Phase I trial of alpelisib in combination with concurrent cisplatin-based chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Deregulation of the PI3K signalling pathway is frequent in squamous cell carcinoma of the head and neck (SCCHN) and may be implicated in radioresistance. We report on the results from a phase I 3 + 3 dose escalation study of alpelisib, a class I α-specific PI3K inhibitor in combination with concurrent cisplatin-based chemoradiation (CRT) in patients with locoregionally advanced SCCHN (LA-SCCHN). METHODS: Eligible patients had previously untreated LA-SCCHN and were candidates for CRT. The primary objective was to evaluate safety and determine the recommended phase II dose (RP2D). Alpelisib was given orally once daily at two dose levels: 200 mg and 250 mg. CRT consisted of cisplatin 100 mg/m2 IV every three weeks and standard fractionation radiotherapy (IMRT) 70 Gy in 35 fractions. RESULTS: Nine patients were enrolled (six alpelisib 200 mg, three 250 mg). Oropharynx was the primary site in all patients (seven p16-positive; five T1-2N2M0, four T3-4N2-3M0 [AJCC 7th edition]). All patients completed CRT within seven weeks. Grade 3 alpelisib-related toxicities occurred in four patients. No dose-limiting toxicity (DLT) was observed at 200 mg among three DLT-evaluable patients. Two of two DLT-evaluable patients treated at 250 mg experienced DLTs (inability to complete ≥75% alpelisib secondary to radiation dermatitis and febrile neutropenia). Thus, RP2D was declared at 200 mg. After median follow-up of 39.7 months, two patients developed pulmonary metastases despite locoregional control. Three-year overall survival was 77.8% (95% CI 36.5%-93.9%). CONCLUSION: Alpelisib at 200 mg has a manageable safety profile in combination with cisplatin-based CRT in LA-SCCHN.

Radiologic-Pathologic Correlation of Tumor Thickness and Its Prognostic Importance in Squamous Cell Carcinoma of the Oral Cavity: Implications for the Eighth Edition Tumor, Node, Metastasis Classification.

BACKGROUND AND PURPOSE: Addressing the performance of an imaging-based parameter compared to a "gold standard" pathologic measurement is essential to achieve accurate clinical T-classification. Our aim was to determine the radiologic-pathologic tumor thickness correlation and its prognostic value in oral squamous cell carcinoma. MATERIALS AND METHODS: All pathologic T1-T3 (seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer) oral squamous cell carcinomas diagnosed between 2010 and 2015 were reviewed. Radiologic tumor thickness was measured on preoperative CT or MR imaging blinded to pathology. The radiologic-pathologic tumor thickness correlation was calculated. The impact of the imaging-to-surgery time interval and imaging technique on the correlation was explored. Intra-/interrater reliability on radiologic tumor thickness was calculated. The correlation of radiologic-versus-pathologic tumor thickness and its performance as the seventh edition T-category modifier was evaluated. Multivariable analysis assessed the prognostic value of the radiologic tumor thickness for overall survival adjusted for age, seventh edition T-category, and performance status. RESULTS: For 354 consecutive patients, the radiologic-pathologic tumor thickness correlation was similar for the image-to-surgery interval of ≤4.0 weeks (ρ = 0.76) versus 4-8 weeks (ρ = 0.80) but lower in those with more than an 8-week interval (ρ = 0.62). CT and MR imaging had similar correlations (0.76 and 0.80). Intrarater and interrater reliability was excellent (0.88 and 0.84). Excluding 19 cases with an imaging-to-surgery interval of >8 weeks, 335 patients were eligible for further analysis. The radiologic-pathologic tumor thickness correlation was 0.78. The accuracy for upstaging the T-classification based on radiologic tumor thickness was 83% for pathologic T1 and 74% for pathologic T2 tumors. Multivariable analysis confirmed the prognostic value of radiologic tumor thickness (hazard ratio = 1.5, P = .02) for overall survival. CONCLUSIONS: This study demonstrates a good radiologic-pathologic tumor thickness correlation. Intrarater and interrater reliability for radiologic tumor thickness was excellent. Radiologically thicker tumor was predictive of inferior survival.

Giant cribriform adenocarcinoma of the tongue showing PRKD3 rearrangement.

Cribriform adenocarcinoma of the tongue and minor salivary glands (CAMSG) was first described 16 years ago. It typically presents as a mass at the base of the tongue with early spread to lymph nodes, but without potential for distant metastases. In the 2005 World Health Organization Classification of Tumors the entity was classified as a possible variant of polymorphous low-grade adenocarcinoma (PLGA). Since then, more than 40 cases have been described in the English literature. Recently, PRKD1-3 translocation was found in more than 80% of CAMSGs. In some of those cases ARID1A or DDX3X was the translocation partner. We reviewed 183 primary carcinomas of major and minor salivary glands, resected at the Medical University of Gdansk, Poland, in the period 1992-2012, and identified only one case of CAMSG. A giant tumor developed at the base of the tongue in a 76-year-old man. The primary tumor was resected with multiple bilateral cervical lymph node metastases. The patient received radiotherapy but died 10 months after the surgery due to causes not related to the primary cancer. The tumor presented PRKD3 rearrangement as confirmed by FISH. As the tumor is extremely rare (it represented only 0.5% of salivary gland tumors in our series), the controversy on its nosological status is still unresolved. This is the first report in the world literature of a patient who died in the course of CAMSG.

Intraosseous mucoepidermoid carcinoma: a review of the diagnostic imaging features of four jaw cases.

The purpose of this case series is to present the common features of intraosseous mucoepidermoid carcinoma (IMC) of the jaws in plain film and CT imaging. Two oral and maxillofacial radiologists reviewed and characterized the common features of four biopsy-proven cases of IMC in the jaws in plain film and CT imaging obtained from the files of the Department of Oral Radiology, Faculty of Dentistry, University of Toronto, Toronto, Canada. The common features are a well-defined sclerotic periphery, the presence of internal amorphous sclerotic bone and numerous small loculations, lack of septae bordering many of the loculations, and expansion and perforation of the outer cortical plate with extension into surrounding soft tissue. Other characteristics include tooth displacement and root resorption. The four cases of IMC reviewed have common imaging characteristics. All cases share some diagnostic imaging features with other multilocular-appearing entities of the jaws. However, the presence of amorphous sclerotic bone and malignant characteristics can be useful in the differential diagnosis.

Primitive non-neural granular cell tumour with lymph node metastasis.

Primitive non-neural granular cell tumour (PNGCT) is a rare tumour of uncertain lineage. This report describes a case of PGNCT with lymph node metastasis. This is thought to be only the second reported case with lymph node involvement.

Mucinous, gland predominant synovial sarcoma of a large peripheral nerve: a rare case closely mimicking metastatic mucinous carcinoma.

Synovial sarcoma is a distinctive soft tissue neoplasm with monophasic and biphasic forms. It is typically a deep-seated soft tissue tumour of the extremities of young adults and occasional cases have been described in large peripheral nerves. A rare example has a predominance of the glandular component and may mimic metastatic carcinoma. Here, a unique synovial sarcoma with <1% spindle cell component involving the posterior tibial nerve is decribed. In addition to having only small bands or islands of stroma, there was also mucin dissection of the surrounding soft tissue. Isolated glands were seen "floating" in pools of mucin. There was abundant intracellular mucin present as well. These latter two findings have not been described in synovial sarcoma thus far, to our knowledge. The diagnosis was confirmed by molecular detection of the t(X;18) by reverse transcription-PCR and confirmed by dual colour break apart fluorescence in situ hybridisation, in a second laboratory. Mucinous, gland predominant synovial sarcoma must be recognised to avoid misdiagnosis of metastatic carcinoma or a glandular malignant peripheral nerve sheath tumour when occurring in a peripheral nerve.

Gastric neuroendocrine carcinoma arising from heterotopic pancreatic tissue.

An 85 year old man presented with symptoms of dyspepsia and increase in stool frequency of two months duration. Upper endoscopy revealed an ulcer and the biopsy was interpreted as carcinoma with endocrine features. A formal distal gastrectomy was planned, but intraoperatively, because of the patient's condition, a wedge resection was performed. Histology revealed a neuroendocrine tumour (grade 1), located mainly in the submucosa, which had caused mucosal attenuation and ulceration. Associated with the tumour and at its periphery was heterotopic pancreatic tissue composed of acini, ducts, and endocrine cells. The tumour was strongly positive for chromogranin and focally for synaptophysin. There was no associated chronic atrophic gastritis or G cell hyperplasia. A discrete focus of high grade neuroendocrine carcinoma (grade 3) within the typical (grade 1) neuroendocrine tumour was also present. This case illustrates a grade 1 neuroendocrine carcinoma, with a small grade 3 focus, arising within or intimately associated with heterotopic pancreatic tissue in the stomach. Although the two entities may be separate, their close topographical association favours the possibility of neuroendocrine carcinoma arising from the heterotopic pancreas. Pathologists should be aware of the occurrence of pancreatic heterotopia in the stomach and the association of carcinoma with it.

The effects of economic circumstances on British students' mental and physical health.

Three-hundred sixty British university students completed a questionnaire providing information on demographic characteristics, financial circumstances, smoking, and drug and alcohol use. A 14-item inventory of physical symptoms, the short form 36 health survey (SF-36), and the General Health Questionnaire (GHQ-12) were used to assess their physical and psychological well-being. Except for physical functioning, all subscales of the SF-36 and the GHQ indicated levels of health significantly below population norms matched for age and sex. Poorer mental health was related to longer working hours outside the university and difficulty in paying bills. Students who had considered abandoning study for financial reasons had poorer mental health, lower levels of social functioning and vitality, and poorer physical health as indicated by variables on the SF-36. They were also heavier smokers. Students' personal debt was significantly associated with their knowing people involved in prostitution, crime, or drug dealing to help support themselves financially.