Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy.

BACKGROUND: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics. METHODS: We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy. RESULTS: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1-mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73-mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity. CONCLUSION: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential.

T1-2 glottic cancer treated with radiotherapy and/or surgery.

BACKGROUND: The optimal treatment strategy for stage I-II glottic squamous cell carcinoma (SCC) is not well-defined. This study analyzed treatment results and prognostic factors. PATIENTS AND METHODS: This is a single-institution retrospective analysis of 244 patients with T1-2 glottic SCC who underwent normofractionated radiotherapy (RT) and/or surgery between 1990 and 2013. The primary endpoint was relapse-free survival (RFS). RESULTS: Median age was 65 years (range: 36-92 years), the majority (82%) having stage I disease. Definitive RT was used in 82% (median dose: 68 Gy, 2 Gy per fraction). Median follow-up was 59 months. The 5­year RFS rates were 83 and 75% (p = 0.05) for stage I and 62 and 50% (p = 0.47) for stage II in the RT and surgery groups, respectively. Multivariate analyses indicate T1 vs. T2 and RT vs. surgery as independent prognostic factors for RFS, with hazard ratios of 0.38 (95% confidence interval, CI: 0.21-0.72) and 0.53 (95% CI: 0.30-0.99), respectively (p < 0.05). The 5­year overall and cause-specific survival rates in the whole cohort were 92 and 96%, respectively, with no significant differences between treatment groups. Anterior commissure involvement was neither a prognostic nor a predictive factor. The incidence of secondary malignancies was not significantly different between patients treated with and without RT (22 vs. 9% at 10 years, respectively, p = 0.18). CONCLUSION: Despite a possible selection bias, our series demonstrates improved RFS with RT over surgery in stage I glottic SCC.

Modelling the lymphatic metastatic progression pathways of OPSCC from multi-institutional datasets.

The elective clinical target volume (CTV-N) in oropharyngeal squamous cell carcinoma (OPSCC) is currently based mostly on the prevalence of lymph node metastases in different lymph node levels (LNLs) for a given primary tumor location. We present a probabilistic model for ipsilateral lymphatic spread that can quantify the microscopic nodal involvement risk based on an individual patient's T-category and clinical involvement of LNLs at diagnosis. We extend a previously published hidden Markov model (HMM), which models the LNLs (I, II, III, IV, V, and VII) as hidden binary random variables (RVs). Each represents a patient's true state of lymphatic involvement. Clinical involvement at diagnosis represents the observed binary RVs linked to the true state via sensitivity and specificity. The primary tumor and the hidden RVs are connected in a graph. Each edge represents the conditional probability of metastatic spread per abstract time-step, given disease at the edge's starting node. To learn these probabilities, we draw Markov chain Monte Carlo samples from the likelihood of a dataset (686 OPSCC patients) from three institutions. We compute the model evidence using thermodynamic integration for different graphs to determine which describes the data best.The graph maximizing the model evidence connects the tumor to each LNL and the LNLs I through V in order. It predicts the risk of occult disease in level IV is below 5% if level III is clinically negative, and that the risk of occult disease in level V is below 5% except for advanced T-category (T3 and T4) patients with clinical involvement of levels II, III, and IV. The provided statistical model of nodal involvement in OPSCC patients trained on multi-institutional data may guide the design of clinical trials on volume-deescalated treatment of OPSCC and contribute to more personal guidelines on elective nodal treatment.

A multi-centric dataset on patient-individual pathological lymph node involvement in head and neck squamous cell carcinoma.

Dataset: We provide a dataset on lymph node metastases in 968 patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC). All patients received neck dissection and we report the number of metastatic versus investigated lymph nodes per lymph node level (LNL) for every individual patient. Additionally, clinicopathological factors including T-category, primary tumor subsite (ICD-O-3 code), age, and sex are reported for all patients. The data is provided as three datasets: Dataset 1 contains 373 HNSCC patients treated at Centre Léon Bérard (CLB), France, with primary tumor location in the oral cavity, oropharynx, hypopharynx, and larynx. Dataset 2 contains 332 HNSCC patients treated at the Inselspital, Bern University Hospital (ISB), Switzerland with primary tumor location in the oral cavity, oropharynx, hypopharynx, and larynx. For these patients, additional information is provided including lateralization of the primary tumor, size and location of the largest metastases, and clinical involvement based on computed tomography (CT), magnetic resonance imaging (MRI), and/or 18FDG-positron emission tomography (PET/CT) imaging. Dataset 3 consists of 263 oropharyngeal SCC patients underlying a previous publication by Bauwens et al. [1], which were treated at CLB. For these patients, additional information including HPV status, lateralization of the primary tumor and clinically diagnosed lymph node involvement is provided. Reuse Potential: The data may be used to quantify the probability of occult lymph node metastases in each LNL, depending on an individual patient's characteristics of the primary tumor and the location of clinically diagnosed lymph node metastases. As such, the data may contribute to further personalize the elective treatment of the neck for HNSCC patients, i.e. definition of the elective clinical target volume (CTV-N) in radiotherapy (RT) and the extent of neck dissection (ND) in surgery. There exists only one similar publicly available dataset that reports clinical involvement per LNL in 287 oropharyngeal SCC patients [2]. The data presented in this article substantially extends the available data, it additionally includes pathologically assessed involvement per LNL, and it provides data for multiple subsites in the head and neck region.

Superior loco-regional control after primary surgery compared to chemo-radiotherapy for advanced stage laryngeal cancer.

Objective: The optimal strategy to treat loco-regionally advanced squamous cell carcinoma of the larynx (LSCC) remains to be defined. The goal of this single institution retrospective study was to report on oncologic outcome of advanced LSCC treated with curative intent. Methods: Patients diagnosed and treated for stage T3-T4a LSCC between 2001 and 2014 were retrospectively analyzed. Time-to-event endpoints were calculated beginning from the date of histologic diagnosis, which were analyzed with log-rank test and Cox proportional hazard models. Results: The cohort was divided into two subgroups: primary radiotherapy with concomitant cisplatin (CRT) (n=30, 38%) and primary surgery (n=48, 62%). Median follow-up was 56 months. Locoregional control (LRC) for the primary surgery and CRT were 95% and 50% in 5 years, respectively (p<0.01). Progression free survival (PFS) for the primary surgery and CRT were 61% and 38% in 5 years, respectively (p=0.23). The overall survival (OS) after primary surgery and CRT in 5 years were 63% vs. 65%, respectively (p=0.93). The 5-years LRC was significantly superior after surgery compared to RT for cT3 primaries (100% vs 50%, p= 0.0022). No significant differences were observed in the remaining subgroups regarding cT stage and PFS or OS. Conclusion: Our series demonstrated superior LRC after primary surgery followed by risk-adapted adjuvant (C)RT compared to primary CRT in cT3 LSCC, but no significant difference in PFS or OS in locally-advanced LSCC. The optimal patient selection criteria for the ideal treatment for loco-regionally advanced LSCC still needs to be defined.

Association of Multiprofessional Preoperative Assessment and Information for Patients With Head and Neck Cancer With Postoperative Outcomes.

IMPORTANCE: Multidisciplinary perioperative assessment for patients undergoing complex oncologic head and neck cancer (HNC) surgery is widely implemented. However, to our knowledge, the association of multiprofessional preoperative assessment, information, and briefing with postoperative outcomes has not been evaluated. OBJECTIVE: To compare postoperative complications, length of hospital stay (LOS), readmissions, mortality, and costs per case among patients undergoing complex oncologic HNC surgery before and after the implementation of a comprehensive preoperative multiprofessional assessment and information day (MUPAID). DESIGN, SETTING, AND PARTICIPANTS: This retrospective, single-center case-control study was conducted at a tertiary referral head and neck anticancer center/university cancer institute and compared patients with HNC who were undergoing complex oncological surgeries between January 2012 and July 2018 before (control group) and after (intervention group) implementation of the institutional MUPAID. Data analysis was conducted between 2019 and 2020. The intervention group comprised patients who participated in the MUPAID beginning in February 2015. These patients were assessed by a multiprofessional team and provided with structured and comprehensive information on the surgical procedure and its functional, social, financial, and psychological effects, as well as the postoperative care, rehabilitation, and follow-up period. Patients in the control group had also undergone complex oncologic HNC surgery and were selected through surgical procedure codes. MAIN OUTCOMES AND MEASURES: The end points were postoperative rate and severity of complications, LOS, readmissions, mortality, and costs per case. RESULTS: The study included 161 patients, 81 in the intervention (25 women [30.9%]) and 80 in the control group (18 women [22.5%]). The groups showed no relevant differences in sociodemographic, disease, and procedural characteristics. The intervention cohort presented with fewer major local and systemic complications (Clavien-Dindo score, III-V: 34.6% vs 52.5%; difference proportion, -0.179; 95% CI, -0.33 to -0.03), shorter median LOS (12 days [IQR, 10-16 days] vs 16 days [IQR, 11-20] days; effect size, 0.482; 95% CI Cohen d, 0.152-0.812) and decreased median charge per case ($50 848 [IQR, $42 510-$63 479] vs $69 602 [IQR, $45 631-$96 280]; effect size, 0.534; 95% CI Cohen d, 0.22-0.85). CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that MUPAID for patients who are undergoing complex oncologic HNC surgery is associated with shortened LOS and costs per case as well as decreased complications severity. These results are promising on a patient level in the potential to minimize individual treatment burden, as well as on an institutional and health care system level in the potential significant optimization of surgical outcomes and financial aspects.

Quantitative analysis of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas.

Methylation of the MGMT promoter is supposed to be a predictive and prognostic factor in glioblastoma. Whether MGMT promoter methylation correlates with tumor response to temozolomide in low-grade gliomas is less clear. Therefore, we analyzed MGMT promoter methylation by a quantitative methylation-specific PCR in 22 patients with histologically verified low-grade gliomas (WHO grade II) who were treated with temozolomide (TMZ) for tumor progression. Objective tumor response, toxicity, and LOH of microsatellite markers on chromosomes 1p and 19q were analyzed. Histological classification revealed ten oligodendrogliomas, seven oligoastrocytomas, and five astrocytomas. All patients were treated with TMZ 200 mg/m2 on days 1-5 in a 4 week cycle. The median progression-free survival was 32 months. Combined LOH 1p and 19q was found in 14 patients; one patient had LOH 1p alone and one patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. LOH 1p and/or 19q correlated with longer time to progression but not with radiological response to TMZ. MGMT promoter methylation was detectable in 20 patients by conventional PCR and quantitative analysis revealed the methylation status was between 12 and 100%. The volumetric response to chemotherapy analyzed by MRI and time to progression correlated with the level of MGMT promoter methylation. Therefore, our retrospective case series suggests that quantitative methylation-specific PCR of the MGMT promoter predicts radiological response to chemotherapy with TMZ in WHO grade II gliomas.

Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma.

Mutations in mitochondrial DNA (mtDNA) have been linked to risk, progression, and treatment response of head and neck squamous cell carcinoma (HNSCC). Due to their clonal nature and high copy number, mitochondrial mutations could serve as powerful molecular markers for detection of cancer cells in bodily fluids, surgical margins, biopsies and lymph node (LN) metastasis, especially at sites where tumor involvement is not histologically apparent. Despite a pressing need for high-throughput, cost-effective mtDNA mutation profiling system, current methods for library preparation are still imperfect for detection of low prevalence heteroplasmic mutations. To this end, we have designed an ultra-deep amplicon-based sequencing library preparation approach that covers the entire mitochondrial genome. We sequenced mtDNA in 28 HNSCCs, matched LNs, surgical margins and bodily fluids, and applied multiregional sequencing approach on 14 primary tumors. Our results demonstrate that this quick, sensitive and cost-efficient method allows obtaining a snapshot on the mitochondrial heterogeneity, and can be used for detection of low frequency tumor-associated mtDNA mutations in LNs, sputum and serum specimens. These findings provide the foundation for using mitochondrial sequencing for risk assessment, early detection, and tumor surveillance.

Long-term functional outcome after laryngeal cancer treatment.

BACKGROUND: The functional outcome after the treatment of laryngeal cancer is tightly related to the quality of life of affected patients. The aim of this study is to describe the long-term morbidity and functional outcomes associated with the different treatment modalities for laryngeal cancer. METHODS: Retrospective chart review of 477 patients undergoing curatively intended treatment for laryngeal cancer at our tertiary referral center from 2001 to 2014: Details on patient and disease characteristics, diagnostics and treatment related functional outcomes were analyzed. RESULTS: With a median follow-up of 51 months, the crude rate of functional larynx preservation was 74.6%. Radiotherapy +/- chemotherapy was the dominant treatment modality (n = 359-75.3%), whereas 24.7% (n = 118) underwent primary surgery, with 58.5% (69) receiving adjuvant treatment. The 5-year laryngectomy-free survival was 57% (95% CI, 48-66%) after surgery vs. 69% (95% CI, 64-75%) after chemoradiotherapy (p < 0.01). In stage III-IVB, these rates were 26% (95% CI, 16-39%) vs. 47% (95% CI, 36-59%), respectively (p < 0.01). Aspiration occurred in 7%, tracheostomy was necessary in 19.8% and feeding tube placement in 25.4%. Feeding tube and tracheostomy necessity was higher in the initially surgically treated group. Primary surgery (HR: 1.67, 95% CI: 1.19-2.32; p < 0.01), stage III-IVB (HR: 4.07, 95% CI: 2.97-5.60; p < 0.01) and tumor recurrence (HR: 3.83, 95% CI: 2.79-5.28; p < 0.01) remained as adverse factors for laryngectomy-free survival. CONCLUSIONS: Preserving the laryngeal function after cancer treatment is challenging. Advanced tumor stages, primary surgery and recurrence are related to a poor functional outcome. Therefore, the criteria for initial decision-making needs to be further refined.

Estimation of Atmospheric Path Delays in TerraSAR-X Data using Models vs. Measurements.

Spaceborne synthetic aperture radar (SAR) measurements of the Earth's surface depend on electromagnetic waves that are subject to atmospheric path delays, in turn affecting geolocation accuracy. The atmosphere influences radar signal propagation by modifying its velocity and direction, effects which can be modeled. We use TerraSAR-X (TSX) data to investigate improvements in the knowledge of the scene geometry. To precisely estimate atmospheric path delays, we analyse the signal return of four corner reflectors with accurately surveyed positions (based on differential GPS), placed at different altitudes yet with nearly identical slant ranges to the sensor. The comparison of multiple measurements with path delay models under these geometric conditions also makes it possible to evaluate the corrections for the atmospheric path delay made by the TerraSAR processor and to propose possible improvements.

NSD1- and NSD2-damaging mutations define a subset of laryngeal tumors with favorable prognosis.

Squamous cell carcinomas of the head and neck (SCCHN) affect anatomical sites including the oral cavity, nasal cavity, pharynx, and larynx. Laryngeal cancers are characterized by high recurrence and poor overall survival, and currently lack robust molecular prognostic biomarkers for treatment stratification. Using an algorithm for integrative clustering that simultaneously assesses gene expression, somatic mutation, copy number variation, and methylation, we for the first time identify laryngeal cancer subtypes with distinct prognostic outcomes, and differing from the non-prognostic laryngeal subclasses reported by The Cancer Genome Atlas (TCGA). Although most common laryngeal gene mutations are found in both subclasses, better prognosis is strongly associated with damaging mutations of the methyltransferases NSD1 and NSD2, with findings confirmed in an independent validation cohort consisting of 63 laryngeal cancer patients. Intriguingly, NSD1/2 mutations are not prognostic for nonlaryngeal SCCHN. These results provide an immediately useful clinical metric for patient stratification and prognostication.

In silico analysis of pathways activation landscape in oral squamous cell carcinoma and oral leukoplakia.

A subset of patients with oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), harbor dysplastic lesions (often visually identified as leukoplakia) prior to cancer diagnosis. Although evidence suggest that leukoplakia represents an initial step in the progression to cancer, signaling networks driving this progression are poorly understood. Here, we applied in silico Pathway Activation Network Decomposition Analysis (iPANDA), a new bioinformatics software suite for qualitative analysis of intracellular signaling pathway activation using transcriptomic data, to assess a network of molecular signaling in OSCC and pre-neoplastic oral lesions. In tumor samples, our analysis detected major conserved mitogenic and survival signaling pathways strongly associated with HNSCC, suggesting that some of the pathways identified by our algorithm, but not yet validated as HNSCC related, may be attractive targets for future research. While pathways activation landscape in the majority of leukoplakias was different from that seen in OSCC, a subset of pre-neoplastic lesions has demonstrated some degree of similarity to the signaling profile seen in tumors, including dysregulation of the cancer-driving pathways related to survival and apoptosis. These results suggest that dysregulation of these signaling networks may be the driving force behind the early stages of OSCC tumorigenesis. While future studies with larger leukoplakia data sets are warranted to further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers, our platform proposes a promising new approach for detecting cancer-promoting pathways and tailoring the right therapy to prevent tumorigenesis.

Septic thrombosis of the internal jugular vein: Lemierre's syndrome revisited.

OBJECTIVES/HYPOTHESIS: Study of the clinical evolution of a primary ear, nose, and throat infection complicated by septic thrombophlebitis of the internal jugular vein. STUDY DESIGN: Retrospective case-control study. PATIENTS AND METHODS: From 1998 to 2010, 23 patients at our institution were diagnosed with a septic thrombosis of the internal jugular vein. Diagnostics included microbiologic analysis and imaging such as computed tomography, magnetic resonance imaging, and ultrasound. Therapy included broad-spectrum antibiotics, surgery of the primary infectious lesion, and postoperative anticoagulation. The patients were retrospectively analyzed. RESULTS: The primary infection sites were found in the middle ear (11), oropharynx (8), sinus (3), and oral cavity (1). Fourteen patients needed intensive care unit treatment for a mean duration of 6 days. Seven patients were intubated, and two developed severe acute respiratory distress syndrome. An oropharynx primary infection site was most prone to a prolonged clinical evolution. Anticoagulation therapy was given in 90% of patients. All 23 patients survived the disseminated infection without consecutive systemic morbidity. CONCLUSION: In the pre-antibiotic time, septic internal jugular vein thrombophlebitis was a highly fatal condition with a mortality rate of 90%. Modern imaging techniques allow early and often incidental diagnosis of this clinically hidden complication. Anticoagulation, intensive antibiotic therapy assisted by surgery of the primary infection site, and intensive supportive care can reach remission rates of 100%.