly associated with liver impairment. CONCLUSIONS: Diagnostic accuracy of all-leukocyte parameters may provide valuable information for diagnosis and follow-up of sepsis in ICU patients, especially those with liver impairment.