Copy Number Variation That Influences the Ionizing Radiation Sensitivity of Oral Squamous Cell Carcinoma.

Genome instability in cancer cells causes not only point mutations but also structural variations of the genome, including copy number variations (CNVs). It has recently been proposed that CNVs arise in cancer to adapt to a given microenvironment to survive. However, how CNV influences cellular resistance against ionizing radiation remains unknown. PRMT5 (protein arginine methyltransferase 5) and APE1 (apurinic/apyrimidinic endonuclease 1), which enhance repair of DNA double-strand breaks and oxidative DNA damage, are closely localized in the chromosome 14 of the human genome. In this study, the genomics data for the PRMT5 and APE1 genes, including their expression, CNVs, and clinical outcomes, were analyzed using TCGA's data set for oral squamous cell carcinoma patients. The two genes were found to share almost identical CNV values among cancer tissues from oral squamous cell carcinoma (OSCC) patients. Levels of expression of PRMT5 and APE1 in OSCC tissues are highly correlated in cancer but not in normal tissues, suggesting that regulation of PRMT5 and APE1 were overridden by the extent of CNV in the PRMT5-APE1 genome region. High expression levels of PRMT5 and APE1 were both associated with poor survival outcomes after radiation therapy. Simultaneous down-regulation of PRMT5 and APE1 synergistically hampered DNA double-strand break repair and sensitized OSCC cell lines to X-ray irradiation in vitro and in vivo. These results suggest that the extent of CNV in a particular genome region significantly influence the radiation resistance of cancer cells. Profiling CNV in the PRMT5-APE1 genome region may help us to understand the mechanism of the acquired radioresistance of tumor cells, and raises the possibility that simultaneous inhibition of PRMT5 and APE1 may increase the efficacy of radiation therapy.

A Daily Assessment Study of Smoking Cessation After a Head and Neck Cancer Diagnosis.

INTRODUCTION: This intensive longitudinal study describes key events in the process of smoking cessation after a new head and neck cancer (HNC) diagnosis. Prior longitudinal studies show some cancer patients quit, while others continue to smoke, but details about the pattern in which these discrete outcomes arise are scarce. This study is meant to help rectify this gap in the literature. AIMS AND METHODS: Participants were 42 HNC patients who reported current smoking at enrollment. Participants were recruited from an outpatient oncology clinic and completed a baseline questionnaire prior to begin a 30-day daily assessment. RESULTS: Few participants (9.52%) achieved 30-day continuous abstinence from smoking. On average, participants reported 9.64 ± 11.93 total days of abstinence. Nearly, all (94.44%, n = 34) participants made at least one quit attempt, with an average of 16.94 ± 11.30 quit attempt days. Fewer participants were able to achieve a 24-hour quit attempt (52.78%, n = 19), with a corresponding average of 5.50 ± 8.69 24-hour days. The median time to first 24-hour quit attempt was 13 days after enrollment. Based on smoking behavioral patterns, participants were categorized into five groups, the most common being "persistent attempters," which involved unsuccessful quit attempts throughout the study. Only 45% of participants (n = 19) used evidence-based treatment, the most common being cessation medication. CONCLUSIONS: This intensive longitudinal study found that cancer diagnosis can spur a lot of efforts to quit smoking. Unfortunately, this study suggests that many quit attempts are short lived, possibly a result of an absence or insufficient use of evidence-based treatments. IMPLICATIONS: For adults who are current smokers at the time of cancer diagnosis, there is a high likelihood of persistent cigarette smoking and use of other tobacco products in the weeks and months after a cancer diagnosis. Furthermore, this study shows that while a lot of quit attempts may occur, few are successful, which may be partly attributable to the low use of evidence-based tobacco treatment. Future research with cancer patients should aim to identify predictors of quit attempts and abstinence as well as treatment utilization.

Tobacco Use and Tobacco Treatment Referral Response of Patients With Cancer: Implementation Outcomes at a National Cancer Institute-Designated Cancer Center.

PURPOSE: Smoking after a cancer diagnosis is linked to cancer-specific and all-cause mortality, among other adverse outcomes. Yet, 10%-20% of US cancer survivors are current smokers. Implementation of evidence-based tobacco treatment in cancer care facilities is widely recommended, yet rarely accomplished. This study focuses on the early outcomes of a population-based tobacco treatment program integrated within an National Cancer Institute-designated cancer center. METHODS AND MATERIALS: The sample consists of 26,365 patients seen at the cancer center during the first 18 months of program implementation. The study is a retrospective chart review of patients' tobacco use and, among current users, patients' treatment referral response. RESULTS: More than 99% of patients were screened for tobacco use. Current (past month) use was observed in 21.05% of patients; cigarettes were the most popular product. Only 17.22% of current users accepted a referral for tobacco treatment; among current users who declined, the majority were not ready to quit (65.84%) or wanted to quit on their own (27.01%). Multiple demographic variables were associated with tobacco use and treatment referral response outcomes. CONCLUSION: Despite cancer diagnosis presenting a teachable moment for tobacco cessation, patients with cancer may not be ready to quit or engage with treatment. Clinically proven strategies to increase motivation, prompt quit attempts, and encourage treatment use should be key components of tobacco treatment delivery to patients with cancer.

Evaluation of antioxidant network proteins as novel prognostic biomarkers for head and neck cancer patients.

OBJECTIVES: Recurrence rates for head and neck squamous cell carcinoma (HNSCC) approach 50% at 5 years. Current staging fails to identify patients with a worse prognosis who might benefit from intensified treatment, which warrants improved prognostic biomarkers. The purpose of this retrospective case study is to identify potential prognostic biomarkers in patients with HNSCC including APE1 (DNA repair/redox gene regulator), NRF2 and PPARGC1A (redox gene regulators), SOD3 and DCN (antioxidant proteins). MATERIALS AND METHODS: Differential protein expression between benign, carcinoma in situ (CIS), and invasive HNSCC tissue specimens from 77 patients was assessed using immunohistochemistry. Protein expression was analyzed with multivariate, pair-wise, and Kaplan-Meier survival analyses to identify potential prognostic biomarkers. Utilizing The Cancer Genome Atlas's transcriptome database, pair-wise and survival analysis was performed to identify potential prognostic biomarkers. RESULTS: APE1, NRF2, PPARGC1A, SOD3, and DCN expression in HNSCC in relation to, lymph node invasion, and patient survival were examined. Elevated APE1 protein expression in CIS corresponded with reduced survival (p = 0.0243). Increased APE1 gene expression in stage T4a HNSCC was associated with reduced patient survival (p < 0.015). Increased PPARGC1A in invasive tumor correlated with reduced survival (p = 0.0281). Patients with lymph node invasion at diagnosis had significantly increased APE1 protein in the primary sites (p < 0.05). Patients with poorly differentiated invasive tumors had reduced PPARGC1A in CIS proximal to the invasive tumor and had elevated DCN and SOD3 in proximal benign tissue (p < 0.05). CONCLUSIONS: The expression of APE1, DCN, and SOD3 is a potential prognostic signature that identifies patients with worsened survival.

Erratum: Author Correction: Identification of novel genetic variants predisposing to familial oral squamous cell carcinomas.

[This corrects the article DOI: 10.1038/s41421-019-0126-6.].

Efficacy of Voice Therapy in Improving Vocal Function in Adults Irradiated for Laryngeal Cancers: A Pilot Study.

BACKGROUND: Radiation therapy (XRT) for laryngeal cancers causes acute and chronic vocal dysfunction. Although these deleterious effects of XRT are well-established, there is a dearth of research with respect to effective voice rehabilitation following XRT for laryngeal cancers. OBJECTIVE: To obtain preliminary data on the efficacy of voice rehabilitation, using vocal function exercises (VFEs) in improving vocal function in adults irradiated for laryngeal cancer. The comparison treatment group (VH) received vocal hygiene counseling. STUDY DESIGN: Randomized clinical trial. METHODS: Participants were randomized to the VFE + VH or VH group. Both interventions lasted 6 weeks. The primary outcome measure was improvement in VHI scores. Secondary outcome measures included auditory-perceptual assessments, acoustic and aerodynamic measures, and laryngeal imaging. RESULTS: Ten participants were recruited for the study. The VFE + VH (n = 6) group demonstrated a statistically significant improvement in the primary outcome measure (P = 0.03), as well as select parameters of all secondary outcome measures. The VH (n = 4) group did not demonstrate a statistically significant improvement in primary or secondary outcome measures. CONCLUSIONS: This study offers preliminary data for the utility of VFEs in the irradiated laryngeal cancer population. However, findings in the VFE + VH group lack generalizability, secondary to sample heterogeneity, and limited sample size.

Identification of novel genetic variants predisposing to familial oral squamous cell carcinomas.

Oral squamous cell carcinoma (OSCC) is a common subtype of head and neck squamous cell carcinoma (HNSCC), but the pathogenesis underlying familial OSCCs is unknown. Here, we analyzed whole-genome sequences of a family with autosomal dominant expression of oral tongue cancer and identified proto-oncogenes VAV2 and IQGAP1 as the primary factors responsible for oral cancer in the family. These two genes are also frequently mutated in sporadic OSCCs and HNSCCs. Functional analysis revealed that the detrimental variants target tumorigenesis-associated pathways, thus confirming that these novel genetic variants help to establish a predisposition to familial OSCC.

Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression.

Autophagy may play a critical role in colon cancer stem cells (CCSCs)-related cancer development. Here, we investigate whether accumulation of infection/injury-induced CCSCs due to impaired autophagy influences colon cancer development and progression. When Apc++ mice were infected with Citrobacter rodentium (CR; 109CFUs), we discovered presence of autophagosomes with increases in Beclin-1, LC3B and p62 staining during crypt hyperplasia. Apc1638N/+ mice when infected with CR or subjected to CR+AOM treatment, exhibited increased colon tumorigenesis with elevated levels of Ki-67, ß-catenin, EZH2 and CCSC marker Dclk1, respectively. AOM/DSS treatment of Apc1638N/+ mice phenocopied CR+AOM treatment as colonic tumors exhibited pronounced changes in Ki-67, EZH2 and Dclk1 accompanied by infiltration of F4/80+ macrophages, CD3+ lymphocytes and CD3/ß-catenin co-localization. Intestinal and colonic tumors also stained positive for migrating CSC markers CD110 and CDCP1 wherein, colonic tumors additionally exhibited stromal positivity. In tumors from CR-infected, CR+AOM or AOM/DSS-treated Apc1638N/+ mice and surgically-resected colon tumor/metastatic liver samples, significant accumulation of p62 and it's co-localization with LC3B and Dclk1 was evident. ApcMin/+ mice when infected with CR and BLT1-/-;ApcMin/+ mice, exhibited similar co-localization of p62 with LC3B and Dclk1 within the tumors. Studies in HCT116 and SW480 cells further confirmed p62/Dclk1 co-localization and Chloroquin/LPS-induced increases in Dclk1 promoter activity. Thus, co-localization of p62 with Dclk1 may hamper Dclk1's elimination to impact colon cancer development and progression.

Morbidity and mortality of synchronous hepatectomy with cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).

BACKGROUND: Liver resection in conjunction with partial colectomy for colon cancer is considered acceptable treatment for isolated metastasis to the liver. This method is unstudied in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for carcinomatosis due to colon cancer and high grade appendiceal cancer. METHODS: A retrospective chart review included patients from 2005 to 2016 undergoing CRS/HIPEC. Cancers other than colorectal adenocarcinoma and high grade appendiceal carcinoma were excluded. Patients were divided into hepatectomy and non-hepatectomy groups. Data was collected by chart review from electronic medical records to assess morbidity and mortality, as well as oncologic outcomes of included patients. RESULTS: The average patient age, length of stay, and sex were similar between groups. For those in the hepatectomy group, 80% underwent minor hepatectomy, and 20% underwent major hepatectomy. The comprehensive complication index (CCI) scores ranged from 0 (no complications), to 100 (death). The average CCI between study groups was similar (27.29 vs. 17.41, P=0.09). Hepatectomy was associated with a higher rate of Clavien-Dindo classifications (CDCs) of III or greater. Complications included pressor requirement, renal failure, blood transfusions, TPN, pleural effusions and leaks requiring drain placement, respiratory failure, UTI, new onset atrial fibrillation, wound infections, and death. CONCLUSIONS: Patients who underwent CRS/HIPEC and hepatectomy for colorectal and high grade appendiceal carcinomatosis had more severe complications at similar rates to non-hepatectomy patients. Complication rates should be considered when selecting patients for aggressive surgical intervention.

A novel endoscopic grading system for prediction of disease-related outcomes in patients with diverticulosis.

BACKGROUND: We describe a simple endoscopic grading system of diverticular disease for the assessment of disease severity and prediction of outcomes. METHODS: A retrospective analysis of prospectively maintained colonoscopy database was conducted. A single endoscopist prospectively graded disease severity according to the number and size of diverticula, the degree of muscular hypertrophy and rigidity of the sigmoid colon. RESULTS: 762 patients were included in the analysis. Mean patient age was 70 years (range 37-97). Endoscopic severity of diverticulosis was predictive of the need for surgery, with 2% in the mild-moderate, 12% in the severe and 33% in the acute group (p < 0001). Time to surgery showed correlation to severity grade, with mean periods of 107.5 months in the moderate group vs. 3 and 2.5 months in the severe and acute group (p < 0001). The mean follow up was 11 years. CONCLUSION: Surgeons should consider using endoscopic grading as an adjunct to clinical management decisions.

Prognostic indicators and survival in salvage surgery for laryngeal cancer.

BACKGROUND: Perineural invasion (PNI) and lymphovascular invasion (LVI) are known to be poor prognostic indicators in primary surgery. The purpose of this study was to determine their impact on survival in the setting of salvage laryngectomy. METHODS: We conducted a retrospective review of patients who underwent salvage laryngectomy between 2006 and 2014. RESULTS: Seventy-eight patients were included in this study; PNI was diagnosed in 48 patients (61.54%) and LVI in 25 patients (32.05%). Median overall survival was 32 months; PNI was associated with decreased survival; and the unadjusted hazard ratio (HR) was 2.69 (P = .006). Cases of LVI trended toward a decreased survival; with an unadjusted HR of 1.74 (P = .076). On multivariate analysis, PNI, LVI, or both conferred decreased survival compared to having neither (P = .01). Extracapsular spread and nodal metastases significantly impacted survival, and positive margins trended toward significance. CONCLUSION: The presence of PNI, LVI, nodal disease, and extracapsular spread significantly affected survival in this cohort of patients with laryngeal cancer.

Outpatient versus observation/inpatient parotidectomy: patient factors and perioperative complications.

The objective of this manuscript is to review a single institution's experience with superficial or total parotidectomy in outpatient and observation/inpatient groups. All patients who underwent superficial or total parotidectomy between 2009 and 2015 were identified. Patients were excluded if they had undergone concurrent surgery such as neck dissection, had prior radiation treatment or surgery at the operative site. Main outcomes were perioperative complications in both groups. 215 consecutive patients were included in the study, 116 (54%) patients in the inpatient group and 99 (46%) in the outpatient group. Aside from a higher observed rate of cardiac disease in the outpatient group (24.2 vs. 11.2%, p = 0.014) and larger mean body mass index (BMI) in the inpatient group (32.448 vs. 30.034, p = 0.017), there were no significant differences for age, sex or smoking status. Average operative time differed between groups with 2 h 42 min for inpatients and 2 h 18 min for outpatients (p < 0.001). There were 26 complications in the inpatient group (22.4%, including two hematomas) and 8 in the outpatient group (8.1%). The rate of seroma/sialocele formation was significantly higher in the inpatient group at 15.5% (n = 18) compared with the outpatient group at 3% (n = 3, p = 0.001). Our study shows that parotidectomy, superficial or total, was performed safely as an outpatient procedure without significant increase in complications when compared to patients observed for at least one night after surgery.

Using low-dose radiation to potentiate the effect of induction chemotherapy in head and neck cancer: Results of a prospective phase 2 trial.

PURPOSE: Low-dose fractionated radiation therapy (LDFRT) induces effective cell killing through hyperradiation sensitivity and potentiates effects of chemotherapy. We report our second investigation of LDFRT as a potentiator of the chemotherapeutic effect of induction carboplatin and paclitaxel in locally advanced squamous cell cancer of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Two cycles of induction therapy were given every 21 days: paclitaxel (75 mg/m2) on days 1, 8, and 15; carboplatin (area under the curve 6) day 1; and LDFRT 50 cGy fractions (2 each on days 1, 2, 8, and 15). Objectives included primary site complete response rate; secondary included overall survival, progression-free survival (PFS), disease-specific survival, and toxicity. RESULTS: A total of 24 evaluable patients were enrolled. Primary sites included oropharynx (62.5%), larynx (20.8%), oral cavity (8.3%), and hypopharynx (8.3%). Grade 3/4 toxicities included neutropenia (20%), leukopenia (32%), dehydration/hypotension (8%), anemia (4%), infection (4%), pulmonary/allergic rhinitis (4%), and diarrhea (4%). Primary site response rate was 23/24 (95.8%): 15/24 (62.5%) complete response, 8/24 (33.3%) partial response, and 1/24 (4.2%) stable disease. With median follow-up of 7.75 years, 9-year rates for overall survival were 49.4% (95% confidence interval [CI], 30.5-79.9), PFS was 72.2% (CI, 55.3-94.3), and disease-specific survival was 65.4% (44.3-96.4). CONCLUSION: Chemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy.

Noncontact diffuse optical assessment of blood flow changes in head and neck free tissue transfer flaps.

Knowledge of tissue blood flow (BF) changes after free tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage. This study used our recently developed noncontact diffuse correlation spectroscopy to monitor dynamic BF changes in free flaps without getting in contact with the targeted tissue. Eight free flaps were elevated in patients with head and neck cancer; one of the flaps failed. Multiple BF measurements probing the transferred tissue were performed during and post the surgical operation. Postoperative BF values were normalized to the intraoperative baselines (assigning "1") for the calculation of relative BF change (rBF). The rBF changes over the seven successful flaps were 1.89 ± 0.15, 2.26 ± 0.13, and 2.43 ± 0.13 (mean ± standard error), respectively, on postoperative days 2, 4, and 7. These postoperative values were significantly higher than the intraoperative baseline values (p<0.001), indicating a gradual recovery of flap vascularity after the tissue transfer. By contrast, rBF changes observed from the unsuccessful flaps were 1.14 and 1.34, respectively, on postoperative days 2 and 4, indicating less flow recovery. Measurement of BF recovery after flap anastomosis holds the potential to act early to salvage ischemic flaps.

p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.

OBJECTIVE: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). STUDY DESIGN: Historical cohort study. SETTING: Tertiary medical center. METHODS: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. RESULTS: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). CONCLUSIONS: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.

Delivery of RNA nanoparticles into colorectal cancer metastases following systemic administration.

The majority of deaths from all cancers, including colorectal cancer (CRC), is a result of tumor metastasis to distant organs. To date, an effective and safe system capable of exclusively targeting metastatic cancers that have spread to distant organs or lymph nodes does not exist. Here, we constructed multifunctional RNA nanoparticles, derived from the three-way junction (3WJ) of bacteriophage phi29 motor pRNA, to target metastatic cancer cells in a clinically relevant mouse model of CRC metastasis. The RNA nanoparticles demonstrated metastatic tumor homing without accumulation in normal organ tissues surrounding metastatic tumors. The RNA nanoparticles simultaneously targeted CRC cancer cells in major sites of metastasis, such as liver, lymph nodes, and lung. Our results demonstrate the therapeutic potential of these RNA nanoparticles as a delivery system for the treatment of CRC metastasis.

Vascular sequelae of mediastinal fibrosis.

Fibrosing mediastinitis is a condition in which mediastinal fat is replaced by fibrous tissue. Complications may arise due to progressive fibrotic infiltration and compression of major vascular, respiratory, and nervous structures within the mediastinum. We describe 3 similar cases of fibrosing mediastinitis with pulmonary vessel involvement. Imaging and intraoperative observation revealed involvement of the pulmonary vasculature in all 3 patients. Perfusion studies showed decreased or absent perfusion to one or both of the lungs. All patients tested negative for histoplasmosis, 2 required lung resection, with the 3rd forgoing surgery.

Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer.

Upregulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models using immunohistochemistry, immunofluorescent staining and confocal microscopy. Cell secretion was evaluated by ELISA and antibody arrays. Proliferation, migration and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC coculture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in 'normalization' of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and antiangiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the antiangiogenic activity noted with knockdown of FASN included: downregulation of VEGF(189), upregulation of antiangiogenic isoform VEGF(165b) and a decrease in expression and activity of matrix metalloproteinase-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor-2 and its downstream signaling and decreased proliferation, migration and tubulogenesis of ECs as compared with control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC.