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Background PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. Methods Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. Results Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. Conclusion Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100).

We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P.001).Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.

Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.

Background Adenoid cystic carcinoma (ACC), an uncommon and indolent salivary gland malignancy, is characterized by varied morphologic and clinical manifestations. Molecular genetic studies of ACC identified certain structural and mutational alterations that may play a driver role in tumor development. The evolution and regional consistency of these events in ACC development progression are uncertain. Methods To investigate the spatial and temporal clonal landscape of ACC, whole-genome sequencing and variant analyses were performed on 34 regionally sampled primary tumors and their concurrent and metachronous metastatic deposits from eight patients. Results The average mutation rate per case (primary and metastasis) was 0.32 per million base pairs, and the average incidence of shared mutations in primary and metastatic specimens in each case was 21.9% (range = 0%-44.4%). The analyses revealed considerable spatial clonal differences within and between primary tumors and metastatic disease. Phylogeny formation displayed branching evolution with a main trunk and two distinct mono-splits in all cases. One of the main branches represented intratumor subclonal diversity, and the other delineated metastatic departure and progression. All metastatic tumors shared clonal linkage to their matching primary in concordance with parallel dissemination of metastasis. Synchronous metastases were genomically more similar to their primary than metachronous metastatic disease. Truncal genetic alterations included somatic mutations in the NOTCH pathway genes (NOTCH1 and SPEN) and t(6;9) associated gene fusions. Conclusions Our study delineated clonal and subclonal phylogeny for primary and metastatic ACC, defined early genetic drivers, and provides a conceptual framework for a rational strategy to integrate heterogeneity in clinical assessment.

Because p53 and p73 are associated with critical cellular processes and can be inactivated or degraded by the human papillomavirus (HPV) E6 oncoprotein, we investigated the combined effects of p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms on the risk of HPV16-associated oral cancer. We analyzed genotype data from 326 patients with squamous cell carcinoma of the oral cavity or oropharynx and 349 cancer-free controls. We found that HPV16 seropositivity was associated with an increased risk of oral cancer [adjusted odds ratio (OR), 3.42; 95% confidence interval (CI), 2.28-5.13], especially among never-smokers (adjusted OR, 8.20; 95% CI, 3.66-18.4) and subjects with variant genotypes [adjusted OR for p53 Arg/Pro + Pro/Pro (Pro carriers), 5.00; 95% CI, 2.72-9.21; adjusted OR for p73 GC/AT + AT/AT (AT carriers), 3.83; 95% CI, 1.98-7.41]. HPV16 seropositivity was also associated with an significantly increased risk of oral cancer in all three risk groups with combined genotypes [adjusted ORs (95% CIs) were 2.28 (1.15-4.54) for p53 Arg/Arg and p73 GC/GC, the low-risk group; 3.97 (2.14-7.36) for p53 Arg/Arg and p73 AT carriers or p53 Pro carriers and p73 GC/GC, the medium-risk group and 5.11 (2.00-13.0) for p53 Pro carriers and p73 AT carriers, the high-risk group]. Moreover, HPV16-seropositive never-smokers in the high-risk group exhibited an approximately 11-fold greater risk of oral cancer (adjusted OR, 11.3; 95% CI, 1.22-106.0) than did HPV16-seronegative never-smokers in the low-risk group. These findings suggest that the combined variants of p53 and p73 significantly increase the risk of HPV16-associated oral cancer, especially among never-smokers.

p73, a novel p53 homolog, has some p53-like activity and plays an important role in modulating cell-cycle control, apoptosis and cell growth. p73 regulates differentiation of head and neck squamous epithelium, and changes in p73 may lead to the development of squamous cell carcinoma of the head and neck (SCCHN). Two linked non-coding exon 2 polymorphisms (designated as G4C14-to-A4T14) were identified recently but their functional relevance is unknown. We hypothesized that this p73 polymorphism plays a role in the etiology of SCCHN. Therefore, in this hospital-based case-control study of 708 patients newly diagnosed with SCCHN and 1229 cancer-free controls, we evaluated the association between the p73 AT variant allele and risk of SCCHN. The controls were frequency-matched to the cases by age (+/-5 years), sex and smoking status, and all subjects were non-Hispanic whites. Our results showed that the frequencies of variant AT allele and genotypes were more common in the cases than in the controls (P = 0.029 and P = 0.009, respectively). Compared with the GC/GC genotype, the variant genotypes (GC/AT + AT/AT) were associated with a statistically significantly increased risk for SCCHN [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.10-1.60]. Further stratification analyses by age, sex, smoking and alcohol status and by cancer sites within the head and neck region indicated that this significantly increased risk was more pronounced in younger (< or =50 years) individuals (adjusted OR = 1.70; 95% CI, 1.19-2.43), women (1.61; 1.09-2.37), current smokers (1.77; 1.25-2.51) and patients with oral cancer (1.54; 1.15-2.07). Our results suggest that this p73 polymorphism may be a risk marker for genetic susceptibility to SCCHN.

Background: Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract (UADT) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy (13-cis-retinoic acid, -interferon, and -tocopherol). Both alleles of the adenine (A)/guanine (G) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts, but the A allele preferentially encodes a protein with an extended half-life. We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein, post-treatment modulation of cyclin D1 protein levels, histologic response to treatment, and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy. Methods: UADT tissue biopsy samples were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions. Tissues were examined for cyclin D1 genotype (by DNA single-strand conformation polymorphism analysis), for cyclin D1 protein expression (by immunohistochemistry), and for cyclin D1 gene copy number (by fluorescence in situ hybridization). Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated. All statistical tests were two-sided. Results: The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer (16 of 18 AA/AG subjects versus four of nine GG subjects; P = .02), decreased histologic response to biochemopreventive treatment (six of 21 AA/AG subjects versus four of 10 GG subjects; P = .70), decreased favorable modulation of cyclin D1 expression by the treatment (seven of 18 AA/AG subjects versus eight of nine GG subjects; P = .02), and shorter progression-free survival (P = .05). Conclusions: The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1, a decreased likelihood of response to biochemopreventive intervention, and an increased rate of progression to cancer development, findings that require validation in a larger cohort. [J Natl Cancer Inst 2003;95:198–205]

Background: The goal of chemoprevention is to reduce the risk of cancer development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents. To determine the potential role of genetic alterations in assessing cancer risk and in evaluating the efficacy of chemopreventive agents, we studied 22 patients with advanced premalignant lesions of the head and neck who were part of a prospective cancer prevention trial that is investigating a regimen of 13-cis-retinoic acid, interferon alfa, and a-tocopherol administered for 12 months or until disease progression. Methods: We used polymerase chain reaction analysis of microsatellite DNA sequences in cells from precancerous lesions to determine the frequencies of genetic alterations—namely, loss of heterozygosity (LOH) and microsatellite instability—at chromosomal loci that are commonly deleted in head and neck cancer. Results: Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i.e., heterozygous) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH in at least one of their lesion biopsy specimens. Among nine patients who exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens and who had completed at least 5 months of therapy, the genetic loss persisted in eight—including three of the four patients who exhibited complete histologic responses (i.e., no evidence of dysplasia in their biopsy specimens). Implication: Our data suggest that clinical and histologic assessments of the response to chemopreventive agents may be insufficient to determine their efficacy and that critical genetic alterations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents. [J Natl Cancer Inst 1998;90:1545‐51]

Concurrent DNA flow cytometric (FCM) and fluorescence in situ hybridization (FISH) analyses were prospectively performed on 24 primary untreated head and neck squamous carcinomas for characterization of the genotypic and phenotypic DNA aberrations of these neoplasms. Eleven tumors (42.0%) manifested DNA diploidy (DI = 1.00) and 15 (58.0%) had DNA aneuploidy (DI 1.00) by FCM. Fluorescence in situ hybridization results showed aneusomy in the majority of DNA diploid and in all DNA aneuploid tumors. The extent of the abnormalities for individual chromosomes and the number of involved chromosomes in a given DNA diploid or aneuploid tumor were significantly different. Overall, a statistical correlation between the FCM DNA index (DI) and the magnitude of the chromosomal aberration by FISH was found. Our results also show a significant association between the DI and histologic differentiation and stage of disease in these neoplasms. In conclusion, (1) chromosomal aneusomy characterizes most DNA diploid (DI = 1.00) and all DNA aneuploid (DI 1.00) head and neck squamous carcinomas; (2) polysomy is the most prevalent finding; (3) loss of the Y chromosome in tumors from male patients is a consistent feature; (4) the FCM DI reflects net chromosomal gains or losses in these neoplasms; and (5) DNA aneuploidy is associated with tumor aggressiveness.

Twenty-eight resected primary non-small cell lung carcinomas were studied for intratumoral DNA variability by flow cytometry (FCM). Three separate tissue specimens from each resected tumor were divided equally for FCM analysis and histologic evaluation. FCM analysis also was performed on fine-needle aspirates (FNAs) from the center of the resected tumor. Histologically, there were 8 squamous carcinomas, 19 adenocarcinomas, and 1 large cell carcinoma. Twenty-three tumors (82%) were aneuploid, and 5 (18%) were diploid. The DNA index in aneuploid neoplasms ranged from 0.91 to 3.30 (mean, 1.64). All 5 diploid and 19 (83%) of the (23) aneuploid neoplasms manifested intratumoral DNA stability. Four (17%) of the aneuploid tumors showed regional DNA heterogeneity expressed as additional stemlines in at least one sample. The FN A yield was sufficient in 21 cases and inadequate for complete analysis in 7 cases. In general, good correlation between FNA and tissue analysis was obtained. However, in three of the aneuploid neoplasms, FNA materials did not reveal an additional nondominant stemline, as noted in the tissue specimens. The authors attribute this finding to a dilutional factor in the aspiration material. The authors conclude that most non-small cell lung carcinomas express DNA stability; FNA provides adequate cellular material for FCM in most cases.

A 22-year-old man presented with symptoms of urinary obstruction and was found to have a 5-cm mass protruding from the left side of the prostate into the prostatic urethra. The lesion was partially removed by transurethral resection (TURP). The patient's symptoms recurred, so he required another TURP four months later; at latest follow-up (four years later), there was no evidence of disease. Light microscopy revealed a myxoid lesion characterized by an atypical fibroblastic proliferation associated with a prominent inflammatory component and granulation tissue-type vasculature. The lesion nearly replaced the prostatic parenchyma and invaded the bladder wall. Immunohistochemistry and electron microscopy showed a predominance of fibroblasts with occasional myofibroblasts. DNA flow cytometric analysis showed that the tumor cells had a diploid DNA content. Given these findings and the indolent clinical course, the authors think that this lesion represents a benign, reactive process consistent with a pseudosarcomatous fibromyxoid tumor, a recently described rare lesion of the genitourinary tract.

To study the histogenesis of and determine the most useful markers for diagnosing anaplastic thyroid carcinoma (ATC), 32 cases, including 2 with numerous osteoclast-like cells, were stained with a battery of antibodies to epithelial (keratin, epithelial membrane antigen [EMA], carcinoembryonic antigen [CEA]), mesenchymal (vimentin, desmin, muscle-specific actin [MSA], Factor VIII-related antigen [FVIII:RAg]), endocrine (thyroglobulin, calcitonin, chromogranin [Cg]), lymphocytic (leukocyte common antigen [LCA]), histiocytic (alpha-1-antitrypsin [alpha 1AT], alpha-1-antichymotrypsin [alpha 1AChy], KP1), melanocytic (HMB-45), and Schwann cell (S-100 protein) markers. Five tumors were associated with papillary carcinoma. In one of these cases, a morphologic continuum between the well-differentiated carcinoma and the ATC was visualized by their positive immunostaining for both vimentin and keratin, thus supporting the hypothesis that the latter tumor originated from the former. Twenty-five (78.1%) tumors expressed keratin, 10 (31.3%) reacted for EMA, and 3 (9.4%) expressed CEA, confirming the epithelial nature of this neoplasm. Reactivity for thyroglobulin was seen in a small number of cells in five (15.6%) thyroglobulin was seen in a small number of cells in five (15.6%) ATCs. Because all of the cases that expressed keratin also stained positively for EMA, CEA, or thyroglobulin, it is believed that keratin is the most useful epithelial marker for diagnosis of ATC. A lack of reactivity for calcitonin and Cg indicates that these tumors are not derived from C cells, as has been proposed by some authors. Reactivity for KP1 (CD68), a monoclonal antibody that reacts with a macrophage-associated antigen, occurred in the osteoclast-like cells but not in the anaplastic tumor cells. This finding, together with negative keratin staining of the osteoclast-like cells, indicates that these cells are not epithelial in nature and therefore should be considered reactive rather than neoplastic. Thirty tumors (93.8%) expressed vimentin, 15 (46.9%) marked for alpha 1AChy, 11 (34.4%) exhibited alpha 1AT, and 11 (34.4%) expressed S-100 protein. Because all of these markers can be seen in a wide variety of tumors of different histogeneses, they have no value in the diagnosis of ATC. Although immunostaining for FVIII:RAg, desmin, and MSA was negative in all of these tumors, these markers can help to differentiate between ATCs and some soft tissue sarcomas with which they can be confused.

The authors studied 69 squamous carcinomas of the middle or lower esophagus to evaluate prognostic factors. Clinical and histologic parameters that were evaluated included weight loss, esophageal obstruction at presentation, site, gross configuration, degree of tumor differentiation, vascular invasion, the status of resection margins, and stage. Blood group antigen (BGA) expression in the tumors was determined immunohistochemically and compared with blood type and antigen reactivity in adjacent normal mucosa. A loss of BGA expression was seen in 27 tumors. This finding was correlated with high stage but was not significantly linked to survival. DNA ploidy was determined by flow cytometry of paraffin-embedded tissues. Forty-one of 52 tumors were aneuploid, and 14 had two or more separate aneuploid populations. However, survival was not correlated with ploidy status. The degree of differentiation and stage of the tumors were the only two independently significant prognostic indicators in this study.

Background Size is considered the single best predictor of malignancy in evaluating adrenal neoplasms identified incidentally during abdominal imaging, yet small adrenal cortical cancers have been reported previously from several centres. Methods This was a retrospective evaluation of the value of tumour size and other preoperative clinical parameters in predicting the presence or absence of malignancy in adult patients who underwent adrenalectomy for an adrenal tumour at this institution. Results One hundred and sixteen patients underwent adrenalectomy. Diagnoses were adrenal cortical carcinoma (n = 38), phaeochromocytoma (n = 27), metastasis to the adrenal gland (n = 11) and benign tumours (n = 40) (cortical adenoma, 23; cyst, two; cortical hyperplasia, five; ganglioneuroma, four; myelolipoma, six). The median size of the adrenal cortical carcinomas was 9·2 (range 1·7–30) cm; five tumours were smaller than 5·0 cm. The median overall size of the benign tumours (excluding phaeochromocytomas) was 4·0 cm; the median size of the adrenal cortical adenomas was 3·0 cm. Eleven benign tumours were larger than 5·0 cm, including two cortical adenomas. The radiographic features of three of five small adrenal cancers correctly predicted malignancy; the remaining two patients with small cancers had symptoms related to functioning tumours. Conversely, the radiographic features of seven of 11 large benign adrenal tumours correctly predicted benign histology, including five of five myelolipomas. Conclusion While size remains a good predictor of histology and clinical behaviour of functioning and non-functioning adrenal neoplasms, both small adrenal cortical cancers and large benign tumours occur with measurable frequency. High-quality imaging studies (computed tomography and magnetic resonance imaging) may be helpful in identifying relatively small yet radiographically atypical adrenal tumours more likely to be cancers, as well as radiographically characteristic benign myelolipomas which may be followed selectively.

Localized fibrous tumor of the serosal cavities (localized fibrous mesothelioma) is a generally benign spindle cell neoplasm of uncertain histogenesis. Fourteen histologically similar primary tumors from different mesothelium-lined sites (11 pleural and 1 each in the pericardium, peritoneal cavity, and pouch of Douglas) and 2 recurrences of those tumors (pericardium and pouch of Douglas) were examined histopathologically and by flow cytometry to relate histologic features and DNA ploidy to biologic behavior (follow-up, 48-255 months among 13 patients). All 16 tumors (14 primaries and 2 recurrences) displayed diploid DNA pattern, and none of 13 patients died of disease (1 patient was lost to follow-up). To elucidate the histogenesis, seven primary tumors were examined for vimentin and keratin immunostaining and six primary tumors were assessed by electron microscopy. All cases exhibited spindle-fibroblastic cell proliferation with a prominent hemangiopericytic pattern. All cases so examined had positive results for vimentin and negative results for keratin. Ultrastructurally, the tumor cells showed mesenchymal-fibroblastic features. These results support a mesenchymal origin, most likely from submesothelial fibroblasts. Further, this neoplasm may recur but retain its basic histologic features, diploidy, and benign outcome.