Clinical Activity of an hTERT-Specific Cancer Vaccine (Vx-001) in "Immune Desert" NSCLC.

BACKGROUND: Tumors can be separated into immunogenic/hot and non-immunogenic/cold on the basis of the presence of tumor-infiltrating lymphocytes (TILs), the expression of PD-L1 and the tumor mutation burden (TMB). In immunogenic tumors, TILs become unable to control tumor growth because their activity is suppressed by different inhibitory pathways, including PD-1/PD-L1. We hypothesized that tumor vaccines may not be active in the immunosuppressive microenvironment of immunogenic/hot tumors while they could be efficient in the immune naïve microenvironment of non-immunogenic/cold tumors. METHODS: The randomized phase II Vx-001-201 study investigated the effect of the Vx-001 vaccine as maintenance treatment in metastatic non-small cell lung cancer (NSCLC) patients. Biopsies from 131 (68 placebo and 63 Vx-001) patients were retrospectively analyzed for PD-L1 expression and TIL infiltration. TILs were measured as tumor-associated immune cells (TAICs), CD3-TILs, CD8-TILs and granzyme B-producing TILs (GZMB-TILs). Patients were distinguished into PD-L1(+) and PD-L1(-) and into TIL high and TIL low. FINDINGS: There was no correlation between PD-L1 expression and Vx-001 clinical activity. In contrast, Vx-001 showed a significant improvement of overall survival (OS) vs. placebo in TAIC low (21 vs. 8.1 months, p = 0.003, HR = 0.404, 95% CI 0.219-0.745), CD3-TIL low (21.6 vs. 6.6 months, p < 0.001, HR = 0.279, 95% CI 0.131-0.595), CD8-TIL low (21 vs. 6.6 months, p < 0.001; HR = 0.240, 95% CI 0.11-0.522) and GZMB-TIL low (20.7 vs. 11.1 months, p = 0.011, HR = 0.490, 95% CI 0.278-0.863). Vx-001 did not offer any clinical benefit in patients with TAIC high, CD3-TIL high, CD8-TIL high or GZMB-TIL high tumors. CD3-TIL, CD8-TIL and GZMB-TIL were independent predictive factors of Vx-001 efficacy. CONCLUSIONS: These results support the hypothesis that Vx-001 may be efficient in patients with non-immunogenic/cold but not with immunogenic/hot tumors.

Deregulation of p53/survivin apoptotic markers correlated to PTEN expression in pterygium neoplastic cells.

PURPOSE: Pterygium is a distinct clinicopathological entity characterized by degenerated and neoplastic-like features. Concerning its rise on normal conjunctiva epithelia, the role of specific gene deregulations including apoptotic/anti-apoptotic factors and significant suppressor genes in signaling transduction pathways is under investigation. In the current study, we co-analyzed p53, survivin and PTEN proteins in pterygia and normal conjunctiva. METHODS: Using a liquid-based cytology assay, 50 cell specimens were obtained by a smooth scraping on conjunctiva epithelia and fixed accordingly. Among them, 38 were pterygia and the remaining (n=12) normal epithelia (control group). Immunocytochemistry assays were implemented on the corresponding slides by applying ani-p53, survivin, and PTEN antibodies. Digital image analysis was performed for evaluating objectively the corresponding immunostaining intensity levels. RESULTS: The majority of the examined pterygia cases overexpressed the markers p53:22/38-57.9%, survivin:30/38-78.9%, and PTEN:25/38-65.7%. Interestingly, overall p53/PTEN co-expression was found to be statistically significant (p=0.022). CONCLUSIONS: Survivin overexpression leads to an increased anti-apoptotic activity playing a central molecular role in the pathogenesis and progression of pterygia. Furthermore, although p53 expression is observed in these lesions, its impact seems to be low compared to survivin's influence on them. Additionally, the role of PTEN in the process is potentially significant providing a suppressor balance to the p53/ survivin complex.

HPV infection in oropharyngeal squamous cell carcinomas: correlation with tumor size.

PURPOSE: Human papillomavirus (HPV) is implicated in carcinogenesis of a variety of epithelia, including oropharyngeal and laryngeal. High risk (HR) HPV persistent infection in head and neck squamous cell carcinomas (HNSCC) is a significant event, but its influence regarding the prognosis and survival in these patients remains under consideration. Our aim was to analyze a series of oropharyngeal (OP) SCCs at the HPV DNA level, correlating them to the survival status of the corresponding patients. METHODS: Using HPV DNA polymerase chain reaction (PCR) microarray technology, 28 formalin-fixed, paraffinembedded primary OPSCCs were cored and analyzed. RESULTS: Positive DNA amplicons for HPV infection were detected in 3 SCC cases (sub types: HPV 31/35/70). Interestingly, HPV persistent infection was associated with larger tumors (p=0.029) which also affected survival status (p=0.007) in the corresponding patients. Overall survival was also significantly dependent on the stage of the malignancies (p=0.022). Furthermore, tumor size was significantly and negatively correlated with age (p=0.015), meaning that younger patients will probably develop larger tumors. CONCLUSIONS: HPV-depended OPSCCs - although not so common as the laryngeal ones, but still not so rare in the rural population in Greece - are characterized by a combination of specific features. Our results showed that survival was adversely effected by the stage of the disease and tumor size and indirectly by the presence of HPV - especially in young adults - while the combined surgery/radiotherapy/ chemotherapy therapy seems to prolong survival. Additionally, HPV co-existence seems to be associated with larger tumors and poor survival.

Numerical Imbalances of Chromosome 7 in Oral Squamous Cell Carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is an aggressive neoplasm. Many chromosomal and gene alterations have been identified in OSCC, including structural and numerical changes. In this study, we implemented a molecular assay of chromosome 7 (Chr7) in order to investigate the level of its numerical instability in OSCC. MATERIALS AND METHODS: Using tissue microarray technology, 30 primary OSCCs were cored and re-embedded into one recipient block. Chromogenic in situ hybridization assay was performed based on Chr7 centromeric probedetection. RESULTS: Chr 7 numerical analysis detected polysomy (trisomy/ tetrasomy) in 4/30 (13.3%) of the examined tissue OSCC cores. Statistical significance was assessed correlating Chr7 numerical aberrations with stage (p=0.015), especially detected in cases not related to human papillomavirus (HPV) (p=0.01). CONCLUSION: Although Chr7 polysomy is a relatively rare gross genetic event in OSSC, it affects their biological behavior leading toa progressively aggressive phenotype (advanced stage). Furthermore, Chr7 polysomy is observed more frequently in non-viral (HPV) cases.

p53 mutations in oral cavity carcinoma.

Head and neck squamous cell carcinoma (HNSCC) includes a variety of SCCs derived from the anatomic regions of the oral and nasal cavity and also of the pharynx and larynx. Oral cavity SCC (OCSCC) demonstrates an increasing rate due to viral -related (High Risk Human Papilloma Virus-HR HPV) persistent infection, cigarette smoking and alcohol consumption. Gross chromosomal alterations (polysomy, aneuploidy) and specific gene aberrations such as amplifications, deletions, point mutations combined or not with epigenetic ones (promoter methylations and miRNA deregulations) are responsible for the progressive transformation of normal squamous epithelia to the corresponding malignant. In the majority of OCSCC cases, critical genes, such as p53 are found to be inactivated, leading to an overactivated cell cycle correlated to carcinogenetic process. P53 (gene location: 17p13.1) is a suppressor gene acting as a key regulator of the cell's genomic stability, function and homeostasis. P53 aberrant overexpression is frequently observed in OCSCC tissues as a result of point mutation or deletion. In the current special article we explored the role of the p53 gene deregulation - especially focused on its mutation status - in OCSCCs.

A unique tripartite collision tumor of the esophagus: A case report.

RATIONALE: We report a unique case of a tripartite esophageal collision tumor consisting of three separate histologic types. PATIENTS CONCERNS: Therapeutic dilemmas on the proper treatment of those rare neoplasms remain unanswered considering both proper surgical therapy and adjuvant therapy. DIAGNOSE: In this paper, we report a unique case of a patient with a tripartite esophageal collision tumor consisting of a small cell carcinoma, an adenocarcinoma of medium differentiation and a signet ring cell carcinoma. Diagnosis is difficult as clinical presentation of the patient was undistinguishable from other, commoner tumor types. INTERVENTIONS: The patient's diagnostic and therapeutic course along with available data on the collisions tumor's biological behavior and treatment are briefly discussed. OUTCOMES: Esophagectomy is the best treatment options for these patients. Unique nature of this tumor demands aggresive oncologic treatment. LESSONS: Collision tumors are rare neoplasms consisting of distinct cell populations developing in juxtaposition to one another without any areas of intermingling. Various cell types can be found. However, collision neoplasms of the esophagus combining adenomatous and neuroendocrine components are exceedingly rare, with only 5 cases described to date in the literature. Given their rarity, limited information is available on their tumorigenesis, biological behavior and clinical course. In general, these tumors are aggressive neoplasms and significantly affect patient treatment and prognosis.

Deregulation of p53-MDM2 auto-regulatory pathway in breast carcinoma.

PURPOSE: p53 tumor suppressor protein (17p13.1) regulates critically the cell cycle and thus it is involved in cancer initiation and prevention. The gene is frequently mutated in breast cancer patients and the mutations have been associated with poor prognosis and response rates to chemotherapy. The purpose of this study was to correlate p53 expression with MDM2, a proto-oncogene (12q14.3), which acts as a major negative regulator in p53-MDM2 auto-regulatory pathway. METHODS: Seventy breast adenocarcinoma cases were included in the study. Sixty tumors were pathologically categorized as invasive ductal adenocarcinomas, whereas the rest of them were diagnosed as pure in situ carcinomas. Immunohistochemistry (IHC) was applied using anti-p53 and anti-MDM2 antibodies in the corresponding tissue sections. RESULTS: Overexpression of p53 protein was observed in 39/60 (65%) invasive cases, while 40/60 (66.7%) expressed MDM2 protein. Interestingly, in 26/60 (43%) cases a combined p53/ MDM2 co-expression was detected, whereas in 7/60 (11%) a combined loss of expression was identified (overall co-expression: p=0.999). Concerning in situ carcinomas, co-expression of p53/MDM2 was observed in 7/10 (70%) cases. CONCLUSIONS: MDM2 oncogene overexpression - predominantly due to gene amplification - is a frequent and critical genetic event in both in situ and invasive breast adenocarcinomas. Accumulation of p53 protein in the nucleus of tumor cells harboring mutant p53 - as the result of its overexpression - does not mean necessarily decreased expression of MDM2. MDM2 directly binds to p53 and represses its transcriptional activity promoting p53 degradation. So targeting the molecule, p53's crucial tumor suppressor function is normally regulated.

Intracholecystic papillary-tubular neoplasm in a patient with choledochal cyst: a link between choledochal cyst and gallbladder cancer?

BACKGROUND: Intracholecystic papillary-tubular neoplasms are rare precursor lesions of gallbladder cancer. They were proposed as a separate pathologic entity in 2012 by Adsay et al. for the unification of a variety of mass-forming precursor lesions including papillary adenomas, tubulopapillary adenomas, intestinal adenomas, and others. They are considered homologous to intrapapillary mucinous neoplasms of the pancreas and intrabiliary papillary neoplasms of the common bile duct. In contrast with the commoner flat-type precursor gallbladder cancer lesions, they follow a more indolent clinical course and probably different genetic pathways to carcinogenesis. They are largely uninvestigated with only a handful of studies providing biological and clinical information. Choledochal cysts are dilation of the common bile duct. Diagnosis is usually established during childhood, and only a minority of patients are diagnosed at adulthood. They are of major clinical importance as they are known predisposing factors for biliary carcinogenesis. CASE PRESENTATION: The current report describes a patient with a simultaneous diagnosis of choledochal cyst and intracholecystic papillary-tubular neoplasm. The patient underwent excision of the extrahepatic biliary tree for a Todani I choledochal cyst, and histological examination of the specimen revealed an intracholecystic papillary-tubular neoplasm of the gallbladder. Authors describe diagnostic and clinical course of the patient alongside clinical and biological characteristics of these rare lesions. CONCLUSIONS: To the best of our knowledge, this is the first report of a patient with a simultaneous diagnosis of choledochal cyst and intracholecystic papillary-tubular neoplasm. Those rare lesions shed light on different forms of gallbladder cancer carcinogenesis and its relationship with choledochal cysts and cholestasis.