A predictive survival model for patients with head and neck squamous cell carcinoma treated with immune check point inhibitors.

BACKGROUND: ICIs have expanded treatment options for HNSCC. A minority of the patients respond to these expensive treatments. PATIENTS AND METHODS: This is a single institutional retrospective review on 121 unresectable or metastatic HNSCC patients treated with ICIs. We predicted that inflammatory markers available through routine blood work, in addition to clinical characteristics may divide patients into groups more or less likely to respond to these agents. Here we develop and internally validate our nomogram to predict survival in patients treated with ICIs.

A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma.

Purpose Vorinostat is a potent HDAC inhibitor that sensitizes head and neck squamous cell carcinoma (HNSCC) to cytotoxic therapy while sparing normal epithelium. The primary objective of this Phase I study was to determine the maximally tolerated dose (MTD) and safety of Vorinostat in combination with standard chemoradiation therapy treatment in HNSCC. Patients and Methods Eligible patients had pathologically confirmed Stage III, IVa, IVb HNSCC, that was unresectable or borderline resectable involving the larynx, hypopharynx, nasopharynx, and oropharynx. Vorinostat was administered at the assigned dosage level (100-400 mg, three times weekly) in a standard 3 + 3 dose escalation design. Vorinostat therapy began 1 week prior to initiation of standard, concurrent chemoradiation therapy and continued during the entire course of therapy. Results Twenty six patients met eligibility criteria and completed the entire protocol. The primary tumor sites included tonsil (12), base of tongue (9), posterior pharyngeal wall (1), larynx (4) and hypopharynx (3). Of the 26 patients, 17 were HPV-positive and 9 were HPV-negative. The MTD of Vorinostat was 300 mg administered every other day. Anemia (n = 23/26) and leukopenia (n = 20/26) were the most commonly identified toxicities. The most common Grade3/4 events included leukopenia (n = 11) and lymphopenia (n = 17). No patient had Grade IV mucositis, dermatitis or xerostomia. The median follow time was 33.8 months (range 1.6-82.9 months). Twenty four of 26 (96.2%) patients had a complete response to therapy. Conclusion Vorinostat in combination with concurrent chemoradiation therapy is a safe and highly effective treatment regimen in HNSCC. There was a high rate of complete response to therapy with toxicity rates comparable, if not favorable to existing therapies. Further investigation in Phase II and III trials is strongly recommended.

Phosphorylation of Nanog is essential to regulate Bmi1 and promote tumorigenesis.

Emerging evidence indicates that Nanog is intimately involved in tumorigenesis, in part, through regulation of the cancer-initiating cell (CIC) population. However, the regulation and role of Nanog in tumorigenesis are still poorly understood. In this study, human Nanog was identified to be phosphorylated by human protein kinase Cɛ at multiple residues, including T200 and T280. Our work indicated that phosphorylation at T200 and T280 modulates Nanog function through several regulatory mechanisms. Results with phosphorylation-insensitive and phosphorylation-mimetic mutant Nanog revealed that phosphorylation at T200 and T280 enhance Nanog protein stability. Moreover, phosphorylation-insensitive T200A and T280A mutant Nanog had a dominant-negative function to inhibit endogenous Nanog transcriptional activity. Inactivation of Nanog was due to impaired homodimerization, DNA binding, promoter occupancy and p300, a transcriptional co-activator, recruitment resulting in a defect in target gene-promoter activation. Ectopic expression of phosphorylation-insensitive T200A or T280A mutant Nanog reduced cell proliferation, colony formation, invasion, migration and the CIC population in head and neck squamous cell carcinoma (HNSCC) cells. The in vivo cancer-initiating ability was severely compromised in HNSCC cells expressing phosphorylation-insensitive T200A or T280A mutant Nanog; 87.5% (14/16), 12.5% (1/8), and 0% (0/8) for control, T200A, and T280A, respectively. Nanog occupied the Bmi1 promoter to directly transactivate and regulate Bmi1. Genetic ablation and rescue experiments demonstrated that Bmi1 is a critical downstream signaling node for the pleiotropic, pro-oncogenic effects of Nanog. Taken together, our study revealed, for the first time, that post-translational phosphorylation of Nanog is essential to regulate Bmi1 and promote tumorigenesis.

Population-based prevalence of symptomatic and asymptomatic astrovirus infection in rural Mayan infants.

Symptomatic and asymptomatic astrovirus infection was prospectively determined in a 3-year birth cohort of Mayan infants. Stool samples from 271 infants and 268 older siblings were tested for astrovirus, adenovirus 40/41, rotavirus and Salmonella, Shigella and Campylobacter species. Concurrent diarrhea, vomiting, fever, or anorexia were noted. Astrovirus was detected in 164 infants (61%) and 20 siblings (7%). Rotavirus (4%) and adenovirus 40/41 (13%) were isolated less frequently. Of all diarrheal episodes reported at a visit, 26% (78/305) were associated with astrovirus; 17% (78/452) of astrovirus infections were associated with diarrhea and 9% with other symptoms. Only diarrhea was associated with astrovirus infection (odds ratio, 1.4; 95% confidence interval [CI], 1.07-1.92; P = .01). Of infants with astrovirus, 70% shed at multiple visits over a period of 2-17 weeks (median, 5). The point prevalence of astrovirus infection was significantly higher among infants than siblings (relative risk, 6.18; 95% CI, 3.93-9.72; P < .0001, chi2). Astrovirus was identified throughout the year, peaked in March and May, and decreased in September. In this population, astrovirus was the most common enteric pathogen isolated; symptomatic infection was prevalent among infants.

Development of chemiluminescent probe hybridization, RT-PCR and nucleic acid cycle sequencing assays of Sabin type 3 isolates to identify base pair 472 Sabin type 3 mutants associated with vaccine associated paralytic poliomyelitis.

Sabin type 3 polio vaccine virus is the most common cause of poliovaccine associated paralytic poliomyelitis. Vaccine associated paralytic poliomyelitis cases have been associated with Sabin type 3 revertants containing a single U to C substitution at bp 472 of Sabin type 3. A rapid method of identification of Sabin type 3 bp 472 mutants is described. An enterovirus group-specific probe for use in a chemiluminescent dot blot hybridization assay was developed to identify enterovirus positive viral lysates. A reverse transcription-polymerase chain reaction (RT-PCR) assay producing a 319 bp PCR product containing the Sabin type 3 bp 472 mutation site was then employed to identify Sabin type 3 isolates. Chemiluminescent nucleic acid cycle sequencing of the purified 319 bp PCR product was then employed to identify nucleic acid sequences at bp 472. The enterovirus group probe hybridization procedure and isolation of the Sabin type 3 PCR product were highly sensitive and specific; nucleic acid cycle sequencing corresponded to the known sequence of stock Sabin type 3 isolates. These methods will be used to identify the Sabin type 3 reversion rate from sequential stool samples of infants obtained after the first and second doses of oral poliovirus vaccine.