Extent of Resection and Long-Term Outcomes for Appendiceal Adenocarcinoma: a SEER Database Analysis of Mucinous and non-Mucinous Histologies.

BACKGROUND: Mucinous appendiceal adenocarcinomas (MAA) and non-mucinous appendiceal adenocarcinomas (NMAA) demonstrate differences in rates and patterns of recurrence, which may inform the appropriate extent of surgical resection (i.e., appendectomy versus colectomy). The impact of extent of resection on disease-specific survival (DSS) for each histologic subtype was assessed. PATIENTS AND METHODS: Patients with resected, non-metastatic MAA and NMAA were identified in the Surveillance, Epidemiology, and End Results database (2000-2020). Multivariable models were created to examine predictors of colectomy for each histologic subtype. DSS was calculated using Kaplan-Meier estimates and examined using Cox proportional hazards modeling. RESULTS: Among 4674 patients (MAA: n = 1990, 42.6%; NMAA: n = 2684, 57.4%), the majority (67.8%) underwent colectomy. Among colectomy patients, the rate of nodal positivity increased with higher T-stage (MAA: T1: 4.6%, T2: 4.0%, T3: 17.1%, T4: 21.6%, p < 0.001; NMAA: T1: 6.8%, T2: 11.4%, T3: 25.6%, T4: 43.8%, p < 0.001) and higher tumor grade (MAA: well differentiated: 7.7%, moderately differentiated: 19.2%, and poorly differentiated: 31.3%; NMAA: well differentiated: 9.0%, moderately differentiated: 20.5%, and 44.4%; p < 0.001). Nodal positivity was more frequently observed in NMAA (27.6% versus 16.4%, p < 0.001). Utilization of colectomy was associated with improved DSS for NMAA patients with T2 (log rank p = 0.095) and T3 (log rank p = 0.018) tumors as well as moderately differentiated histology (log rank p = 0.006). Utilization of colectomy was not associated with improved DSS for MAA patients, which was confirmed in a multivariable model for T-stage, grade, and use of adjuvant chemotherapy [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.81-1.22]. CONCLUSIONS: Colectomy was associated with improved DSS for patients with NMAA but not MAA. Colectomy for MAA may not be required.

Management of Pericardial Effusion in Patients With Solid Tumor: An Algorithmic, Multidisciplinary Approach Results in Reduced Mortality After Paradoxical Hemodynamic Instability.

OBJECTIVE: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage versus interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. BACKGROUND: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. METHODS: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. RESULTS: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs 4%; 90-day: 4% vs 6%, P =0.7) and mortality (30-day: 21% vs 17%, P =0.3; 90-day: 39% vs 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33-2.1] vs 6.5 mo [5.0-8.9], P <0.001; IR percutaneous drainage, 3.7 mo [0.23-6.8] vs 5.0 mo [4.0-8.1], P =0.044). CONCLUSIONS: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and postintervention intensive care resulted in lower incidence of PHI and improved outcomes.

Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma.

BACKGROUND: Tumor immune microenvironment (TIME) and cancer antigen expression, key factors for the development of immunotherapies, are usually based on the data from primary tumors due to availability of tissue for analysis; data from metastatic sites and their concordance with primary tumor are lacking. Although of the same origin from primary tumor, organ-specific differences in the TIME in metastases may contribute to discordant responses to immune checkpoint inhibitor agents. In immunologically 'cold' tumors, cancer antigen-targeted chimeric antigen receptor (CAR) T-cell therapy can promote tumor-infiltrating lymphocytes; however, data on distribution and intensity of cancer antigen expression in primary tumor and matched metastases are unavailable. METHODS: We performed a retrospective review of a prospectively maintained database of patients who had undergone curative resection of pathological stage I-III primary lung adenocarcinoma from January 1995 to December 2012 followed by metastatic recurrence and resection of metastatic tumor (n=87). We investigated the relationship between the primary tumor and metastasis TIME (ie, tumor-infiltrating lymphocytes, tumor-associated macrophages, and programmed death-ligand 1 (PD-L1)) and cancer antigen expression (ie, mesothelin, CA125, and CEACAM6) using multiplex immunofluorescence. RESULTS: Brain metastases (n=36) were observed to have fewer tumor-infiltrating lymphocytes and greater PD-L1-negative tumor-associated macrophages compared with the primary tumor (p<0.0001); this relatively inhibitory TIME was not observed in other metastatic sites. In one in three patients, expression of PD-L1 is discordant between primary and metastases. Effector-to-suppressor (E:S) cell ratio, median effector cells (CD20+ and CD3+) to suppressor cells (CD68/CD163+) ratio, in metastases was not significantly different between patients with varying E:S ratios in primary tumors. Cancer antigen distribution was comparable between primary and metastases; among patients with mesothelin, cancer antigen 125, or carcinoembryonic antigen adhesion molecule 6 expression in the primary tumor, the majority (51%-75%) had antigen expression in the metastases; however, antigen-expression intensity was heterogenous. CONCLUSIONS: In patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma.

A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Patients With Esophageal Adenocarcinoma.

OBJECTIVE: To investigate the utility of serum soluble mesothelin-related peptide (SMRP) and tumor mesothelin expression in the management of esophageal adenocarcinoma (ADC). BACKGROUND: Clinical management of esophageal ADC is limited by a lack of accurate evaluation of tumor burden, treatment response, and disease recurrence. Our retrospective data showed that tumor mesothelin and its serum correlate, SMRP, are overexpressed and associated with poor outcomes in patients with esophageal ADC. METHODS: Serum SMRP and tumoral mesothelin expression from 101 patients with locally advanced esophageal ADC were analyzed before induction chemoradiation (pretreatment) and at the time of resection (posttreatment), as a biomarker for treatment response, disease recurrence, and overall survival (OS). RESULTS: Pre and posttreatment serum SMRP was ≥1 nM in 49% and 53%, and pre and post-treatment tumor mesothelin expression was >25% in 35% and 46% of patients, respectively. Pretreatment serum SMRP was not significantly associated with tumor stage ( P = 0.9), treatment response (radiologic response, P = 0.4; pathologic response, P = 0.7), or recurrence ( P =0.229). Pretreatment tumor mesothelin expression was associated with OS (hazard ratio: 2.08; 95% CI: 1.14-3.79; P = 0.017) but had no statistically significant association with recurrence ( P = 0.9). Three-year OS of patients with pretreatment tumor mesothelin expression of ≤25% was 78% (95% CI: 68%-89%), compared with 49% (95% CI: 35%-70%) among those with >25%. CONCLUSIONS: Pretreatment tumor mesothelin expression is prognostic of OS for patients with locally advanced esophageal ADC, whereas serum SMRP is not a reliable biomarker for monitoring treatment response or recurrence.

Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma.

Background: The attenuated, genetically engineered vaccinia virus has been shown to be a promising oncolytic virus for the treatment of patients with solid tumors, through both direct cytotoxic and immune-activating effects. Whereas systemically administered oncolytic viruses can be neutralized by pre-existing antibodies, locoregionally administered viruses can infect tumor cells and generate immune responses. We conducted a phase I clinical trial to investigate the safety, feasibility and immune activating effects of intrapleural administration of oncolytic vaccinia virus (NCT01766739). Methods: Eighteen patients with malignant pleural effusion due to either malignant pleural mesothelioma or metastatic disease (non-small cell lung cancer or breast cancer) underwent intrapleural administration of the oncolytic vaccinia virus using a dose-escalating method, following drainage of malignant pleural effusion. The primary objective of this trial was to determine a recommended dose of attenuated vaccinia virus. The secondary objectives were to assess feasibility, safety and tolerability; evaluate viral presence in the tumor and serum as well as viral shedding in pleural fluid, sputum, and urine; and evaluate anti-vaccinia virus immune response. Correlative analyses were performed on body fluids, peripheral blood, and tumor specimens obtained from pre- and post-treatment timepoints. Results: Treatment with attenuated vaccinia virus at the dose of 1.00E+07 plaque-forming units (PFU) to 6.00E+09 PFU was feasible and safe, with no treatment-associated mortalities or dose-limiting toxicities. Vaccinia virus was detectable in tumor cells 2-5 days post-treatment, and treatment was associated with a decrease in tumor cell density and an increase in immune cell density as assessed by a pathologist blinded to the clinical observations. An increase in both effector (CD8+, NK, cytotoxic cells) and suppressor (Tregs) immune cell populations was observed following treatment. Dendritic cell and neutrophil populations were also increased, and immune effector and immune checkpoint proteins (granzyme B, perforin, PD-1, PD-L1, and PD-L2) and cytokines (IFN-γ, TNF-α, TGFß1 and RANTES) were upregulated. Conclusion: The intrapleural administration of oncolytic vaccinia viral therapy is safe and feasible and generates regional immune response without overt systemic symptoms. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01766739, identifier NCT01766739.

Durvalumab and PET-Directed Chemoradiation in Locally Advanced Esophageal Adenocarcinoma: A Phase Ib/II Study.

OBJECTIVE: To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma. BACKGROUND: Neoadjuvant induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy. METHODS: Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response. RESULTS: We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 [22% (1-sided 90% lower bound: 13.3%)] patients with major pathologic response in 22 [61% (1-sided 90% lower bound: 50%)] patients. Twelve and 24-month overall survival was 92% and 85%, respectively. CONCLUSIONS: The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data.

Micropapillary and Solid Histologic Patterns in N1 and N2 Lymph Node Metastases Are Independent Factors of Poor Prognosis in Patients With Stages II to III Lung Adenocarcinoma.

INTRODUCTION: High-grade histologic patterns are associated with poor prognosis in patients with primary nonmucinous lung adenocarcinoma (ADC). We investigated whether the presence of micropapillary (MIP), solid (SOL), or both patterns in lymph node (LN) metastases has prognostic value. METHODS: Patients who underwent lobectomy for pathologic stages II to III lung ADC with N1 or N2 LN metastases (N = 360; 2000-2012) were analyzed. We assessed overall survival (OS), lung cancer-specific cumulative incidence of death (LC-CID), and cumulative incidence of recurrence (CIR) between patients with and without MIP/SOL patterns in LN metastases. Multivariable Cox regression analysis was used to quantify the association between MIP/SOL patterns and outcomes. RESULTS: MIP and SOL in LN metastases were associated with a higher incidence of smoking history (p = 0.004), tumor necrosis (p = 0.013), and spread of tumor through air spaces (p < 0.0001), a higher prevalence of MIP or SOL in the primary tumor (p < 0.0001), shorter OS (5-y OS, 40% [95% confidence interval or CI: 29%-56%] versus 63% [48%-83%] for no MIP/SOL in LNs, p = 0.03), higher LC-CID (5-y, 43% [29%-56%] versus 14% [4%-29%], p = 0.013), and higher CIR (5-y, 65% [50%-77%] versus 43% [25%-60%], p = 0.057). MIP and SOL in LN metastases were independently associated with poor outcomes: OS (hazard ratio [HR] = 1.81 [95% CI: 1.00-3.29], p = 0.05), LC-CID (HR = 3.10 [1.30-7.37], p = 0.01), and CIR (HR = 2.06 [1.09-3.90], p = 0.026). CONCLUSIONS: MIP/SOL histologic patterns in N1 or N2 LN metastases are associated with worse outcomes in patients with stages II to III lung ADC. MIP/SOL histologic patterns in LN metastases can stratify patients with high-risk stages II to III lung ADC.

Brief Report: Contralateral Lobectomy for Second Primary NSCLC: Perioperative and Long-Term Outcomes.

Introduction: Anatomical resection-often by lobectomy-is the standard of care for patients with early stage NSCLC. With increased diagnosis, survival, and prevalence of persons with early stage NSCLC, the incidence of second primary NSCLC, and consequently, the need for contralateral lobectomy for a metachronous cancer, is increasing. Perioperative outcomes after contralateral lobectomy are unknown. Methods: Among patients who underwent contralateral lobectomy for second primary NSCLC during 1995 to 2020, we evaluated 90-day mortality and major morbidity (Clavien-Dindo grades 3-5) rates and their association with clinicopathologic variables, including the year of contralateral lobectomy and duration between lobectomies. Results: A total of 98 patients underwent contralateral lobectomy for second primary NSCLC; 51 during an early time period (1995-2009) and 47 from a late time period (2010-2020). There were five mortalities and 23 patients with major morbidities after contralateral lobectomy; both rates decreased in 2010 to 2020 compared with 1995 to 2009 (mortality 10%-0%, major morbidity 35%-11%). Major morbidity was associated with an interval of less than 1 year between lobectomies, a diffusing capacity of the lung for carbon monoxide <80%, and right lower lobe resections. Mortality was associated with squamous cell carcinoma. Patients who underwent contralateral lobectomy for stage I NSCLC had 74% (95% confidence interval: 64%-85%) 3-year overall survival and 15% (95% confidence interval: 6.5%-24%) 3-year lung cancer cumulative incidence of death. Conclusions: Contralateral lobectomy for second primary early stage NSCLC was associated with poor outcomes before 2010. Since 2010, perioperative and long-term outcomes of contralateral lobectomy have been comparable with reported outcomes after unilateral lobectomy.

Concurrent Surgery and the Role of the Pediatric Attending Surgeon: Comparing Parents' and Surgeons' Expectations.

BACKGROUND: The common practice of performing concurrent or overlapping operations has been intensely scrutinized by lay media and academic press to investigate its safety and cost-effectiveness. However, there is little information about its use within the pediatric population. Even less is known about parents' expectations about the surgeon's role on the day of operation and how they align with those of pediatric surgeons and surgical trainees, despite the potential for significant discrepancies in expectations to erode trust and damage the physician-family relationship. STUDY DESIGN: A 5-point Likert-style survey was designed to characterize expectations about the degree of involvement by pediatric attending surgeons throughout a surgical case (1 = strongly disagree, 3 = neutral, 5 = strongly agree). The survey was administered to parents of pediatric patients undergoing elective operations during a 3-month interval at a single academic institution. The survey was also administered to surgeons and surgical residents at the same institution. Multivariate multiplicity-adjusted t-tests were used to identify significant differences between responders. RESULTS: One hundred and ten parents and 84 pediatric surgeons and trainees completed the survey. Parents' responses to the survey ranged from 4.15 to 4.89, compared with 2.75 to 4.86 from surgeons. The differences achieved statistical significance (p < 0.05) for 8 of 9 statements. Statistically significant differences were fewer, but still present, between attending surgeons and surgical trainees, as well as between surgeons with and without children. CONCLUSIONS: There is a significant mismatch between parents' expectations and those of pediatric surgeons about the role of the surgeon on the day of operation, with parents consistently expecting more direct involvement by the attending surgeon. These discrepancies can have implications for both parent/patient satisfaction and medical education.