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We defined the occult nodal metastasis (ONM) rate of clinical node-negative salivary gland malignancies and examined the role of elective neck dissection (END). Meta-analysis querying four databases, from inception of databases to March 25th, 2020. Fifty-one studies with 11 698 patients were included. ONM rates were 64% for salivary ductal carcinoma (SDC), 51% for undifferentiated carcinoma, 34% for carcinoma ex-pleomorphic adenoma (CXPA), 32% for adenocarcinoma not otherwise specified (ANOS), 31% for lymphoepithelial carcinoma (LE), 20% for mucoepidermoid carcinoma, 17% for acinic cell carcinoma, and 17% for adenoid cystic carcinoma. T3/T4 tumors had a 2.3 times increased risk of ONM than T1/T2 tumors. High-grade tumors had a 3.8 times increased risk of ONM than low/intermediate-grade tumors. ONM rates were exceedingly high for T3/T4, high-grade, and undifferentiated, SDC, ANOS, CXPA, and LE tumors, indicating the potential role of END.

OBJECTIVE. Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENE(mi)) and role of adjuvant concurrent chemoradiation (CRT) for ENE(mi) remain unclear. This study evaluates (1) the prognostic significance of ENE(mi) in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients. STUDY DESIGN. Retrospective cohort study. SETTING. Commission on Cancer (CoC)–accredited facilities. METHODS. This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENE(mi) or no ENE who had undergone margin-negative surgery. The association of ENE(mi) with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENE(mi) receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS. RESULTS. We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENE(mi). On multivariable analysis, ENE(mi) was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENE(mi) who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27). CONCLUSION. For patients with HPV-negative HNSCC, pN+ with ENE(mi) is associated with worse OS than pN+ without ENE. However, for patients with ENE(mi), concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENE(mi) requires additional investigation.

Cancers that arise in the head and neck region are comprised of a heterogeneous group of malignancies that include carcinogen- and human papillomavirus (HPV)-driven mucosal squamous cell carcinoma as well as skin cancers such as cutaneous squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma. These malignancies develop in critical areas for eating, talking, and breathing and are associated with substantial morbidity and mortality despite advances in treatment. Understanding of advances in the management of these various cancers is important for all multidisciplinary providers who care for patients across the cancer care continuum. Additionally, the recent Coronavirus Disease 2019 (COVID-19) pandemic has necessitated adaptations to head and neck cancer care to accommodate the mitigation of COVID-19 risk and ensure timely treatment. This review explores advances in diagnostic criteria, prognostic factors, and management for subsites including head and neck squamous cell carcinoma and the various forms of skin cancer (basal cell carcinoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and melanoma). Then, this review summarizes emerging developments in immunotherapy, radiation therapy, cancer survivorship, and the delivery of care during the COVID-19 era.

Service firms routinely enhance their offerings to satisfy and retain current customers and to attract new customers. We show theoretically that service improvements can be prioritized by simultaneously taking into account the likely incremental revenue (through increased customer value) and the incremental cost of making the improvement. The customer values obtained from a sample of respondents, and cost estimates obtained from managers of the service providing organization are combined to prioritize improvements using a ‘bang for the buck’ (i.e. value/cost) rule. Such a prioritization would be helpful to come up with a ‘short list’ of service improvements. The items on the short list can be evaluated in detail for their ‘Return on Quality’. The approach for prioritization is illustrated in the context of improving passenger train service between a pair of cities in India. An adaptive self-explicated approach is used for obtaining customer values and cost estimates. The customer values so elicited displa...

Aims: S-nitrosylation and S-glutathionylation, redox-based modifications of protein thiols, are recently emerging as important signaling mechanisms. In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis. Results: Our studies show that STAT3 in stimulated microglia underwent two distinct redox-dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr705). Consequently, the interleukin-6 (IL-6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys259 was the target Cys residue of GSNO-mediated S-nitrosylation of STAT3. The replacement of Cys259 residue with Ala abolished the inhibitory role of GSNO in IL-6-induced STAT3 phosphorylation and transactivation, suggesting the role of Cys259 S-nitrosylation in STAT3 phosphorylation. Innovation: Microglial proliferation is regulated by NO via S-nitrosylation of STAT3 (Cys259) and inhibition of STAT3 (Tyr705) phosphorylation. Conclusion: Our results indicate the regulation of STAT3 by NO-based post-translational modification (S-nitrosylation). These findings have important implications for the development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer. Antioxid. Redox Signal. 20, 2514–2527.

Introduction: Management of medically inoperable non-small-cell lung cancer (NSCLC) has been historically challenging, with poor rates of local control and disease-specific survival. Nearly all published series of standard fractionation radiotherapy have utilised doses

To compare toxicities, disease control, and survival outcomes for patients treated with either cisplatin/irinotecan versus carboplatin/paclitaxel concurrent chemoradiotherapy for locally advanced esophageal cancer.Single-institution retrospective comparison between treatment groups: the cisplatin/irinotecan group was treated with 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy, whereas the carboplatin/paclitaxel group began with chemoradiotherapy followed by 2 additional cycles of chemotherapy. Acute toxicities, response rates, disease control, survival outcomes, and patterns of failure were compared between the groups.Between January 2000 and December 2007, 57 patients were identified for inclusion in the present study (38 cisplatin/irinotecan and 19 carboplatin/paclitaxel). Groups were well-balanced by clinical-, pathologic-, staging-, and treatment-related factors. Thirty-five patients (92%) in the cisplatin/irinotecan group and 18 patients (95%) in the carboplatin/paclitaxel group completed the concurrent phase of chemoradiotherapy. There were no significant differences in hematologic or nonhematologic toxicities between the groups. At a median survivor follow-up of 37.6 months (range: 7.3-59.3 months) for the entire population, 22 patients were alive (16 without evidence of disease). The 3-year overall survival estimates was 19.7% for the cisplatin/irinotecan group versus 56.1% for the carboplatin/paclitaxel group (P = 0.022). Estimated 3-year cancer-specific survivals were 24.6% for the cisplatin/irinotecan group versus 59.3% for the carboplatin/paclitaxel group (P = 0.033).Concurrent chemoradiotherapy with carboplatin/paclitaxel is well-tolerated and provided superior overall and disease-specific survival compared with cisplatin/irinotecan chemoradiotherapy in the present study population. Further investigation is warranted.

Purpose To describe incidence and identify factors associated with development of severe acute esophagitis during hyperfractionated radiotherapy with concurrent chemotherapy (BID-CRT) in patients with limited-stage small-cell lung cancer (SCLC). Methods and Materials Retrospective cohort analysis of patient-, tumor-, and treatment-related variables was performed to identify factors associated with Radiation Therapy Oncology Group (RTOG) Grade 3 acute esophagitis. Twice-daily chemoradiotherapy (BID-CRT) involved 45 Gy at 1.5 Gy per fraction, treated twice daily with concurrent platinum-based chemotherapy. Logistic regression analyses were used to identify factors associated with esophagitis. Results Between June 1999 and June 2007, 48 patients underwent curative intent BID-CRT for SCLC and were included in the analysis. Median radiotherapy dose was 45 Gy (range, 42–51 Gy) delivered with a median 4 cycles of chemotherapy (range, 2–6). RTOG Grade 3 acute esophagitis developed in 11 patients. No patient developed Grade 4 or 5 esophagitis. Simple logistic regression analyses demonstrated a highly significant association between Grade 3 acute esophagitis and mean esophageal dose ( p = 0.002) as well as relative volume dosimetric area under curve (RV-AUC; p = 0.004). Using multiple regression analysis, RV-AUC was identified as the only factor associated with Grade 3 esophagitis ( p = 0.004). The most strongly associated dosimetric volume was the V15 (Grade 3 esophagitis rates of 15% vs. 64% for V15 Conclusions RV-AUC is the factor most associated with development of Grade 3 acute esophagitis in limited stage SCLC patients receiving BID-CRT.

Background. Reirradiation of locoregionally recurrent, previously irradiated head/neck cancer may be considered in situations of unresectability, medical inoperability, or adverse pathologic features found at salvage resection. Methods. Retrospective cohort analysis of toxicity and survival outcomes in locoregionally recurrent, previously irradiated patients with head/neck cancer treated with hyperfractionated split-course radiotherapy and concurrent chemotherapy. Results. Between March 1998 and September 2006, 39 patients initiated reirradiation at median of 2.3 years (range, 0.5–19) following prior radiotherapy. At median survivor follow-up of 24.5 months (range, 3–63.9), 10 patients are alive without evidence of disease. Median survival is 19.0 months, with estimated 1-, 2-, and 3-year overall survivals of 60.1%, 45.1%, and 22.7%, respectively. Locoregional failure was the predominant site of postreirradiation recurrence. Male sex, total radiotherapy dose, cycles of chemotherapy completed, and clinical response were associated with improved overall survival. Conclusions. Reirradiation can offer long-term survival for patients with recurrent, previously irradiated head/neck cancers. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

Seven head and neck cancer patients participated in a driving evaluation in a driving simulator. Radiation dose on the temporal lobes was moderately associated with time to complete a cognitive test and with driving performance. Results indicated that incidental irradiation may contribute to a decrease in cognition and in unsafe driving performance, which seems to be time-dependent.

Background: There has been an increasing focus on late functional effects of head and neck cancer (HNC) treatment. This study was undertaken to evaluate the incidence of late proximal esophageal stricture in patients undergoing total laryngectomy (TL) and radiation therapy (RT). Material and Methods: An institutional retrospective review of HNC patients treated between 1995 and 2003 with TL and RT was undertaken. Thirty-three patients with stage II–IV disease were included; 25 patients had TL and postoperative RT (group 1), while 8 patients had definitive RT with salvage laryngectomy (group 2). Results: The median follow-up was 28 months. At the last follow-up, 25 patients (76%) were alive and disease free. Four had died and 3 developed distant metastasis. Dysphagia or stenosis developed in 40% in group 1 and 75% in group 2 patients. The median time to dysphagia was 5.5 months for all patients. Conclusions: The incidence of esophageal stenosis was 33% for all patients. Contributing factors for esophageal stenosis after TL and RT include continued alcohol and tobacco use, the dose-volume relationship of the RT and normal tissue damage from the tumor and the treatment.

Background: Retrospective analysis of patients with medically inoperable non-small cell lung cancer treated with continuous high-dose external beam radiation therapy at the Medical University of South Carolina. Methods: We identified 35 patients with non-small cell lung cancer treated 1998-2002. None were candidates for resection for reasons including: pulmonary function ( n = 23), previous cancer ( n = 9), other co-morbidities ( n = 2), and refusal of surgery ( n = 1). Median percent predicted forced expiratory volume in 1 second was 41.5%. Median age was 71 years. Five patients had more than one primary tumor: three were concurrently treated, two were sequentially treated. Lesion sizes were n = 24); 3-5 cm ( n = 12), and >5 cm ( n = 5). Nodal stage was as follows: N0 ( n = 33) and N1 ( n = 2). Radiation therapy was administered once daily: median dose was 80.5 Gy/35 fx/2.3 Gy/fx. The clinical target volume was tumor plus nodes ≥1.0 cm. V 20 data were available for 12 patients, with a mean value of 15.7%. Results: Thirty-four patients completed treatment. Median follow-up was 23.0 months. There were 26 deaths: 19 died from non-small cell lung (73%) and seven died from co-morbid illness (27%). Median survival was 24 months (95% CI, 18.0-31.9 months). Four patients were alive with disease, and five were alive disease-free at 10- and 68-month follow-ups. Of 41 lesions, local failure occurred in 15 lesions (37%) of which 3 local failure patients (9%) failed concomitantly in untreated regional lymph nodes. There were no isolated nodal recurrences. Distant progression: 10 patients (29%) of which 6 distant progression without local failure. Two patients who both had prior lobectomies experienced grade 5 toxicities. Conclusion: Continuous high-dose external beam radiation therapy 80.5 Gy administered in 35 fractions was tolerated. Treatment-related death was rare (6%) and isolated to patients with prior lobectomies in an extremely high-risk population. Most mortality was lung cancer-related. The dose of 80.5 Gy in 7 weeks is supported for patients with single lesions and no prior lobectomy. Local failure dominates and higher effective doses should be explored.

Major randomised trials have employed elective nodal irradiation as part of combined modality therapy for limited-stage small-cell lung cancer (SCLC). The present investigation describes patterns of failure, disease control, and survival outcomes for involved-field radiotherapy with concurrent chemotherapy, without elective irradiation of uninvolved mediastinal nodal regions.Retrospective analysis of SCLC patients treated with curative-intent accelerated, twice-daily radiotherapy and concurrent platinum-based chemotherapy at an academic institution. Treatment fields were reviewed, and patients who completed ≥42 Gy in 1.5 Gy twice-daily fractions to involved fields (without elective irradiation of uninvolved mediastinal lymphatic regions) were included in the present analysis. Initial patterns of failure, disease control and overall survival were recorded.Fifty-two patients fulfilled study criteria and were included in the present analysis. All but one patient completed three to four cycles of chemotherapy, and 10 patients experienced grade 3 acute esophagitis. At a median survivor follow-up of 35 months (range 5.5-91.9), 22 patients were alive (15 without recurrence) and 30 had died (23 of/with disease, four of unknown cause, two of other cause and one of treatment toxicity). Initial site(s) of disease failure were loco-regional only (11 patients), distant only (14) and loco-regional plus distant (3). There were no cases of isolated out-of-field mediastinal recurrence in the absence of supraclavicular or more distant disease. The estimated 3-year disease-free and overall survivals were 36% and 44%, respectively.Involved-field radiotherapy did not appear to have an adverse impact on the anticipated patterns of failure, disease control, or overall survival in this population of limited-stage SCLC patients.

OBJECTIVE: To investigate actual driving performance in a group of patients with cancer in the head and neck region. DESIGN: A nonrandomized controlled trial. PARTICIPANTS: Ten patients with cancer in the head and neck region participated in a driving evaluation using a virtual reality driving simulator. Driving performance from the simulator and observer ratings on participants' driving behaviors were compared between a group of patients with cancer in the head and neck region and a group of 50 community control subjects. MAIN OUTCOME MEASURES: Average speed, mean brake reaction time, steering variability, the total number of (fatal and nonfatal) collisions during the 12-minute evaluation course on the driving simulator, and the score of the 18-item Simulator Driving Performance Scale. RESULTS: Using Mann-Whitney U tests, the brake reaction time and the steering variability in the cancer group were significantly longer and larger, respectively, than those in the control group (P = .04) and (P = .02). However, no significant differences were found between the 2 groups in the mean rank scores for average speed, total number of collisions, and Simulator Driving Performance Scale (P >.05 for all). CONCLUSIONS: This pilot study provides preliminary evidence indicating inferior driving performance in a group of patients with cancer in the head and neck region when compared with a community control group. Further study is needed to investigate factors attributing to the difference. Language: en