Completion Thyroidectomy is Less Common Following Updated 2015 American Thyroid Association Guidelines.

BACKGROUND: The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1 and 4 cm may be treated with thyroid lobectomy alone. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy (CT) for low-risk DTC and factors influencing surgical decision-making. METHODS: All patients from 2014 to 2018 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included. Patients were divided into "pre" and "post" guideline cohorts (2014-2015 and 2016-2018, respectively). The rate of CT was compared between the two cohorts. Patient demographics and tumor characteristics were examined for association with CT. RESULTS: A total of 163 patients met study criteria: 63 patients in the 2014-2015 ("pre") and 100 in the 2016-2018 ("post") group. In the "pre" period, 41 (65.1%) patients received CT compared with 43 (43.0%) in the "post" period (p < 0.01)-a 34% decrease in the rate of completion surgery (p < 0.01). Of low-risk patients with DTC between 1 and 4 cm in size, 17 of 35 (48.6%) received CT in the "pre" period compared with 15 of 60 (25.0%) in the post period-a 48.6% decrease in the rate of completion surgery (p = 0.02). Greater tumor size, capsular invasion, and multifocality were associated with CT in low-risk "post" guideline patients (p < 0.05 for all). CONCLUSIONS: The rate of CT decreased significantly by 48.6% for low-risk patients with DTC between 1 and 4 cm, demonstrating recognition of the 2015 ATA guidelines. However, 25% of these patients underwent CT, suggesting additional factors influencing the decision for further treatment.

The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature.

Limited data exist on safety and efficacy of immune checkpoint inhibitors (ICIs) among organ transplant recipients. The objective of this study was to report a case series of two patients with renal transplant who received treatment with an ICI and to conduct a pooled analysis of published cases to describe the safety and efficacy of ICIs in organ transplant patients. A systematic search in the Google Scholar and PubMed databases was carried out to include all the published cases of organ transplant patients who received treatment with ICIs including programmed cell death protein 1 (PD-1), programmed death-ligand 1, or cytotoxic lymphocyte antigen-4 inhibitors since their inscription to January 31, 2019. In the present series of two cases with renal allografts who received pembrolizumab, one patient with squamous cell carcinoma of the skin experienced complete response (CR), whereas another patient with melanoma had a mixed response. Both patients experienced allograft rejection, but graft was salvaged. The pooled analysis of 64 patients published in literature showed that overall allograft rejection rate is 41% in organ transplant recipients following ICI therapy. The graft rejection rate was 44% (17/39) for renal, 39% (7/19) for liver, and 20% (1/5) for cardiac allografts. The highest risk was seen among patients who were treated with PD-1 inhibitors, 20/42 (48%)-13/24 (54%) on nivolumab and 7/18 (39%) on pembrolizumab. The risk was lowest with ipilimumab, 23% (3/13). The overall response rate (CR + partial response [PR]) was 20% with ipilimumab, 26% with nivolumab, and 53% with pembrolizumab, whereas disease control rate (CR + PR + stable disease) was 35% with ipilimumab, 37% with nivolumab, and 53% with pembrolizumab. None of the variables including age, gender, type of cancer, type of allograft, type of immunosuppression, time since transplantation to initiation of ICI, and prior history of rejection were significantly associated with the transplant rejection on univariate analysis. The efficacy of ICI among patients with organ transplant appears promising, warranting testing in prospective clinical trials. The risk of rejection and allograft loss is considerable; therefore, the risk and alternative form of therapies should be thoroughly discussed with the transplant patients prior to initiating ICI therapy. IMPLICATIONS FOR PRACTICE: Transplant recipients are at higher risk of developing cancers. Although immune checkpoint inhibitors have been shown to improve the outcome in more than one cancer type, transplant recipients were excluded from these trials. Most of the data on the safety and efficacy of immune checkpoint inhibitors in transplant patients are based upon case series and case reports. The pooled data from these reports suggest that anti-programmed death-ligand 1 inhibitors have reasonable safety and efficacy among organ transplant patients, which warrants testing in clinical trials.

The Benefits of Adjuvant Trastuzumab for HER-2-Positive Salivary Gland Cancers.

BACKGROUND: Although high-grade salivary gland cancers (SGCs) often express androgen receptor (AR) and/or HER-2/neu, therapeutically targeting these receptors in SGC remains investigational. We investigated the prevalence of receptor expression and the benefit of adjuvant HER-2 directed therapy in the high-risk postoperative setting and explored the clinical utility of sequentially targeting these receptors in the setting of advanced disease. MATERIALS AND METHODS: We clinically annotated 95 patients with SGC (excluding adenoid cystic carcinoma) treated at our institution from 2002 to 2019 and recorded AR, HER-2/neu status, and tumor genomic profiling results when available. Clinicopathologic information was then integrated with outcomes. RESULTS: Of 95 patients, most had high-risk histologies, with salivary duct carcinoma (SDC) as the most frequent diagnosis (43, 45%). Thirty-five (37%) experienced recurrence (51% SDC). HER-2/neu was positive (1-3+) by immunostaining in 34 of 52 (65%) evaluable cases. There was no difference in survival based on HER-2/neu or AR expression. Nine of 17 (53%) patients with HER-2+ SDC received adjuvant chemoradiation with trastuzumab. Median disease-free survival (DFS) and overall survival (OS) were longer among patients with HER-2/neu 3+ staining tumors who received adjuvant trastuzumab versus those who did not (DFS, 117 vs. 9 months; p = .02; OS, 74 vs. 43 months; p = .02), with no difference among other HER-2/neu subgroups (0-2+). Two of nine (22%) patients treated with adjuvant trastuzumab demonstrated recurrence, both with low HER-2/neu staining intensity (1+). Longer time to recurrence (hazard ratio, 0.94; p = .01) predicted improved outcomes. Both androgen deprivation and HER-2-directed therapies had clinical benefit beyond the first-line metastatic setting, with partial response observed beyond second-line use. CONCLUSION: Although prospective data are lacking, the use of adjuvant trastuzumab in high-risk patients with SGC appears beneficial, particularly among patients with tumors exhibiting HER-2/neu 3+ immunostaining. IMPLICATIONS FOR PRACTICE: Results of this study showed an improved disease-free and overall survival in patients treated with adjuvant trastuzumab for high-risk salivary gland cancers with strong HER-2/neu staining intensity. Following recurrence or metastatic spread, sequential HER-2, and androgen-directed therapies may benefit certain patients with salivary gland cancer.

Histological features of BRAF V600E-mutant anaplastic thyroid carcinoma.

AIMS: Treatment with a BRAF inhibitor, alone or in combination with a MEK inhibitor, may be considered for BRAF-mutant anaplastic thyroid carcinoma (ATC). The purpose of this study was to characterise the histology of BRAF V600E-mutant ATC. METHODS AND RESULTS: We identified 28 ATC that were consecutively resected between 2003 and 2019. All tumour slides for each case were evaluated for the presence of a precursor tumour and for ATC morphology (sarcomatoid, pleomorphic giant cell, epithelioid or squamous). BRAF V600E mutation status was determined by BRAF V600E IHC or molecular analysis (OncoPanel NGS). Eighteen (64%) ATC had an associated well-differentiated precursor, including 10 (36%) with associated papillary thyroid carcinoma (PTC) and eight (29%) with associated follicular thyroid carcinoma (FTC) or Hürthle cell carcinoma (HCC). Most ATC (19 cases, 68%) demonstrated a mixed anaplastic morphology. Squamous morphology was present in four cases. Ten (36%) ATC had a BRAF V600E mutation. All ATC that had a PTC precursor had a BRAF V600E mutation (and all ATC with a BRAF V600E mutation had a PTC precursor), whereas no ATC with an FTC or HCC precursor had a BRAF V600E mutation. All four cases of ATC with a squamous morphology had a PTC precursor and a BRAF V600E mutation. CONCLUSION: In our cohort, the presence of a PTC precursor predicted the presence of the BRAF V600E mutation, whereas ATC with an FTC or HCC precursor lacked a BRAF V600E mutation. A squamous morphology was associated with the presence of a PTC precursor and a BRAF V600E mutation.

A potential diagnostic pitfall for hobnail variant of papillary thyroid carcinoma.

AIMS: Hobnail variant of papillary thyroid carcinoma (PTC) is an aggressive PTC subtype characterised by a hobnail cytomorphology. However, some classic PTC have a 'hobnail-like' cytomorphology associated with thick, hyalinised, variably oedematous fibrovascular cores that appears to be a form of ischaemic/degenerative atypia. METHODS AND RESULTS: We studied three cohorts to compare the histopathological characteristics and clinical outcome of 'hobnail-like' classic PTC and true hobnail variant of PTC: cohort 1, PTC consecutively resected between 2016 and 2017 (to assess frequency of 'hobnail-like' cytomorphology); cohort 2, 20 'hobnail-like' classic PTC resected between 2005 and 2007 (to assess clinical outcome); and cohort 3, seven true hobnail variant of PTC. A 'hobnail-like' cytomorphology was identified in 16% of consecutively resected PTC. Compared with true hobnail variant, 'hobnail-like' classic PTC occurred in younger patients (mean age 40 years versus 68 years, P < 0.001), were smaller tumours (mean tumour size 2.1 cm versus 4.4 cm, P < 0.001), had a lower rate of gross extrathyroidal extension (0% versus 71%, P < 0.001), had a lower proliferative rate (≥3 mitoses per 10 high-power fields seen in 0% versus 71%, P < 0.001; Ki67 index ≥5% in 0% versus 86%, P < 0.001), a lower rate of secondary pathogenic mutations (for cases with molecular data, 0% versus 100%, P = 0.0061) and improved survival (for cases with sufficient clinical outcome data, 10-year disease-free survival of 93% versus 0%, P = 0.0016). CONCLUSION: Classic PTC can show ischaemic/degenerative atypia that mimics the hobnail cytomorphology of true hobnail variant; however, these tumours lack aggressive histopathological features and pursue an indolent clinical course.

Epstein-Barr virus-specific adoptive immunotherapy for recurrent, metastatic nasopharyngeal carcinoma.

BACKGROUND: Early-stage and intermediate-stage nasopharyngeal cancer (NPC) generally carry a good prognosis, but for patients with recurrent, metastatic disease, options are limited. In the current study, the authors present a phase 1/2 study to evaluate the efficacy of Epstein-Barr virus (EBV)-stimulated cytotoxic T-lymphocyte (EBV-CTL) immunotherapy in this patient population. METHODS: Screening for patients with active, recurrent, metastatic EBV-associated NPC began in February 2007, and the study was closed to accrual in January 2012. After informed consent was obtained, patients had their blood drawn to initiate manufacturing of the EBV-CTL product. During product manufacturing, patients were placed on interim standard-of-care chemotherapy, and only after disease progression on the interim chemotherapy did patients receive investigational immunotherapy. Patients were restaged every 2 months until disease progression and then followed for survival. RESULTS: A total of 28 patients were enrolled, and 21 patients were treated. There was 1 complete response achieved, and at the time of last follow-up, the patient had been in remission for >8 years since treatment. The median progression-free survival was 2.2 months, and the median overall survival was 16.7 months. Two other patients, after failing EBV-CTL immunotherapy, unexpectedly demonstrated strong responses to the chemotherapy regimens they had previously failed. Patient EBV viral load and EBV-CTL specificity for tumor-associated viral antigens did not appear to correlate with clinical response. CONCLUSIONS: A durable response was observed with EBV-CTL immunotherapy, but the overall response rate for patients with recurrent, metastatic NPC was low. Further research is necessary to increase the efficacy of EBV-specific immunotherapy in patients with incurable NPC, and to characterize mechanisms for refacilitation to chemotherapy. Cancer 2017;123:2642-50. © 2017 American Cancer Society.

Response and acquired resistance to everolimus in anaplastic thyroid cancer.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. METHODS: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. FINDINGS: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). INTERPRETATION: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer.

BACKGROUND: Preclinical and clinical studies suggest potential synergy between high dose per fraction focal radiation and immunotherapy. However, conventionally fractionated radiation regimens in combination with concurrent chemotherapy are more commonly administered to patients as definitive treatment and may have both immune-stimulating and -suppressive effects. METHODS: We prospectively collected longitudinal samples from head and neck squamous cell carcinoma patients receiving definitive radiation therapy. We quantified changes in populations of circulating immune cells and chemokines CXCL9, 10, and 16. Analyses of humoral and cellular immune responses were conducted in select patients via proteomic analysis and T-cell receptor sequencing. RESULTS: Treatment not only increased circulating CD-8+ T-effector cells, but also myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly PD-1+ T cells. Significant decreases in CXCL10 and increases in CXLC16 were noted. Treatment also increased the percentage of unique and dominant TCR clones, and increased humoral responses as measured by proteomic array. CONCLUSIONS: Our results suggest that fractionated chemoradiation leads to quantifiable effects in circulating immune mediators, including a balance of stimulatory and suppressive mechanisms. These results suggest future combinations with immune checkpoint blockade.

Acupuncture for Chemoradiation Therapy-Related Dysphagia in Head and Neck Cancer: A Pilot Randomized Sham-Controlled Trial.

INTRODUCTION: Dysphagia is common in head and neck cancer patients after concurrent chemoradiation therapy (CRT). This study evaluated the feasibility of conducting a randomized sham-controlled trial and collected preliminary data on safety and efficacy of acupuncture. PATIENTS AND METHODS: Head and neck cancer (HNC) patients with stage III-IV squamous cell carcinoma were randomized to 12 sessions of either active acupuncture (AA) or sham acupuncture (SA) during and following CRT. Patients were blinded to treatment assignment. Swallowing-related quality of life (QOL) was assessed using the MD Anderson Dysphagia Inventory (MDADI) total and subscale scores. RESULTS: Multiple aspects of trial feasibility were confirmed. Forty-two of 196 patients screened (21%) were enrolled and randomized to receive AA (n = 21) or SA (n = 21); 79% completed at least 10 of 12 planned acupuncture sessions; 81% completed the study follow-ups. The majority of patients reported uncertainty regarding their treatment assignment, with no difference between the AA and SA groups. Audits confirmed both AA and SA treatments were delivered with high fidelity. No serious acupuncture-related side effects were observed. MDADI total scores significantly improved from baseline to 12 months post-CRT in both groups (AA: +7.9; SA +13.9; p = .044, p < .001). Similar patterns were observed for the MDADI global subscale (AA: +25.0; SA +22.7; p = .001, p = .002). Intent-to-treat analyses suggested no difference between the treatment groups (p = .17, p = .76 for MDADI total and global scores, respectively). CONCLUSION: A sham-controlled randomized trial evaluating acupuncture in dysphagia-related QOL in HNC found the procedure to be feasible and safe. Further investigation is required to evaluate efficacy. IMPLICATIONS FOR PRACTICE: Dysphagia or swallowing difficulty is an important and common condition after concurrent chemoradiation therapy in head and neck cancer patients. In addition to current available supportive care, acupuncture may offer potential for treating dysphagia. This study demonstrated that both active acupuncture and sham acupuncture are safe and were associated with improved dysphagia-related quality of life from baseline to 12 months after concurrent chemoradiation therapy. This study was not designed to inform underlying specific versus nonspecific effects. Future larger-scale pragmatic clinical trials evaluating the effectiveness of acupuncture versus standard of care are warranted, and further mechanistic research is needed to understand how active versus purportedly sham acupuncture procedures affect dysphagia-related symptoms.

Induction chemotherapy for locoregionally advanced head and neck cancer: past, present, future?

The treatment of patients with locoregionally advanced squamous cell cancer of the head and neck is still evolving. Induction chemotherapy (IC) is widely used in this patient population and it is unclear how to best incorporate IC into multimodality treatment. Recently, the results of two randomized clinical trials were presented (the PARADIGM and Docetaxel Based Chemotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer trials), which showed no demonstrable benefit of IC followed by concurrent chemoradiation over concurrent chemoradiotherapy alone. However, a lower rate of distant metastatic disease was noted, suggesting that patients who are at high risk for metastatic disease may benefit from IC. This review summarizes how IC has evolved over the years, provides an update of recent developments, and discusses how IC may develop in the future.

Trastuzumab for the treatment of salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with high mortality and poor response to treatment. A significant fraction of SDCs are HER2 positive. This retrospective review examines HER2 testing in SDC and the outcome of trastuzumab-based therapy in adjuvant and palliative settings. METHODS: A total of 13 patients with SDC and HER2/neu expression by immunohistochemistry of 1-3+ were treated with trastuzumab in adjuvant (n = 8) or palliative (n = 5) setting. Adjuvant therapy consisted of concurrent radiation and chemotherapy with weekly paclitaxel, carboplatin, and trastuzumab (TCH) for 6 weeks followed by TCH for 12 weeks and trastuzumab alone for 1 year. Palliative treatment for metastatic disease consisted of TCH every 3 weeks for 6 cycles followed by trastuzumab for variable time periods with or without second-line chemotherapy for progression. All patients had fluorescence in situ hybridization testing for HER2/neu gene amplification. RESULTS: The median duration of follow-up was 27 months (range: 8-48 months). In all, 62% of adjuvant patients (5/8) had no evidence of disease more than 2 years from completion of therapy. All patients with metastatic disease (5/5 patients) responded to treatment with TCH. One patient achieved a complete response and remains with no evidence of disease 52 months after initiation of TCH. The median duration of response was 18 months (range: 8-52 months). CONCLUSION: HER2/neu positivity and treatment with trastuzumab correlated well with long-term survival and response in our patients. Based on this data, we propose that HER2/neu status be examined routinely in all patients with SDCs and the treatment be directed accordingly.

Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial.

BACKGROUND: At a minimum follow-up of 2 years, the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) versus cisplatin and fluorouracil (PF) in locally advanced head and neck cancer. We report the long-term results at 5 years' minimum follow-up. METHODS: TAX 324 was a randomised, open-label phase 3 trial comparing three cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2), followed by intravenous cisplatin 100 mg/m(2) and fluorouracil 1000 mg/m(2) per day, administered as a continuous 24-h infusion for 4 days) with three cycles of PF (intravenous cisplatin 100 mg/m(2), followed by fluorouracil 1000 mg/m(2) per day as a continuous 24-h infusion for 5 days) in patients with stage III or IV squamous-cell carcinoma of the head or neck. Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin. Randomisation was done centrally with the use of a biased-coin minimisation technique. At study entry, patients were stratified according to the site of the primary tumour, nodal status (N0 or N1 vs N2 or N3), and institution. For this long-term analysis, data as of Dec 1, 2008, were gathered retrospectively from patients' medical records. Overall and progression-free survival were the primary endpoints. Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity. The intention-to-treat analysis included data from all 501 patients (255 TPF, 246 PF); data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up. TAX 324 was registered at ClinicalTrials.gov, NCT00273546. FINDINGS: Median follow-up was 72·2 months (95% CI 68·8-75·5). Overall survival was significantly better after treatment with TPF versus PF (hazard ratio [HR] 0·74, 95% CI 0·58-0·94), with an estimated 5-year survival of 52% in patients treated with TPF and 42% in those receiving PF. Median survival was 70·6 months (95% CI 49·0-89·0) in the TPF group versus 34·8 months (22·6-48·0) in the PF group (p=0·014). Progression-free survival was also significantly better in patients treated with TPF (median 38·1 months, 95% CI 19·3-66·1, vs 13·2 months, 10·6-20·7; HR 0·75, 95% CI 0·60-0·94). We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups. In the TPF group, three (3%) of 91 patients remained feeding-tube dependent, compared with eight (11%) of 71 patients in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, versus eight (11%) of 71 in the PF group. INTERPRETATION: Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer. Patients who are candidates for induction chemotherapy should be treated with TPF. FUNDING: Sanofi-Aventis.

Glycolytic inhibition with 3-bromopyruvate suppresses tumor growth and improves survival in a murine model of anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes. METHODS: Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 µM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis. RESULTS: Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P < .001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group. CONCLUSION: Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.

A Robust Method for Perfusable Microvascular Network Formation In Vitro.

Micropost-based microfluidic devices are widely used for microvascular network (MVN) formation in diverse research fields. However, consistently generating perfusable MVNs of physiological morphology and dimension has proven to be challenging. Here, how initial seeding parameters determine key characteristics of MVN formation is investigated and a robust two-step seeding strategy to generate perfusable physiological MVNs in microfluidic devices is established.

Oligometastatic adenoid cystic carcinoma: Correlating tumor burden and time to treatment with outcomes.

BACKGROUND: There is limited information on the management and outcomes of oligometastases (OM) in adenoid cystic carcinoma (ACC). METHODS: Retrospective study of 42 patients with metastatic ACC of the head and neck. Imaging studies were analyzed to identify patients with OM (1-5 lesions) at any point during follow-up. RESULTS: There was radiographic evidence of OM in 33/42 (79%) patients. Eighteen patients had OM when treated for metastases, with median overall survival (OS) of 36.0 versus 9.2 years for patients with polymetastases (6+ lesions, HR 0.38, 95%CI 0.14-0.89). Earlier locally ablative treatment, but not systemic treatment, of patients with OM predicted improved survival 3 years after metastasis (HR 0.15, 95%CI 0.02-0.63) and postponed systemic treatment by 80 more months (HR 0.22, 95%CI 0.07-0.71). CONCLUSIONS: There is a considerable population of ACC patients with detectable oligometastases, and early locally ablative treatment of oligometastases may be associated with improved outcomes.

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS). PATIENTS AND METHODS: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling. RESULTS: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders. CONCLUSIONS: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.See related commentary by Sacco and Cohen, p. 435.

Papillary Thyroid Carcinoma with High-Grade Features Versus Poorly Differentiated Thyroid Carcinoma: An Analysis of Clinicopathologic and Molecular Features and Outcome.

Background: Similar to poorly differentiated thyroid carcinoma (PDTC), papillary thyroid carcinoma with high-grade features (PTC HGF) demonstrates increased mitotic activity and/or necrosis; however, PTC HGF is excluded from the World Health Organization (WHO) definition of PDTC based on maintained nuclear features of PTC. Methods: Consecutive tumors that met criteria for PTC HGF, defined as tumors with maintained nuclear features of PTC and mitoses numbering 5 or more per 10 contiguous high-power fields and/or tumor necrosis, and PDTC (defined as per the WHO criteria) were identified. Clinicopathologic characteristics, follow-up data, and targeted next-generation sequencing results were compared between groups. Results: There were 15 PTC HGF and 47 PDTC. PTC HGF was associated with a higher rate of pT4 disease (53% vs. 13%, p = 0.0027) and lymph node metastases (73% vs. 38%, p = 0.049). The disease-specific survival was worse for patients with PTC HGF compared with those with PDTC using Kaplan-Meier estimation (p < 0.001) and was worse in subgroup analysis evaluating patients with widely invasive PDTC (i.e., those with a similar rate of pT4 disease) and PTC HGF (p = 0.040). PTC HGF had a higher BRAFV600E mutation rate (42% vs. 3%; p = 0.003), a trend toward more gene fusions (25% vs. 3%; p = 0.052), and a higher rate of relative gain of 1q (67% vs. 15%; p = 0.002) than PDTC. Conclusions: Our results demonstrate that PTC HGF are important to recognize based on their aggressive behavior. The molecular differences between PTC HGF and PDTC suggest that PTC HGF should be considered a distinct group from PDTC.

Oncogenic Mutations in PI3K/AKT/mTOR Pathway Effectors Associate with Worse Prognosis in BRAFV600E -Driven Papillary Thyroid Cancer Patients.

PURPOSE: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E -mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. EXPERIMENTAL DESIGN: We reviewed clinicopathologic data of 225 patients with BRAFV600E -mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E ) and compared their clinical features and outcomes with those without additional oncogenic alterations. RESULTS: Additional oncogenic alterations were identified in 16% of tumors. Patients in the "BRAF+additional mutations" group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5-1,246.5; P = 0.0043). CONCLUSIONS: Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E -mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.