bluuebunny/crossref_metadata_2025 huggingface dataset:
A combined genomic and immune profile in patients with head and neck squamous cell carcinoma treated with immunotherapy: A pilot study.
Authors: Botticelli Andrea , Mezi Silvia , Pomati Giulia , Zizzari Ilaria , Cerbelli Bruna , Mammone Giulia , Corsi Alessandro , di Gioia Cira , D'Amati Giulia , della Rocca Carlo , Catalano Carlo , De Vincentiis Marco , Polimeni Antonella , Valentini Valentino , Tombolini Vincenzo , Nuti Marianna , Marchetti Paolo
Published: May 2020

e18506

Background: In head and neck squamous cell carcinoma (HNSCC) only a small subset of patients (pts) really benefits from immunotherapy, suggesting the need of validated molecular and immunological predictive biomarkers. The aim of the study was to evaluate both the genomic and immune profile of HNSCC correlating it to early progression to immunotherapy. Methods: This is a pilot study evaluating immune and molecular profile in platinum-refractory HNSCC pts treated with Nivolumab. Blood samples were collected at baseline (T0) and at second cycle of therapy (T1). The immune profile was studied by multiplex assay, evaluating circulating: CD137, CTLA4, PD1, PDL1, PDL2, CD27, TIM3, LAG3, GITR, HVEM, BTLA, CD80, CD28 and IDO. The comprehensive genomic profile was evaluated at baseline on formalin-fixed paraffin-embedded samples of the tumor through Foundation One Cdx test. The results obtained were correlated with early progression (within 3 months from the start of therapy). Results: Ten pts were enrolled in the study. Early progression occurred in 6 pts (60%). Median progression free survival and overall survival were 3 months (1-11) and 6.5 months (1-12), respectively. In all patients ≥ 5 genetic mutations were detected; median number of mutation was 6 (5-14); 8/10 pts had a tumor mutational burden less than 10 Muts/mb. The more frequent genetic alterations involved the cycline-dependent-kynase pathway (9/10), the transcription factor associated gene TP53 (8/10) and the PI3K-Akt-PTEN signaling pathways (5/10). Less frequent alterations involved FGFR family (4/10), NOTCH signaling pathway (3/10) and TERT (4/10). Early progression was slightly associated with the number of mutations detected (p = 0.06). The rising or falling trend of circulating levels of biomarkers were detected in 9/10 pts and included modification in IDO (1/10), LAG3 (3/10), GITR (3/10), BTLA (3/10), CD137 (4/10), CTLA4 (4/10), PD1 (2/10), Tim3 (3/10), CD28 (3/10), HVEM (3/10), CD80 (2/10). No modifications were recorded in PDL1, PDL2 and CD27. Conclusions: Our results, although in a small cohort, highlighted the complexity and heterogeneity of landscape in HNSCC pts. A novel evaluation that combines molecular and immune profile is needed. In the context of a poor prognosis disease the combination of personalized molecular and immune approaches could represent a promising strategy to improve survival.
Long-term outcomes of locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumor with neuroendocrine differentiation treated with neoadjuvant chemotherapy.
Authors: Kumar Amit , Noronha Vanita , Patil Vijay Maruti , Joshi Amit , Menon Nandini Sharrel , Prabhash Kumar
Published: May 2020

e18507

Background: Sinonasal tumors are a rare subgroup of head and neck cancers. Locally advanced esthesioneuroblastoma and sinonasal neuroendocrine tumors (SNEC) are treated with a multidisciplinary approach with combination of surgery followed by adjuvant radiation or chemo radiation; but have unsatisfactory outcomes. Hence we devised the approach of administering neoadjuvant chemotherapy (platinum and etoposide) followed by surgery and adjuvant chemoradiation. This approach had the advantage of improved response rates, orbital preservation and improvement in short term outcomes. The present analysis was done to estimate the 5 year outcomes and late adverse events of locally advanced sinonasal tumors treated with induction chemotherapy followed by local therapy. Methods: Twenty five patients with locally advanced esthesioneuroblastoma or SNEC treated between August 2010 to August 2014 with induction chemotherapy followed by local therapy were selected. The 5 year outcomes and late adverse events (CTCAE version 4.02) were noted. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. COX regression analysis was used to identify factors impacting PFS and OS. Results: The median follow up was 5.15 years. The 5 year PFS in esthesioneuroblastoma cohort and in SNEC cohort was 63.5% (95%CI 28.9-84.7) and 34.6% (95%CI 10.1-61.1) respectively (p = 0.1). The only factor impacting PFS on multivariate analysis was response to neoadjuvant chemotherapy (p = 0.033). The 5 year OS in esthesioneuroblastoma cohort and in SNEC cohort were 91.7% (95%CI 53.9-98.9) and 46.2% (95%CI 19.2-69.6) respectively (p = 0.024). Any grade late adverse event was seen in 20 patients (80%). Metabolic late adverse events were seen in 19 patients (76%). Conclusions: Neoadjuvant chemotherapy in advanced sinonasal cancers is associated with improvement in 5 year outcomes. However late side effects especially metabolic are seen in these patients and should be evaluated during follow up. Keywords: Sinonasal; Adverse event; Esthesioneuroblastoma; SNEC; Induction; Neoadjuvant [Table: see text]
Initial safety and tumor control results from a phase I prospective trial evaluating a novel alpha-emitting radionuclide for the treatment of locally advanced recurrent squamous cell carcinomas of the skin and head and neck.
Authors: Popovtzer Aron ,   Alpha Tau
Published: May 2020

e18509

Background: The purpose of this study is to report on the feasibility and safety of Diffusing Alpha-emitters Radiation Therapy (DaRT), including interstitial implantation of a novel alpha-emitting brachytherapy source, to treat locally advanced and recurrent squamous cell carcinomas (SCC) of the skin and head and neck. Methods: This prospective, first-in-human Phase I multicenter study included 28 eligible patients with 31 lesions. The primary endpoint was the feasibility and safety of the DaRT treatment approach. The secondary endpoint was initial tumor response and local progression-free survival (PFS) outcomes. Eligibility criteria included biopsy-proven SCC of the skin and head neck with either recurrent or previously-treated disease with either surgery or prior external beam radiotherapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (Version 4.03). Tumor response was assessed at follow-up (30-45 days following treatment) using the Response Evaluation Criteria in Solid Tumors (Version 1.1). Results: Acute toxicity events included mostly erythema and swelling at the implantation site followed by pain and mild skin ulceration. Pain and Grade 2 skin ulcerations resolved in most patients within 3-5 weeks. Complete response (CR) to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); seven lesions (6/28; 21.4%) manifested a partial response ( > 30% tumor reduction). Among the 22 lesions with a CR, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median of 4.9 months (range: 2.43-5.52 months). The one-year local PFS probability at the implanted site was 60% (95% Confidence Interval, CI: -28.61-81.35%) for complete responders. Overall survival (OS) at 12 months post-DaRT implantation was 75% (95% CI: 46.14-89.99%); among complete responders, OS was 93% (95% CI: 59.08-98.96%). Conclusions: Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without Grade 3 or higher toxicities. Longer follow-up observations and larger studies are underway to validate these findings. Clinical trial information: NCT03015883 NCT03353077.
Efficacy and tolerability of weekly 40mg/m² cisplatin radiosensitizing modified regimen for locally-advanced head and neck squamous cell carcinoma radical treatment with chemoradiotherapy: A university hospital experience.
Authors: Bighetti Bruna , Neto José Tristão , Pereira Renata do Socorro Monteiro , SOUZA LAÍS CRISTHINE , Santoro Ilka Lopes , Tadokoro Hakaru , Ribas Christian , De Mello Ramon Andrade
Published: May 2020

e18512

Background: Cisplatin-based chemoradiotherapy (CRT) is a well-established regimen used for adjuvant and/or head-and-neck squamous cell carcinoma (HNSCC) radical treatment. The most classic protocol for chemoradiotherapy remains the administration of Cisplatin 100mg/m² EV D1 q3-week period, 3 cycles. The objective of this study is to assess the efficacy and tolerability of the weekly 40mg/m² cisplatin regimen. Methods: we conducted a retrospective study from 2007-2020 with 102 patients treated at a national reference institution. All of them with HNSCC received concurrent CRT with weekly cisplatin 40mg/m² EV D1. We analyzed the overall survival (OS), local recurrence and tolerability in this scheme. Results: The median cisplatin cumulative dose received by our patients was 240mg/m². Hence, we divided them in two groups for the analysis: Group A (41 patients) received less than 240mg/m² cisplatin total dose and Group B (61 patients) received more or equal 240mg/m² cisplatin total dose. Both groups were equally balanced between sex, clinic stage, histologic grade and clinic status. We found that the Group A experienced 5 deaths (12.2%) while the Group B experienced 6 deaths (9.8%). The mean time to recurrence disease in the Group A was 45.68 months and in Group B 60.22 months (p = 0.958). The estimated overall survival in the Group A was 150 months and in the Group B was 116.4 months (p = 0.443). Conclusions: The weekly cisplatin dose regimen showed to be feasible, more tolerable, and less toxic and with no difference in terms of OS then the classic 3-week cisplatin protocol in the CRT setting. Our group suggests that the 240mg/m² cumulative cisplatin weekly schedule should be a better option for CRT treatments then the classic cisplatin regimen. A phase III clinical trial is warranted to further understanding of this framework. Key-words: head and neck cancer, cisplatin, radiotherapy
Single-institute outcomes of palliative chemotherapy in metastatic head and neck squamous cell carcinoma (HNSCC).
Authors: Parikh Rujul H , Fleming Christopher W , Reddy Chandana A. , Koyfman Shlomo A. , Joshi Nikhil , Woody Neil McIver , Burkey Brian B. , Scharpf Joseph , Lorenz Robert R , Prendes Brandon , Ku Jamie , Lamarre Eric , Schwartzman Larisa , Adelstein David J. , Geiger Jessica Lyn
Published: May 2020

e18513

Background: Distantly metastatic HNSCC carries a poor prognosis with limited palliative systemic treatment options and a paucity of literature examining factors impacting outcomes of such therapy. We sought to evaluate characteristics conferring more favorable responses to frontline palliative systemic therapy after distant failure (DF). Methods: From an IRB-approved database, we identified 332 pts with metastatic HNSCC treated from 1999 to 2019. Pts with locoregional HNSCC who developed DF and subsequently were treated with palliative systemic therapy were included. Pts were categorized by disease factors, and outcomes were analyzed for progression-free survival (PFS) and overall survival (OS) with Kaplan-Meier curves and log-rank p-values. Results: A total of 85 pts were identified with median age 59.5 years (37-89); 82.4% male, 90.6% Caucasian, 52.9% with > 10 pack-years tobacco use history. Oropharynx primary was the most common site (36.5%) followed by oral cavity (23.5%). All 31 oropharynx cancer pts were HPV-related. Sixty-six pts initially received definitive chemoradiotherapy, with 43 receiving concurrent radiosensitizing cisplatin. Median time to DF was 15 months (m). Thirty pts (35.3%) had concurrent locoregional failure with DF. 62.4% had only one metastatic organ site, with lung-only metastasis in 43.5%. Carboplatin/paclitaxel was the most commonly used frontline palliative chemotherapy (50.6%); 22.4% received frontline nivolumab or pembrolizumab, and 9.4% were treated with frontline platinum/5-FU/cetuximab (9.4%). 63.5% of pts achieved a best response of stable disease or better with frontline therapy. At two years after initial DF, 6 pts (7%) were disease-free. Sixteen pts were alive at last follow-up. After DF, median PFS was 6.5 m and median OS was 10.6 m. On univariate analysis, HPV-related disease was associated with increased PFS (9.5 vs 5.1 m, p < 0.0001) and increased OS (21.1 vs 7.7 m, p < 0.0001). Pts with one metastatic organ site had better OS (11.0 vs 6.2 m, p = 0.047). There was a trend of increased OS with lung-only metastasis (14.4 vs 7.7 m, p = 0.0776), and absence of concurrent locoregional failure (10.8 vs 8.3 m, p = 0.1153). Conclusions: Our results demonstrate that HPV-related metastatic HNSCC is associated with a statistically significant increased PFS and OS. Additionally, there was a trend of increased OS with lower locoregional and distant metastatic burden at DF though statistical significance was not achieved.
Clinicopathological characteristics and survival outcome in oral cavity cancer with masticator space involvement (T4b): A retrospective single-institutional experience.
Authors: K P Abdulla , Geotge Nebu Abraham , M C Hajara , Mohan Raj
Published: May 2020

e18517

Background: Oral cavity cancer with the masticator space involvement is considered as very advanced localised disease and staged as T4b in AJCC 8th edition, along with the involvement carotid artery,base of skull or prevertebral fascia. NCCN treatment guidelines consider this as inoperable disease and advocate non surgical options or palliative treatment. This study intends to compare the different treatment modalities in T4b oral cavity cancer and their impact on survival. Methods: This is a retrospective study of 150 patients with T4b oral cavity ca, from 2013to 2015 and follow up data till 31 st July 2019 were collected. All patients had biopsy proven SCC and CT evidence of masticator space involvement. Results: Total of 150 patients were included. 102 patients had received curative treatment and 48 patients had received palliative treatment. 30% in the curative group and 42% in the palliative group were supra notch disease. In the curative group 84% were treated with surgery and adjuvant treatment and remaining had received RT with or without chemotherapy. 90% patients in the surgically treated group had attained margin negative resection. 4 year OS in the curatively treated group was 58.9% and in the palliative group was 12%. 2 year OS was 69% and 31% respectively, (p=0.001). The survival of supra notch disease was not different from infra notch disease neither in the curative group (61% v/s 57%, p=0.452) nor in the palliative group (10% v/s 14%, p=0.13). The surgically treated patients in the curative arm had significant survival advantage over the patients who had received only RT with or without chemotherapy, (63.5% v/s 34%, p=0.001). Conclusions: Curatively treated oral cavity cancer with masticator space involvement has survival outcome comparable to the published survival data of those without masticator space involvement. Clinicopathological spectrum of supra notch disease is not different from infra notch disease, and their prognosis is similar to infr anotch disease, if margin negative resection is attained. Radical intent treatment, preferably surgery should be offered to all patients with masticator space involvement, if negative margin is anticipated from preoperative imaging.
DNA methylation profiling in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.
Authors: Starzer Angelika Martina , Heller Gerwin , Tomasich Erwin , Feldmann Katharina , Hatziioannou Teresa , Traint Stefan , Minichsdorfer Christoph , Schwarz-Nemec Ursula , Nackenhorst Maja , Muellauer Leonhard , Preusser Matthias , Berghoff Anna Sophie , Fuereder Thorsten
Published: May 2020

e18527

Background: Biomarkers for response prediction to immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) patients are needed for a personalized therapy regimen. Therefore, we investigated the predictive potential of inflammatory biomarkers and DNA methylation. Methods: We profiled the methylation status of 850.000 CpG sites in formalin-fixed, paraffin-embedded primary HNSCC samples collected before ICI therapy start using Infinium Methylation EPIC microarrays. Tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1) expression were analyzed employing immunohistochemistry staining. Methylation profile, TIL density and PD-L1 expression were correlated with best radiological response to ICI treatment. Results: 29 patients (median age of 61; range 28-80) years; 8 (27.6%) females, 21 (72.4%) males) with HNSCC were included. Median number of prior systemic therapies was 1 (range 0-3). Median number of ICI applications was 6 (range 1-45). 2/29 (6.9%) patients achieved an objective response (complete response or partial response) under anti-PD-1 therapy. Median progression-free survival (PFS) and median overall survival (OS) were 3.3 months (range 0-28.8) and 7.2 months (range 0-29.4), respectively. 7/29 (24.1%) patients were still alive and one of these patients was still on ICI therapy at data cut-off. Methylation analyses revealed a combination of methylation changes (both hypo- and hypermethylation) that was predictive for response to ICI. 11/27 (40.7%) patients had PD-L1 expressing tumor cells ( > 1% PD-L1 expression). Median density of CD8+ TILs was 423.49 cells/mm2 tumor (range 5.71-11528.43 cells/mm2) and median density of CD3+ TILs was 794.82 cells/mm2 tumor (range 1.68-8811.74 cells/mm2). There was no correlation of PD-L1 expression, density of CD8+ or CD3+ TILs with response or disease control (p > 0.05). Conclusions: In contrast to PD-L1 expression and TIL density, methylation profiles were associated with response to ICI treatment in HNSCC patients.
Multigene profiling to identify clinically relevant actionable mutations in head and neck cancers: An Indian study.
Authors: Kunigal Sateesh S. , Thakur Shalini , Shivkumar Yogesh , M L Sheela , CR Krishna , Bahadur Urvashi , Nayar Ravi , Gopinath Kodaganur S. , Ghosh Mithua , Ajaikumar Basavalinga Sadasivaiah , Rao Vishal Uchila Shishir
Published: May 2020

e18529

Background: Head and Neck squamous cell carcinoma (HNSCC) represents approximately 5-10% of malignancies worldwide. Despite the advances in treatment modalities there lies a disparity in response, owing to the underlying molecular and genetic make up. In the era of precision medicine, it is important to profile each disease and customise treatment to improve the outcomes by identifying predictive or prognostic indicators at the molecular and genetic level. Methods: 100 patients with HNSCC, diagnosed at our centre from April 2015-17 were profiled by targeted deep sequencing for hotspot mutations in 48 cancer-related genes using Illumina’s TSCAP panel and MiSeq technology. The average coverage across 220 hot spots was greater than 1000X. Data was processed using Strand Avadis NGS. Mutations identified in the tumor were assessed for ‘actionability’ i.e. response to therapy and impact on prognosis. The clinical data for these patients was collected retrospectively and analysed for treatment outcomes with standard therapy. The association of mutations with habits, stage at presentation, poor treatment outcomes and prognosis was also analysed. Results: Somatic variants were detected in 63.1% of cases. Genetic aberrations were identified in major RAS/RAF signalling pathway in 10 % of cases out of which HRAS activating mutations were the most common (n=4). HRAS was co-mutated with PI3KCA (n=3) and PTEN deletions (n=2). Based on the result, Cetuximab was discontinued in 2 patients with metastatic HNSCC. Other targetable mutations included ATM (n=1), STK11 (n=1), RB1 (n=1) and BRAF (n=1). Disruptive and non-disruptive mutations in TP53 alone were found in 43.8% of H&N cancers, varying widely among different histology with variable treatment outcome. Interestingly all metastatic/recurrent patients, with very short progression free survival of 9-12 months (PFS) post Cisplatinum based chemotherapy, were found to have mutated TP53. TP53 was also found to be co- mutated with ATM gene (n=1), an important prognostic marker, indicating poor response to chemotherapy and radiotherapy. The patients with recurrence and poorer prognosis (n =5) showed point mutations in codon regions 173 -273. Conclusions: Indian patients with HNSCC display a wide mutational landscape with specific actionable targets. Although traditional treatment modalities remain the standard of care, specific mutations may be utilised to customise treatment, prognosticate and predict outcomes.
Prognostic value of HER2, PD-L1 and RET mRNA expression in salivary gland tumor.
Authors: Kutukova Svetlana , Imyanitov Evgeny , Raskin Grigory , Ivaskova Julia V. , Beliak Natalia P. , Yaremenko Andrey I. , Razumova Alexandra , Pakhomova Natalia
Published: May 2020

e18534

Background: The objective of our study was to evaluate the cytologically, morphologically and IGH detection of salivary gland (SGT), expression of HER2 and PD-L1, CPS and determine these associations with patient survival. Methods: The study included 59 patients with a confirmed diagnosis of salivary gland cancer (stage II-IVA) by cytology, morphology and IGH analyses. After that HER2, in tumor and tumor infiltrating immune cell PD-L1 expression (with CPS) was determined using IHC-testing. RET mRNA gene expression calculated with using real-time PCR. Results: Aspiration biopsies results: only in 22 (37.29%) cases the malignant tumor was cytologically confirmed. An IHC study showed the proportion of high-grade tumors significantly exceeded 3.82 times the proportion of low-grade tumors (p < 0.00001). Low grade SGT were 2 times more often recorded by morphological studies (p = 0.0172), high grade SGT - 1.37 times more often by IHC study (p = 0.0176). HER2 expression: (0) – 29(60.42%), (1+) – 11(22.92%), (2+) – 4(8.33%), (3+) – 4(8.33%). Median OS HER2-neg pp was 170.25±24.49 mo (95% CI 125.25-218.26), median OS of 8 pp (16.33%) with HER2 (2+,3+) was 41,00 mo (95%CI 4.50-72.00) (HR 0,07; 95% CI 0,01-0,38; p = 0.00715). Median PFS HER2-neg pp was 168.00 mo (95% CI 75.00-168.00), median PFS of 8 pp (16.33%) with HER2 (2+,3+) was 19,00 mo (95%CI 1.00-31.00) (HR 0,23; 95% CI 0.04-1.22; p = 0.01641). PD-L1 expression was: in tumor cells 0-90% in 11/49 pp (22.45%), in immune cells 0-50% in 26/49 pp (53.06%) (p = 0.0006). CPS was 0-100, median CPS 5 (95% CI 0.03-10.00). Median OS pp with CPS > 1 was 72.00 mo (95% CI 19.5-72.00); with CPS < 1 hasn’t yet been achieved (OR 0.26; 95% CI 0.09-0.75; p = 0.0124). RET mRNA expression was detected in 13 of 48 cases (27.08%). The expression level ranged from 0 to 0.205. The median PFS in the RET mRNA-positive pp was 168.00 mo (95% CI 16.00-168.00) and tended to exceed the median TTP in the RET mRNA-naive patient group. Conclusions: The results suggest that the understanding the receptor status of salivary gland cancer can be effective prognostic factors.
Mechanism of sensitivity to TPF chemoagents and its potential alternative of erbB2 in oral cancer with GDF15 overexpression.
Authors: Zhong Lai-Ping , Zhao Tong-chao , Ju Wu-tong , Liang Si-yuan , Wang Li-zhen , Li Jiang , Zhu Dong-wang , Zhang Zhi-yuan
Published: May 2020

e18542

Background: To explore the mechanism of sensitivity to docetaxel, cisplatin, and 5-fluorouracil (TPF) chemoagents in patients with oral squamous cell carcinoma (OSCC) and growth differentiation factor 15 (GDF15) overexpression recruited in a TPF induction chemotherapy trial; and to explore potential alternative agents for patients who might not benefit from TPF induction chemotherapy. Methods: GDF15-overexpression and silenced OSCC cells were used to investigate sensitivity to TPF chemoagents in vitro and in vivo. Immunoprecipitation combined with mass spectrometry was used to screen out the possible receptor for GDF15, and associated signaling pathways were detected after intervention with the possible receptor of GDF15. The efficacy of an inhibitor of the phosphorylation of the possible GDF15 receptor was evaluated by treatment of GDF15-overexpression OSCC cells in vitro and in vivo. Results: Overexpression of GDF15 in OSCC cell lines and xenografts lead to an increase of chemotherapeutics sensitivity on apoptosis effects induced by docetaxel, cisplatin and 5-fluorouracil, through a caspase -dependent pathway. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential binding protein of GDF15, as verified by coimmunoprecipitation. When GDF15 was overexpressed, the phosphorylation of erbB2 and downstream PI3K/AKT and MAPK/ERK pathways was significantly upregulated, but was downregulated when GDF15 expression was interfered. The erbB2 phosphorylation inhibitor CI1033 significantly inhibited the proliferation and colony-forming ability of GDF15-overexpression OSCC cells as well as the growth of xenografts. CI1033 might be used as a potential targeted drug or alternative of TPF chemoagents for OSCC patients with GDF15 overexpression. Conclusions: OSCC with GDF15 overexpression exhibit sensitivity to TPF chemoagents through a caspase-dependent pathway. ErbB2 phosphorylation inhibitors might be used as potential targeted drugs or an alternative of TPF chemoagents for OSCC patients with GDF15 overexpression.
Incidence of hypothyroidism in head and neck squamous cell carcinoma patients receiving radiotherapy with and without immune checkpoint inhibitors.
Authors: Leddon Jennifer , Chirra Martina , Agrawal Arushi , Roof Logan , Trotier Danny , Shaikh Hira , Stone Timothy , Jandarov Roman , Takiar Vinita , Wise-Draper Trisha Michel
Published: May 2020

e18551

Background: Treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) involves a combination of surgery, chemotherapy, and radiotherapy (RT). RT for HNSCC is a known risk factor for the development of hypothyroidism. Recently, anti-PD1 therapies have been approved for recurrent and metastatic HNSCC and are moving to the forefront of HNSCC care. Similarly, thyroid dysfunction is a common immune-related adverse event following anti-PD1 therapy. Whether the addition of anti-PD1 to RT increases the likelihood of developing hypothyroidism remains unknown. Methods: The rate of hypothyroidism in HNSCC patients receiving RT (+/- chemotherapy and surgery) was compared to HNSCC patients receiving RT + anti-PD1 therapy either concurrently or after RT. Exclusion criteria were preexisting thyroid dysfunction, RT dose < 45 Gy and patients with incomplete treatment records. We defined clinical hypothyroidism as an elevation of TSH with low T3, T4 or elevation of TSH with symptoms requiring levothyroxine initiation. Hypothyroidism incidence was compared using Fisher’s exact test. Results: 153 patients were evaluated. In the RT group (N = 103), patients received RT +/- surgery or chemotherapy. 82/103 (80%) were male, median age was 57 and primary tumor groups included oropharynx 62/103 (60%), larynx 29/103 (28%), oral cavity 9/103 (9%) and other 3/103 (3%). In the RT + anti-PD1 group (N = 50), 36/50 (72%) were males, median age was 57 and primary tumor groups included oral cavity 19/50 (38%), oropharynx 17/50 (34%), larynx 8/50 (16%), and other 6/50 (12%). In the RT group, median follow up after RT was 801 days. In the RT+ anti-PD1 group, median follow up was 595 days from RT and 388 days from anti-PD1. The rate of hypothyroidism was significantly higher in the RT group 22.3% (23/103) versus 6% (3/50)after anti-PD1 therapy (p = 0.011). Multinomial logistical regression found no significant difference in hypothyroidism based on age, sex, or BMI. Larynx as primary tumor location was an independent risk factor for development of hypothyroidism (OR 4.74, p = 0.002). Conclusions: The addition of anti-PD1 therapy to standard HNSCC treatments does not significantly increase the risk of developing hypothyroidism. In fact, this study finds a lower incidence of hypothyroidism in HNSCC patient receiving RT + PD1 therapy which may be due to shorter duration of follow up and lower proportion of laryngeal cancer patients who are at relatively higher risk for surgical hypothyroidism.
Factors impacting use of adjuvant therapy in lip and oral cavity squamous cell carcinoma: A NCDB analysis.
Authors: Ramadas Poornima , Wang Dongliang , Huang Danning , Sivapiragasam Abirami
Published: May 2020

e18556

Background: Two trials followed by a combined analysis of the trials in head and neck squamous cell carcinoma (SCC) established that the benefit of adjuvant chemotherapy concurrent with radiation (CRT) was only noted in patients with extracapsular extension of nodal disease (ECE) and positive resection margins (PM). Despite this recommendation, other high-risk pathological features including pT3 or pT4 disease, positive lymph nodes, perineural involvement, vascular tumor embolism and level IV or V lymph node involvement have been noted to increase the risk of recurrence and adjuvant chemotherapy has been utilized for these patients. We report an observational study to evaluate the factors impacting use of CRT in patients with oral cavity and lip SCC. Methods: We conducted a retrospective study of patients with oral cavity and lip SCC who underwent resection of primary tumor with or without neck dissection in the reporting hospital in the NCDB database. We compared demographic, clinical and pathological characteristics of patients who received adjuvant CRT versus radiation alone. Multivariate analysis was performed using logistic regression model. Results: Out of the 58,481 patients reported to have surgery in NCDB from 2004 to 2016, 11,413 patients received adjuvant therapy. In univariate analysis, patients who received CRT were most likely less than 65 years of age, males, patients with no insurance or private insurance, lower Charlson Deyo score, Stage IVA, pT4, grade 2 or higher, tumor size > 4cm, positive lymph nodes, involvement of level IV and V nodes, lymphovascular invasion, ECE and PM. In multivariate analysis, factors which influenced receiving CRT were age between 40 and 65 years, males, Stage IVA (compared to Stage I to III), positive nodes, ECE and PM. A total of 984 patients received CRT without having ECE or PM. Conclusions: In addition to ECE and PM, positive lymph nodes was the major pathological factor in patients receiving CRT compared to RT alone.
Low-dose cisplatin administration through the superficial temporal artery combined with definitive radiotherapy for maxillary sinus squamous cell carcinoma.
Authors: Masubuchi Tatsuo , Kitani Yosuke , Fushimi Chihiro , Kawakita Daisuke , Takahashi Hideaki , Takeishi Etsuro , Kaneko Tetsuharu , Kanno Chihiro , Yamazaki Morio , Tanaka Junpei , Kitajima Tatsuya , Hanyu Kenji , Toya Kazuhito , Takahashi Akane , Okura Naoki , Akahane Masaaki , Miura Kouki , Kamata Shin-etsu , Tada Yuichiro
Published: May 2020

e18562

Background: Although patients with locoregional advanced maxillary sinus squamous cell carcinoma (MSSCC) are often treated with surgery followed by postoperative radiotherapy (RT), the cosmetic and functional outcomes are unsatisfactory. Moreover, the efficacy and safety of intra-arterial chemoradiotherapy are controversial. Methods: In this study, we investigated the efficacy and safety of low-dose cisplatin administration through the superficial temporal artery (STA) combined with definitive RT in patients with MSSCC. Between January 2009 and December 2018, 57 patients were administered weekly intra-arterial infusions of cisplatin (30–50 mg/m2/5h) through the STA with simultaneous intravenous infusions of sodium thiosulfate. Overall response rate (ORR), local progression-free survival (LFS), maxillectomy-free survival (MFS), progression-free survival (PFS), overall survival (OS), and safety were evaluated retrospectively. The impact of clinical factors on survival was investigated using the Cox proportional hazard models. Results: The median follow-up time was 44 months (range, 10–80 months). There were 4, 26, 23, and 4 patients with cT2, cT3, cT4a, and cT4b, respectively. All patients completed the planned treatment except for one patient who discontinued owing to facial palsy. The ORR was 98% with 51 and 5 patients having complete and partial responses, respectively. The 3-year LFS, PFS, and OS were 74%, 63%, and 81%, respectively for all patients and 100%, 81%, and 94%, respectively for 22 patients received 70 Gy irradiation. Notably, the 3-year MFS was 95% for all patients and 100% in patients received 70 Gy RT. The most common grade 3 or more toxic event was oral mucositis (22.8%). Additionally, 4 (7.0%) patients had catheter-related infections. Late grade 3 or more adverse events included optic nerve disorder (8.8%), osteonecrosis (7.0%), encephalopathy (1.8%), and increased creatinine levels (1.8%). Salvage surgery including hard palate resection and orbital exenteration were performed in 2 and 1 patients, respectively. No clinical factor was correlated with survival outcomes in our study cohort. Conclusions: Low-dose cisplatin through STA combined with RT, especially 70 Gy RT, was associated with promising tumor response, high organ preservation rate, and tolerable adverse events in MSSCC patients. Further prospective studies are warranted to compare these outcomes with primary surgery.
Treatment failure pattern of oropharyngeal cancer, especially for the aspect of retropharyngeal lymph node.
Authors: Kang Byung-Hee , Kim Jin Ho , Wu Hong-Gyun , Kim In Ah , Eom Keun-Yong
Published: May 2020

e18565

Background: In radiotherapy for head and neck cancer, it is very important to define the appropriate treatment volumes that determine the treatment outcome and toxicity. We examined the feasibility of omitting elective retropharyngeal (RP) nodal irradiation in oropharyngeal cancer. Methods: We performed a retrospective review from 2009 to 2016; 197 patients with oropharyngeal squamous cell carcinomas were treated with definitive or postoperative radiation therapy at the Seoul National University Hospital or Seoul National University Bundang Hospital. Of these patients, 151 patients (76%) were treated ipsilateral RP nodal areas up to the upper edge of C1 vertebral body, while the other 46 patients (24%) were not. We reviewed patterns of failures, disease free survival, and patient-reported chronic xerostomia status in each patient group. Results: During follow-up period, 2 patient developed RP nodal recurrences (4-108 months, median =46 months). There was no significant between-group difference in disease free survival, with a rate of 80.7% in the high RP nodal-irradiation group and 87.2% in the RP nodal spared group (P=0.17). Patients in the high RP nodal-irradiation group had higher mean ipsilateral parotid gland dose (median 28.7±7.5 Gy vs. 21.3±7.6 Gy, P<0.001) and higher rates of chronic xerostomia (72.2% vs. 58.7%, P=0.030). Conclusions: Only 2 patients with omission of high RP node irradiation developed high RP node failure, and no significant difference in DFS was shown. Omission of high RP nodal irradiation resulted in reduced ipsilateral parotid gland dose, consequently with less chronic xerostomia.
Papillary thyroid microcarcinoma: Analysis of outcomes and features predicting risk of recurrence.
Authors: Dravid Chandra Shekhar , Sr Priya , Pai P. S. , Chaukar D.
Published: May 2020

e18569

Background: Papillary thyroid microcarcinoma (PTMC) is an enigmatic entity - diverse opinions exist on its clinical course and management. We aimed to analyse disease outcomes and to identify high-risk factors in PTMCs. Methods: This is a retrospective analysis of patients of PTMC treated in our hospital between 2000 and 2014. Clinico-radiological features, treatment details, long term outcomes and recurrence patterns were noted; these were analysed statistically. Results: 160 patients were studied; 61% were females; 86% were aged 55 years or below; 95% cases presented with an enlarged neck node or thyroid nodule or distant metastasis while 5% were incidentalomas. Total thyroidectomy with radioiodine ablation was done in 77% while hemithyroidectomy was done in 23% patients. Follow up ranged between 2 and 238 months. There were 11 (7%) disease related events (nodal or distant metastases or death due to persistent disease). 4 (2.5%) patients died of disease. On univariate analysis, a larger thyroid primary (p 0.001), pre-operatively radiologically identifiable disease in the thyroid (p 0.02) and the lesion not being an incidentaloma (p 0.01) were associated with development of adverse events. Multivariate analysis confirmed the latter two factors as high risk (p 0.05 and 0.00). Nodal metastasis increased with a larger primary (p 0.001), which was multifocal (p 0.00), bilateral (p 0.01) and showed extrathyroid extension (p 0.00). Distant metastases were related with advanced age (p 0.02), presence of involved nodes (p 0.04), larger primary tumour (p 0.15), multifocal tumour (p 0.17), bilateral foci (p 0.02) and extrathyroidal extension (p 0.06). Correspondingly, Kaplan Meier curves showed a better overall survival (OS) and disease free survival (DFS) with incidentalomas as compared to cases presenting with symptoms (Median OS 84 months vs 78 months; Median DFS 79 months vs 77 months) and cases where the lesion was not seen on radiology (Median OS 80 months vs 76 months; Median DFS 80 months vs 75 months). However neither was significant statistically. Addition of Radioiodine ablation did not confer survival advantage (p 0.6). Conclusions: PTMCs are associated with adverse events despite the size of the primary lesion. Stratification as per the above risk factors can improve event free survival. Conversely, aggressive treatment may be deferred in cases of lesions discovered incidentally or on routine screening.
CTNNB1, PIK3CA, EIF1AX, and PTEN polymorphisms found in aggressive types of differentiated thyroid cancer.
Authors: Adilbay Dauren , Adilbayev Galym , Orazgalieva Madina , Shipilova Viktoria , Kidirbayeva Gulzhan , Sloneva Nina , Amandosova Aizhan , Ossikbayeva Saniya
Published: May 2020

e18578

Background: Thyroid cancer incidence is rapidly increasing in all developing and developed nations. Despite the benign nature of most thyroid cases, there are aggressively behaving subgroups that need proper attention and tailored treatment. As of today, thyroid cancers stratified using the latest AJCC 8th edition staging system, which dramatically changed the staging system. Despite the implementation of the new system, there is still a need for better stratification of patients to groups that will benefit from extensive treatment. Methods: Retrospective analysis of 23 patients with papillary and follicular thyroid cancer treated in a tertiary cancer center in 2012 and 2013. All patients underwent different types of surgical treatment, FFPE blocks are obtained from pathology archives and additionally reviewed by two independent pathologists. DNA extracted from 20 patients FFPE blocks; 3 cases excluded. DNA analyzed by NGS on the MiniSeq Illumina platform using a custom panel of 14 genes and 200 SNPs associated with thyroid cancers. Results: All identified polymorphisms were selected based on the COSMIC registry. After excluding all types filtered based on frequency, 1329 polymorphisms identified. Fifty-two types are pathologic based on ClinVar database. All benign cases based on Polyphen and Clinvar excluded from the analysis. In patients with aggressive types of papillary and follicular thyroid cancer NRAS and HRAS identified in 8.33% cases, EIF1AX in 25% cases, PIK3CA in 58.33% cases, KRAS in 41.66 cases, TSHR in 33.3% cases and BRAF in 50% cases. Conclusions: We identified mutations in genes probably associated with the aggressive behavior of differentiated thyroid cancer. These mutations can be used as stratification criteria in the future after more data and trials confirm the results.
Cancer in Belize: Characteristics of patients presenting to a public oncology clinic.
Authors: Valtis Yannis , Pierson Leah , Garrity Philip , Yacab Ramon Argenes , Huang Franklin W.
Published: May 2020

e19000

Background: Belize is a middle-income country in Central America with significant inequality. To date, data on the oncologic burden of disease has been imputed from mortality data. The first-ever public oncology program was started in 2018, which allowed us to analyze the presenting characteristics of patients with cancer. Methods: 284 patients were seen at the Karl Heusner Memorial Hospital (KHMH) oncology clinic between April 2018 and July 2019. We performed a retrospective chart review and extracted patient characteristics to understand the burden of cancer in Belize. Results: Of 284 patients seen, 63% had a confirmed pathologic diagnosis of cancer and the remaining were clinically suspected to have cancer. 56% were female and the median age was 55. Breast, cervix, colon, and prostate were the most common types of cancer seen. Breast and cervical cancers disproportionately affected young women with a median age at presentation of 51 and 45 respectively. 28% of patients presented with Stage IV disease. 43% of patients were deemed candidates only for comfort care. Conclusions: The burden of oncologic disease in Belize is significant and represents a wide variety of cancers. Breast and cervical cancers disproportionately affect young women in Belize. A significant proportion of patients presented with late stage disease, likely due to the lack of screening programs and cancer awareness in the country. Addressing the country’s cancer burden will require strengthening local pathology and surgical oncology capabilities, establishing a public chemotherapy treatment program, and referring patients to radiation oncology in nearby countries.
Profiling and prognostic implications of variants of unknown significance (VUS) in solid tumors.
Authors: Sadaps Meena , Estfan Bassam N. , Wei Wei , Sohal Davendra , Kruse Megan Lynn
Published: May 2020

e19012

Background: While precision oncology is becoming increasingly integrated into standard of care for most incurable solid tumor malignancies, there is paucity of data regarding the clinical significance of VUS. In this study, we aim to evaluate whether the number of VUS is associated with overall survival (OS). We also analyze racial disparities pertaining to the number of VUS present and identify which, if any, genes possess prognostic implications. Methods: This is a retrospective review of 389 consecutive patients seen at Cleveland Clinic from 2014 to 2016 with incurable solid tumor malignancies, for whom next-generation sequencing (NGS) was ordered using Foundation One™ (Cambridge, MA). Demographics, number of VUS, genes involved, and race were summarized. OS was estimated by Kaplan-Meier and compared by log rank test. Results: Median age was 60 years, 202 (52%) patients were female, 338 (86.7%) were Caucasian, and 31 (8.0%) were African American. On NGS, 376 (97%) patients had VUS reported. The median number of VUS was 9 (range 1-116). When dichotomized at the median, the number of VUS did not affect OS. Genes most commonly implicated in reported VUS were LRP1B (88, 22.6%), MLL3 (83, 21.3%), MLL2 (73, 18.8%), ARID1B (70, 18.0%), PRKDC (60, 15.4%), PREX2 (58, 18.7%), and SPTA1 (56, 14.4%). Patients found to have a variant of unknown significance in MLL2 had worse median OS as compared to those who did not (2.61 vs 3.76 years respectively; p = 0.033). When profiled by race, Caucasians had lower numbers of VUS (p = 0.002; Table). Conclusions: We did not find a clear association between the number of VUS and OS. MLL2, a gene known to predict poor prognosis as a pathogenic variant, was seen in our study to have similarly poor prognostic implications as a variant of unknown significance. Racial disparities in genomics exist as African Americans are under-represented and have greater numbers of VUS as compared to Caucasians. Further research is warranted to elucidate these disparities. [Table: see text]
Neighborhood disparities in timeliness of treatment for early stage lung cancer patients.
Authors: Obrochta Chelsea A , Gibbons Joseph , Nara Atsushi , Murphy James Don , Thompson Caroline A.
Published: May 2020

e19017

Background: Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death in the United States, accounting for approximately 25% of all cancer deaths. The National Comprehensive Cancer Network (NCCN) provides evidence-based cancer treatment recommendations. Evidence suggests that a patient’s receipt of guideline-concordant treatment (GCT) increases survival, especially for screen-detected, earlier stage cancers. Neighborhoods are key determinants of health and the neighborhood social and built environments can influence cancer treatment and outcomes. Minority segregated neighborhoods often have limited health resource availability. The objective of this study is to estimate the relationship between neighborhood segregation on racial and ethnic disparities in timely receipt of GCT in early-stage lung cancer patients in California. Methods: We studied 22,903 patients diagnosed with stage I/II non-small cell lung cancer (2006-2015) in the California Cancer Registry. The primary outcome of the study is receipt of GCT according to the 2016 NCCN guidelines defined as the administration of proper initial and adjuvant treatment(s) according to cancer site and stage, and measured using surgery type, chemotherapy type, and radiation type. The secondary outcome was timely receipt of care as defined as the initiation of surgery, radiation, or chemotherapy within 45 days of diagnosis for initial treatment and the initiation of chemotherapy +/- radiation within 6 months of initial surgery for N1 patients for adjuvant treatment. Multivariable hierarchical logistic regression will be used to estimate the effect of neighborhood segregation on timely receipt of GCT, adjusting for individual- and neighborhood-level covariates, and stratified by patient race/ethnicity. Results: Overall, 81.39% of patients received GCT; 57.63% of them within 45 days of diagnosis. Under-treatment and treatment delay were more frequent in patients who were black or Hispanic, had public insurance, and were of lower socioeconomic status. We hypothesize that increased neighborhood segregation will decrease a patient’s likelihood of adherence to GCT and timely GCT. Conclusions: This research is vital to improving our understanding of cancer-related health disparities and promoting health in vulnerable neighborhoods. With rising numbers of early stage lung cancers due to screening smokers, administration of timely proper treatment is critical.