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Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. - The Lancet. Oncology
About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer.We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753.Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18Â·8 months (IQR 14Â·2-26Â·0) in cohort 1 and 12Â·0 months (6Â·7-20Â·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38Â·5%, 95% CI 20Â·2-59Â·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased Î³-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2.Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients.F Hoffmann-La Roche.Copyright Â© 2016 Elsevier Ltd. All rights reserved.
The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform. - JAMA oncology
Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies.To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease.After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600Ã—) exonic coverage of 410 cancer genes and whole-genome copy number analysis.Next-generation sequencing of tumors and matched normal DNA.Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease.Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]).These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.
Patterns of nodal failure after intensity modulated radiotherapy for nasopharyngeal carcinoma. - The Laryngoscope
To evaluate the sites of nodal failure (NF) of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT).Retrospective chart review.We reviewed the records of 165 patients with nonmetastatic NPC treated with IMRT between July 1998 and April 2011 at our institution. Recurrent nodes were delineated on imaging and coregistered with the original treatment planning computed tomography. Failures were assessed as in-field, out-field, or marginal based on the relative volumes of the recurrent nodes covered by the original dose distribution.Ten patients had NF at a median follow-up of 70.4 months for surviving patients. The 3- and 5-year overall survival and NF rates were 88.7%, 76.0% and 5.8%, 7.7%, respectively. Six of the nodal failures were in-field, of which five occurred in level II; whereas four had out-field failures, all of which were in the protected parotid gland area. There were no recurrences in level 1b despite this region being protected. The cumulative 3- and 5-year failure rates in the parotid gland area were 2.2% and 3.1%, respectively. Three patients with parotid failure initially had subcentimeter, nonspecific nodules in the same locations of the parotid gland as the recurrent nodes.Nodal failure is uncommon after IMRT in NPC. Recurrence in the parotid gland region accounts for all of the out-field failures and 40% of NF in our study. Comprehensive assessment of nodules in or around the parotid gland is therefore a key aspect of treatment planning and follow-up.4. Laryngoscope, 2016.Â© 2016 The American Laryngological, Rhinological and Otological Society, Inc.
Metabolic signatures of Huntington's disease (HD): (1)H NMR analysis of the polar metabolome in post-mortem human brain. - Biochimica et biophysica acta
Huntington's disease (HD) is an autosomal neurodegenerative disorder affecting approximately 5-10 persons per 100,000 worldwide. The pathophysiology of HD is not fully understood but the age of onset is known to be highly dependent on the number of CAG triplet repeats in the huntingtin gene. Using (1)H NMR spectroscopy this study biochemically profiled 39 brain metabolites in post-mortem striatum (n=14) and frontal lobe (n=14) from HD sufferers and controls (n=28). Striatum metabolites were more perturbed with 15 significantly affected in HD cases, compared with only 4 in frontal lobe (p<0.05; q<0.3). The metabolite which changed most overall was urea which decreased 3.25-fold in striatum (p<0.01). Four metabolites were consistently affected in both brain regions. These included the neurotransmitter precursors tyrosine and l-phenylalanine which were significantly depleted by 1.55-1.58-fold and 1.48-1.54-fold in striatum and frontal lobe, respectively (p=0.02-0.03). They also included l-leucine which was reduced 1.54-1.69-fold (p=0.04-0.09) and myo-inositol which was increased 1.26-1.37-fold (p<0.01). Logistic regression analyses performed with MetaboAnalyst demonstrated that data obtained from striatum produced models which were profoundly more sensitive and specific than those produced from frontal lobe. The brain metabolite changes uncovered in this first (1)H NMR investigation of human HD offer new insights into the disease pathophysiology. Further investigations of striatal metabolite disturbances are clearly warranted.Copyright Â© 2016 Elsevier B.V. All rights reserved.
Mammary analog secretory carcinoma of the thyroid gland: A primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion. - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
ETV6-NTRK3 fusion was identified in several cancers including the recently described mammary analog secretory carcinoma (MASC) of the salivary glands and a minority of papillary thyroid carcinomas. We describe three cases of primary MASC of the thyroid gland and provide a detailed clinical and pathological characterization of the tumor morphology, immunoprofile, and genetic background. Immunohistochemistry for PAX8, TTF-1, thyroglobulin, mammaglobin, GCDFP-15, S-100 protein, and p63 was used to define the tumor immunophenotype. Fluorescence in situ hybridization for ETV6 rearrangement was performed in three, and the next-generation sequencing assay MSK-IMPACTâ„¢ (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) was performed in two cases. Primary MASC of the thyroid occurred in two women and one man, age 47-72 years. All patients presented with high T stage, infiltrative, locally aggressive tumors with extrathyroidal extension. Two cases were associated with well-differentiated papillary thyroid carcinoma. Histologically, they appeared as low-grade tumors, resembling MASC of the salivary glands and labeled positive for mammaglobin, GCDFP-15, S-100 protein, p63, weakly positive for PAX8, and negative for TTF-1 and thyroglobulin. Fluorescence in situ hybridization revealed ETV6 rearrangement in all cases. In two tested cases MSK-IMPACTâ„¢ confirmed the presence of ETV6-NTRK3 gene fusion. Two patients had at least two local recurrences, one was alive with disease, and one was alive and free of disease after 14 and 17 years, respectively. The third patient was alive and free of disease after 2 years. MASC of the thyroid is histologically, immunophenotypically, and genetically similar to its salivary gland counterpart. Thyroid MASC can be associated with a well-differentiated papillary thyroid carcinoma component, supporting follicular cell origin. Clinically, these carcinomas may show frequent recurrences but are associated with long-term survival. Patients with MASC of the thyroid may potentially benefit from Trk molecular-targeted therapy.Modern Pathology advance online publication, 10 June 2016; doi:10.1038/modpathol.2016.115.
Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. - Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
As proton beam radiation therapy (PBRT) may allow greater normal tissue sparing when compared with intensity-modulated radiation therapy (IMRT), we compared the dosimetry and treatment-related toxicities between patients treated to the ipsilateral head and neck with either PBRT or IMRT.Between 01/2011 and 03/2014, 41 consecutive patients underwent ipsilateral irradiation for major salivary gland cancer or cutaneous squamous cell carcinoma. The availability of PBRT, during this period, resulted in an immediate shift in practice from IMRT to PBRT, without any change in target delineation. Acute toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.Twenty-three (56.1%) patients were treated with IMRT and 18 (43.9%) with PBRT. The groups were balanced in terms of baseline, treatment, and target volume characteristics. IMRT plans had a greater median maximum brainstem (29.7 Gy vs. 0.62 Gy (RBE), â€‹P < 0.001), maximum spinal cord (36.3 Gy vs. 1.88 Gy (RBE), â€‹P < 0.001), mean oral cavity (20.6 Gy vs. 0.94 Gy (RBE), â€‹P < 0.001), mean contralateral parotid (1.4 Gy vs. 0.0 Gy (RBE), P<0.001), and mean contralateral submandibular (4.1 Gy vs. 0.0 Gy (RBE), â€‹P < 0.001) dose when compared to PBRT plans. PBRT had significantly lower rates of grade 2 or greater acute dysgeusia (5.6% vs. 65.2%, P<0.001), mucositis (16.7% vs. 52.2%, P=0.019), and nausea (11.1% vs. 56.5%, P=0.003).The unique properties of PBRT allow greater normal tissue sparing without sacrificing target coverage when irradiating the ipsilateral head and neck. This dosimetric advantage seemingly translates into lower rates of acute treatment-related toxicity.Copyright Â© 2015 Elsevier Ireland Ltd. All rights reserved.
Hypopharyngeal squamous cell carcinoma: Three-dimensional or Intensity-modulated radiotherapy? A single institution's experience. - The Laryngoscope
Compare outcomes of hypopharyngeal carcinoma that received conventional radiotherapy versus intensity-modulated radiotherapy (IMRT).Retrospective single-institution trial.Between April 1990 and May 2011, 100 patients with hypopharyngeal cancer underwent curative radiotherapy (RT) at our institution: 50 with IMRT and 50 with conventional RT. The median age was 63 years. There were 12 T1, 22 T2, 37 T3, and 28 T4 patients. The majority of patients (82%) had nodal disease: 54% N2 and 8% N3. The majority of patients (83%) received chemotherapy. Of the patients who received chemotherapy, 84% received a platinum-based regimen. The median RT dose was 7,000 cGy. The majority of patients (62%) had prophylactic percutaneous endoscopic gastrostomy tube placement. Toxicities were reviewed. Local control (LC), locoregional control (LRC), freedom from distant metastasis (FFM) rates, functional larynx preservation (LP), laryngectomy-free survival (LFS), and overall-survival (OS) curves were generated using the Kaplan-Meier method. The log-rank test was used to test prognostic variables.With a median follow up of 48.4 months, the 3/5-year LC, LRC, FFM, LP, LFS and OS rates were 74%/69%, 77%/74%, 70%/66%, 51%/29%, 49.6%/31.8%, and 49%/34%, respectively. The median OS was 2.9 years. The 3-year LC rate for IMRT was 77% versus 81% for conventional RT (Pâ€‰=â€‰.91); 3-year LRC for IMRT was 85% versus 76% for conventional RT (Pâ€‰=â€‰.32). There was no increased local failure with IMRT. There was no difference in the rate of stricture with IMRT (32%) versus conventional RT (25.3%) (Pâ€‰=â€‰.86).IMRT achieved comparable LC and LRC rates to conventional RT.4 Laryngoscope, 126:620-626, 2016.Â© 2015 The American Laryngological, Rhinological and Otological Society, Inc.
Palliative head and neck radiotherapy with the RTOG 8502 regimen for incurable primary or metastatic cancers. - Oral oncology
To report on our institutional experience of palliative radiotherapy (RT) of cancers in the head and neck by the RTOG 8502 'QUAD SHOT' regimen.Seventy-five patients completed at least 1 cycle of palliative RT to the head and neck for primary or metastatic disease based on the RTOG 8502 regimen (3.7 Gy twice daily over 2 consecutive days at 4 week intervals per cycle) between 2/2005 and 7/2014.Median patient age was 76 years (range 23-97). The most common histologies were squamous cell carcinoma (55%), non-anaplastic thyroid carcinoma (10%) and salivary gland carcinoma (9%). Thirty patients (40%) received prior RT at the palliative site. Twenty-eight patients (37%) completed at least three RTOG 8502 cycles. Sixty-five percent of all patients had a palliative response. Median overall survival was 5.67 months (range, 0.20-34.5). Grade 3 toxicity in 4 patients (5%) consisted of acute dermatitis and functional mucositis. Palliative response was significantly correlated with increasing number of RTOG 8502 cycles (p = 0.012), but not KPS, prior RT, palliative chemotherapy, prior surgery, histology or stage. On survival analysis, palliative response (p < 0.001), KPS â©¾ 70 (p = 0.001), and greater number of RTOG 8502 cycles (p = 0.022) remained independent predictors of improved survival.For patients with incurable malignant disease in the head and neck, the palliative RTOG 8502 'QUAD SHOT' regimen provides excellent rates of palliative response with minimal associated toxicity. Patients who are able to complete greater number of RT cycles have higher rates of palliative response and overall survival.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Definitive chemoradiation for primary oral cavity carcinoma: A single institution experience. - Oral oncology
While surgery with or without adjuvant radiation therapy (RT) is the standard of care for oral cavity cancer (OCC), a select group requires nonsurgical treatment. We provide a single-institution experience using definitive chemotherapy and RT for primary OCC.We examined 73 patients with previously untreated, non-metastatic primary OCC treated definitively from 1990 to 2011. There were 39 male and 34 female, with a median age of 63 years (range, 35-89). The disease distribution was Stage I and II (7% each), Stage III (14%), and Stage IV (73%). Oral tongue was the most common (48%), followed by floor of mouth (19%), retromolar trigone (13.7%), and others (8.2%). Median tumor dose was 70 Gy. Sixty-two percent of patients (n=45) were treated with concurrent chemotherapy, predominantly platinum-based.Median follow-up among surviving patients was 73.1 months (interquartile range 14.2-81.4 months). Actuarial 5-year overall survival was 15%. Incidences of locoregional and distant failures were 41.1% and 20.5%, respectively. Kaplan-Meier estimated 5-year rates of locoregional control and freedom from distant metastasis were 37% and 70%, respectively. Mucositis was the most common â©¾Grade 3 acute toxicity (49%). Incidences of Grade 3 late dysphagia and trismus were 15% and 13%, respectively.This study demonstrates over 20 years of experience using definitive chemoradiation for OCC at our institution. Our results illustrate the challenges in treating patients with advanced disease who are not surgical candidates, and the need for adequate and early treatment to prevent distant disease and improve survival outcomes.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. - JAMA
Wiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen-matched allogeneic hematopoietic stem cell (HSC) transplantation is often curative but is associated with significant comorbidity.To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.Gene-corrected autologous HSCs were infused in 7 consecutive patients with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors (age range, 0.8-15.5 years; mean, 7 years) following myeloablative conditioning. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months.A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.Primary outcomes were improvement at 24 months in eczema, frequency and severity of infections, bleeding tendency, and autoimmunity and reduction in disease-related days of hospitalization. Secondary outcomes were improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis.Six of the 7 patients were alive at the time of last follow-up (mean and median follow-up, 28 months and 27 months, respectively) and showed sustained clinical benefit. One patient died 7 months after treatment of preexisting drug-resistant herpes virus infection. Eczema and susceptibility to infections resolved in all 6 patients. Autoimmunity improved in 5 of 5 patients. No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support and thrombopoietic agonists. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment. All 6 surviving patients exhibited high-level, stable engraftment of functionally corrected lymphoid cells. The degree of myeloid cell engraftment and of platelet reconstitution correlated with the dose of gene-corrected cells administered. No evidence of vector-related toxicity was observed clinically or by molecular analysis.This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome. Controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.
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