Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts.
Background Nasal osteotomy is a commonly performed procedure during rhinoplasty for both functional and cosmetic reasons. Teaching and learning this procedure proves difficult due to the reliance on nuanced tactile feedback. For surgical simulation, trainees are traditionally limited to cadaveric bones, which can be costly and difficult to obtain. Objective This study aimed to design and print a low-cost midface model for nasal osteotomy simulation. Methods A 3D reconstruction of the midface was modified using the free open-source design software Meshmixer (Autodesk Inc). The pyriform aperture was smoothed, and support rods were added to hold the fragments generated from the simulation in place. Several models with various infill densities were printed using a desktop 3D printer to determine which model best mimicked human facial bone. Results A midface simulation set was designed using a desktop 3D printer, polylactic acid filament, and easily accessible tools. A nasal osteotomy procedure was successfully simulated using the model. Conclusions 3D printing is a low-cost, accessible technology that can be used to create simulation models. With growing restrictions on trainee duty hours, the simulation set can be used by programs to augment surgical training.
Background. Status 1A patients are prioritized over liver disease patients regardless of Model for End-stage Liver Disease (MELD) score. We aimed to identify groups with high waitlist mortality in Status 1A and MELD ≥40 patients to determine who would most benefit from transplantation. Methods. Data on patients listed as Status 1A (n = 4447) and MELD ≥40 (n = 3663) over 15 years (2002–2017) was obtained from United Network for Organ Sharing/Organ Procurement and Transplant Network registry. They were divided into 2—derivation and validation groups. Risk factors associated with 28-day waitlist mortality were identified in derivation group and provided risk scores to divide patients into risk groups. Score system was applied to validation group to check its applicability. Results. Risk factors for waitlist mortality in Status 1A included life support, performance status, severe coagulopathy, severe hypo or hypernatremia, and grade 3–4 encephalopathy. Risk factors in MELD ≥40 included higher MELD scores (≥45), age, sex, race, life support, and encephalopathy. On comparing 7- and 28-day mortality, both were higher in Status 1A and MELD ≥40 high-risk groups compared with low-risk groups in the derivation group (P < 0.001). Probability of transplantation was lowest for high-risk MELD ≥40 patients compared with all other groups (P < 0.001). These findings were reproduced in the validation set. Our proposed risk stratification system also showed acceptable 1-year graft and patient survival in high-risk groups. Conclusions. Our risk scoring system for extremely ill liver transplant candidates successfully stratified risk of waitlist mortality. Waitlist outcomes might be improved by modifications involving categorization of patients based on the presence/absence of risk factors.
6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death-ligand 1 (PD-L1). PD-1/PD-L1 immune checkpoint inhibition (ICI) shows promise in HNSCC, but durable responses have been seen in only a fraction of patients. Metformin, a biguanide oral anti-hyperglycemic, has shown promise in altering immunity within the tumor microenvironment (TME) towards a stronger anti-tumor distribution of immune cells. We aimed to investigate the combined effect of metformin and durvalumab in patients with HNSCC. Methods: This was a single-center prospective phase 1, window of opportunity clinical trial in which previously untreated patients with any stage resectable HNSCC were randomized 3:1 to durvalumab + metformin (Arm A) or durvalumab alone (Arm B) during a four-week period between diagnosis and surgical resection. Six patients were included in a safety lead-in of durvalumab and metformin and an additional 32 patients were randomized. The primary endpoint was immune cell polarization. Here we report pathologic and radiographic effect. Pathologic effect was graded independently by two pathologists. Radiographic effect was evaluated using the immune-related Response Criteria (irRC). Results: Thirty-eight patients were enrolled (29 Arm A, 9 Arm B). Three patients withdrew consent prior to intervention (2 Arm A, 1 Arm B) and were excluded from analysis. AJCC 8th edition staging was as follows: Stage I (n = 21), Stage II (n = 2), Stage III (n = 3), Stage IVa (n = 6), Stage IVb (n = 3). Primary tumor sites included the oropharynx (n = 20, all p16+), oral cavity (n = 11), larynx (n = 2), maxillary sinus (n = 1), and unknown (n = 1). Pathologic effect was observed in 55% (18/33) of evaluable patients: 60% in Arm A vs 37.5% in Arm B (p = 0.418). 40% of patients with involved lymph nodes had discordance of pathologic effect at the primary site versus lymph node. Radiographic response based on irRC among 30 evaluable patients included 1 CR, 1 PR, 24 SD, and 4 PD. There was a significant correlation between pathologic effect and radiographic disease control, defined as CR, PR, and SD (p = 0.021), but no correlation when looking only at radiographic responders (p = 0.925). No patients experienced Grade 3–4 treatment or immune-related adverse events or a delay in surgery due to trial participation. All patients remained resectable. Conclusions: Our data demonstrate that the study intervention was well-tolerated in HNSCC patients. There was a trend towards an increased proportion of pathologic responders in the group receiving metformin. Additional studies targeting the TME are needed to further elucidate whether synergistic effects between metformin and durvalumab were seen in this patient cohort. Clinical trial information: NCT03618654.
Background: Recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) bears a dismal prognosis. Although checkpoint inhibitors (CPI) demonstrated efficacy in R/M HNSCC, only a subset of patients benefits. Taxane based CPI combination therapy might improve the outcome. Thus, we performed this prospective phase I/II trial to investigate the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in this setting.Methods: Patients with R/M HNSCC of the oropharynx, hypopharynx, larynx or oral cavity, who failed prior platinum therapy, were included. Patients received DTX 75mg/ m ˇ 2 plus P 200mg, q21, for up to six cycles followed by P maintenance therapy for a maximum of two years. The primary endpoint was overall response rate (ORR) and safety. Patients were monitored for response every 12 weeks employing iRECIST criteria. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS).Results: Twenty-two patients were enrolled. The median age was 63 (44-77) years. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. While 4 (50%) oropharyngeal carcinoma patients were p16 positive, all patients showed PDL-1 expression defined as a combined positive score (CPS) 1.The ORR was 22.73% (95% CI 10.12%-43.44%) and one (4.5%) complete response was achieved. Disease control occurred in 12 patients resulting in a DCR of 54.55% (95% CI 34.6%-73.08%). The median PFS was 5.8 months (95% CI 2.7-11.6) and the median OS 20.4 months (95% CI 6.3-NR). The 1 year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune related AEs were grade 1/2 fatigue (68.2%), skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia.Conclusions: DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients and warrants further investigations in larger clinical trials.Clinical trial identification: NCT02718820.
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