Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. HYPOTHESIS: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. DESIGN: Cross-sectional study. SETTING: University Research Laboratory. SUBJECTS: 158 patients with nHH/KS. METHODS: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. MAIN OUTCOME MEASURES: P/LP variants in nHH/KS genes. RESULTS: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. CONCLUSION: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.

Delays in Colorectal Cancer Screening for Latino Patients: The Role of Immigrant Healthcare in Stemming the Rising Global Incidence of Colorectal Cancer.

The significant global burden of colorectal cancer accentuates disparities in access to preventive healthcare in most low- and middle-income countries (LMICs) as well as large sections of underserved populations within high-income countries. The barriers to colorectal cancer screening in economically transitioning Latin America are multiple. At the same time, immigration from these countries to the USA continues to increase. This case highlights the delays in diagnosis experienced by a recent immigrant from a country with no established colorectal cancer screening program, to an immigrant population in the USA with similar poor screening coverage. We discuss common challenges faced by Latinos in their home countries and the USA, as well as strategies that could be implemented to improve screening coverage in US immigrant populations.

Colorectal Cancer Screening Programs in Latin America: A Systematic Review and Meta-Analysis.

Importance: Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally, with increasing incidence and mortality in Latin America. CRC screening programs can reduce disease burden, but information on screening programs in Latin America is limited. Objective: To describe characteristics (eg, type of program, uptake, neoplastic yield) of CRC screening programs in Latin America. Data Sources: PubMed, Ovid MEDLINE, EMBASE, Cochrane, PsycINFO, Web of Science Core Collection, LILACS, and SciELO were searched from inception to February 2023. Relevant references from bibliographies, conference proceedings, and gray literature were considered. The search strategy included English, Spanish, and Portuguese terms. Study Selection: Included were studies of CRC screening programs in Latin America using fecal immunochemical test (FIT) or colonoscopy as the primary screening method. Four reviewers independently assessed study eligibility based on titles, with review of abstracts and full texts as needed. Data Extraction and Synthesis: Guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed for data abstraction and quality assessment. Descriptive information was extracted, and data were pooled using a random-effects model. Main outcomes and Measures: Program performance indicators included rates of participation and FIT positivity, adenoma detection rate (ADR), advanced adenoma detection rate (AADR), CRC detection rate, and colonoscopy quality indicators. Results: There were 17 studies included from upper middle-income and high-income countries in Latin America with a total of 123 929 participants. Thirteen studies used FIT as the initial screening method, whereas 4 used screening colonoscopy. The participation rate in FIT-based programs was 85.8% (95% CI, 78.5%-91.4%). FIT positivity rates were 15.2% (95% CI, 9.6%-21.8%) for the 50-ng/mL threshold and 9.7% (95% CI, 6.8%-13.0%) for the 100-ng/mL threshold. For FIT-based studies, the pooled ADR was 39.0% (95% CI, 29.3%-49.2%) and CRC detection rate was 4.9% (95% CI, 2.6%-7.9%); for screening colonoscopy-based studies, the pooled ADR was 19.9% (95% CI, 15.5%-24.8%) and CRC detection rate was 0.4% (95% CI, 0.1%-0.8%). Conclusions and Relevance: This systematic review and meta-analysis suggests that CRC screening in upper middle-income countries in Latin America is feasible, detecting rates of neoplasia comparable with those of high-income regions. Population-based screening programs should be developed or enhanced in these settings. There is a knowledge gap regarding feasibility and yield of screening programs in lower middle-income countries.

Investigation of subfertility in the female Nsmf knockout mouse.

OBJECTIVE: To study if a pituitary or ovarian defect contributes to subfertility of the female Nsmf knockout (KO) mouse, an animal model of the hypogonadotropic hypogonadism gene NSMF. DESIGN: Analysis of hypothalamic, pituitary and ovarian gene expression at baseline, serum gonadotropin levels before and after gonadotropin-releasing hormone (GnRH) stimulation, ovarian response and implantation after superovulation, gonadotropin effects after ovariectomy, and ovarian NSMF protein expression. SETTING: University research laboratory. PATIENTS: None; mice were used. INTERVENTIONS: Gonadotropin-releasing hormone stimulation, superovulation, and ovariectomy in separate experiments. MAIN OUTCOME MEASURES: Gene expression in the hypothalamus, pituitary, and ovary; ovarian response and implantation after superovulation; serum gonadotropins after GnRH stimulation and ovariectomy; Western blot to measure ovarian NSMF expression. RESULTS: We found increased hypothalamic Kiss1, Gnrh1, and Jak2 mRNA expression in female Nsmf KO vs. wild type (WT) mice. However, pituitary gonadotropin, and GnRH receptor gene expression was not affected, and serum gonadotropin levels were normal. Gonadotropins increased after ovariectomy for both groups. Baseline Kiss1, Fshr, Prkaca, Prkar1a, and Gdf9 ovarian mRNA expression was increased and Cyp19a1 expression was decreased in Nsmf KO mice, while superovulated Nsmf KO mice had reduced ovarian Kiss1r, Prkar1a, and Fshr mRNA expression, 50% less oocytes, and normal implantation. Western blot demonstrated NSMF protein expression in the ovary of WT mice. CONCLUSIONS: Altered hypothalamic and ovarian gene expression was demonstrated in female Nsmf KO mice. It is possible that increased hypothalamic Gnrh1 and Kiss1 mRNA expression could compensate for reduced NSMF enabling a normal pituitary gonadotropin response. Impaired superovulation response, altered ovarian gene expression, and decreased number of oocytes indicate ovarian dysfunction, but a uterine factor cannot be excluded. These findings provide an anatomic basis for future mechanistic studies of subfertility in female Nsmf KO mice.

The microbial genotoxin colibactin exacerbates mismatch repair mutations in colorectal tumors.

Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin. Colibactin-producing E. coli promote colorectal cancer (CRC) in preclinical models, and in vitro induce a specific mutational signature that is also detected in human CRC genomes. Yet, how colibactin exposure affects the mutational landscape of CRC in vivo remains unclear. Here we show that colibactin-producing E. coli-driven colonic tumors in mice have a significantly higher SBS burden and a larger percentage of these mutations can be attributed to a signature associated with mismatch repair deficiency (MMRd; SBS15), compared to tumors developed in the presence of colibactin-deficient E. coli. We found that the synthetic colibactin 742 but not an inactive analog 746 causes DNA damage and induces transcriptional activation of p53 and senescence signaling pathways in non-transformed human colonic epithelial cells. In MMRd colon cancer cells (HCT 116), chronic exposure to 742 resulted in the upregulation of BRCA1, Fanconi anemia, and MMR signaling pathways as revealed by global transcriptomic analysis. This was accompanied by increased T>N single-base substitutions (SBS) attributed to the proposed pks+E. coli signature (SBS88), reactive oxygen species (SBS17), and mismatch-repair deficiency (SBS44). A significant co-occurrence between MMRd SBS44 and pks-associated SBS88 signature was observed in a large cohort of human CRC patients (n=2,945), and significantly more SBS44 mutations were found when SBS88 was also detected. Collectively, these findings reveal the host response mechanisms underlying colibactin genotoxic activity and suggest that colibactin may exacerbate MMRd-associated mutations.

Intestinal bacteria and colorectal cancer: etiology and treatment.

The etiology of colorectal cancer (CRC) is influenced by bacterial communities that colonize the gastrointestinal tract. These microorganisms derive essential nutrients from indigestible dietary or host-derived compounds and activate molecular signaling pathways necessary for normal tissue and immune function. Associative and mechanistic studies have identified bacterial species whose presence may increase CRC risk, including notable examples such as Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis, and pks+ E. coli. In recent years this work has expanded in scope to include aspects of host mutational status, intra-tumoral microbial heterogeneity, transient infection, and the cumulative influence of multiple carcinogenic bacteria after sequential or co-colonization. In this review, we will provide an updated overview of how host-bacteria interactions influence CRC development, how this knowledge may be utilized to diagnose or prevent CRC, and how the gut microbiome influences CRC treatment efficacy.

The Clinical Utility and Cost of Routine Staging Exam under Anesthesia for Oral Cavity Squamous Cell Carcinoma.

INTRODUCTION: The standard complete evaluation of patients with head and neck squamous cell carcinoma (HNSCC) has included a staging exam under anesthesia (EUA) since the 1970s. The EUA for all sites of HNSCC has historically consisted of panendoscopy for the purpose of diagnostic biopsy, accurate staging of primary disease, and identification of second primary tumors. However, due to the accessibility of the oral cavity, the sole purpose of EUA for tumors of this site is to identify second primary tumors. Since the EUA became the gold standard for evaluation of HNSCC, there have been significant advancements in less invasive technologies such as CT, PET-CT, MRI, and fiberoptic examination. In this study, we sought to determine the value to patient care and cost-effectiveness of EUA in patients with oral cavity squamous cell carcinoma (OCSCC). METHODS: A retrospective chart review identified 77 patients who underwent EUA for OCSCC. RESULTS: The most common subsites were the oral tongue and floor of mouth (59.7% and 24.7% respectively). All underwent direct laryngoscopy, 94.8% underwent esophagoscopy, and 20.8% underwent flexible transnasal examination in clinic prior to EUA. For 90.9% of patients, the EUA did not change initial T-staging based on clinical examination and imaging. The remaining 9.1% of patients were upstaged after EUA, however this change did not impact the treatment plan. Second primary tumors were identified in 3.9% of patients, all were found in either the oral cavity or oropharynx, and were also identified with clinical examination or imaging. Analysis of patient charges determined an average cost of $8,022.93 per patient under the current paradigm involving EUA, however with a new algorithm eliminating mandatory EUA average cost decreases to $1,448.44. CONCLUSION: Formal EUA has historically been the gold standard for all HNSCC tumors. However, when performed for cases of oral cavity carcinoma, it is safe and cost effective to limit its use to select clinical scenarios.

Perplexing findings during laparoscopic evaluation for tubal factor infertility resulting from a gastric leak after bariatric surgery: A case report.

Tubal factor is the primary type of female infertility, accounting for 25-35% of cases. Common causes include inflammation due to pelvic inflammatory disease, septic abortion, tubal surgery, and surgical adhesions. Bariatric surgery is becoming increasingly popular as rates of obesity rise, with over 256,000 surgeries performed in 2019. Half of these procedures were performed on women of reproductive age. This is the first reported case of a patient with tubal factor infertility as a result of a gastric leak from a remote sleeve gastrectomy that led to extensive abdominal and pelvic adhesions.

Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival.

Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells (hTS/Men1-/-). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development in comparison with control Men1-/- and Men1+/ΔN3-8 mice. We also observed a decrease in overall survival of hTS/Men1+/- and hTS/Men1-/- mice as compared with control mice. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics, and was associated with a higher frequency of somatic mutations, DNA damage, and genomic instability. In addition, we analyzed the survival of 88 patients with PanNETs and observed that high TS protein expression independently predicted worse clinical outcomes. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1-mutant background. This work will refocus attention on new strategies to inhibit TS activity for PanNET treatment.

Chronic Laryngotracheal Granulomatous Disease Secondary to Sporothrix schenckii in an Immunocompromised Patient.

OBJECTIVE: To describe a rare presentation of laryngotracheal granulomatous disease secondary to sporotrichosis. METHODS: The authors report a case of laryngeal sporotrichosis in an immunocompromised patient, with accompanying endoscopic images and pathology. RESULTS/CASE: A 72-year-old immunocompromised female with a history of rose-handling presented with a year of hoarseness and breathy voice. Flexible nasolaryngoscopy showed diffuse nodularity; biopsy of the lesions demonstrated granulomatous inflammatory changes, and fungal culture grew Sporothrix schenkii. Long-term itraconazole treatment was initiated, with improvement in dysphonia and few residual granulomas on follow-up examination. CONCLUSION: When evaluating granulomatous disease of the airway, a broad differential including infectious or inflammatory etiologies should be considered, especially in immunocompromised patients. Adequate tissue samples should be collected to facilitate special staining. The current recommendations for laryngeal sporotrichosis include treatment with a prolonged course of itraconazole.

Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism.

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

Shining a Light on Colibactin Biology.

Colibactin is a secondary metabolite encoded by the pks gene island identified in several Enterobacteriaceae, including some pathogenic Escherichia coli (E. coli) commonly enriched in mucosal tissue collected from patients with inflammatory bowel disease and colorectal cancer. E. coli harboring this biosynthetic gene cluster cause DNA damage and tumorigenesis in cell lines and pre-clinical models, yet fundamental knowledge regarding colibactin function is lacking. To accurately assess the role of pks+ E. coli in cancer etiology, the biological mechanisms governing production and delivery of colibactin by these bacteria must be elucidated. In this review, we will focus on recent advances in our understanding of colibactin's structural mode-of-action and mutagenic potential with consideration for how this activity may be regulated by physiologic conditions within the intestine.

Non-HPV-Related Head and Neck Squamous Cell Carcinoma in a Young Patient Cohort.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is rare in patients younger than 40 years. Many practitioners suspect HNSCC is a more aggressive disease in this age group, and perhaps increasing in incidence; however, there are scant and conflicting data to support this assertion. We sought to compare outcomes for young patients with non-human papillomavirus (HPV)-related HNSCC to those of older patients. METHODS: A retrospective chart review of patients with HNSCC treated from 2004 to 2016 at 2 tertiary referral centers. Patients aged 18 to 40 with p16-negative HNSCC were included in the young patient cohort (n = 59). A randomly selected stage- and subsite-matched cohort aged 55 to 65 was analyzed for comparison (n = 114). RESULTS: When considering all patients with HNSCC, patients younger than 40 were more likely to have oral tongue cancer (62.7%) compared to patients age 55 to 65 (16.9%). When an older patient cohort was stage- and subsite-matched to the young patient cohort, there were more never smokers (49.2% vs 17.5% of older patients, P < .01) and females (40.7% vs 24.6% of older patients, P = .028) in the young patient group. The young patient cohort had better average overall survival than the older group (14.4 vs 8.1 years, respectively, P = .02), but similar average disease-free survival (6.2 years vs 6.6 years, respectively, P = .67); 50.9% of young patients had tumors with adverse histologic features versus 42.0% of older patients (P = .28). The young patients demonstrated a superior average conditional survival after recurrence (9.8 years vs 3.2 years for older patients, P < .01). CONCLUSIONS: Despite the limitations of study design, these data suggest that young patients who develop non-HPV-related HNSCC tend to have similarly aggressive disease, but longer overall survival and better survival after recurrence. These findings may be attributable to better overall health as evidenced by fewer comorbidities.

Prevalence and Associated Dietary Factors of Rome IV Functional Gastrointestinal Disorders in Rural Western Honduras.

BACKGROUND: The literature is limited regarding the prevalence of functional gastrointestinal disorders (FGIDs) in Central America, and the role of dietary factors. METHODS: The Rome IV diagnostic questionnaire and National Cancer Institute Diet History questionnaire were administered in one-on-one interviews to a distributed cross section of the general adult population of Western Honduras. Our aim was to estimate prevalence of common FGIDs and symptoms and their relationships to dietary habits. RESULTS: In total, 815 subjects were interviewed, of whom 151 fulfilled criteria for an FGID (18.5%). Gastroduodenal FGIDs were noted in 9.4%, with epigastric pain syndrome (EPS) more common than postprandial distress syndrome, 8.5% versus 1.6%. Among bowel disorders, functional abdominal bloating (FAB) was most prevalent (6.3%), followed by irritable bowel syndrome (3.6%), functional diarrhea (FDr; 3.4%), and functional constipation (1.1%). A significant inverse association was noted between regular bean intake and any FGID (OR 0.41, 95% CI 0.27-0.63), driven by IBS and FDr. Vegetable consumption was associated with lower prevalence of functional diarrhea (OR 0.12; 95% CI 0.04-0.35) and any diarrheal disorder (OR 0.11; 95% CI 0.04-0.31). Subjects with a median daily intake of ≥ 4 corn tortillas had 1.75 (95% CI 1.22-2.50) times the odds of having any FGID. CONCLUSIONS: FGIDs were common in this rural low-resource setting in Central America, with an intriguing distribution of specific FGIDs. EPS and FAB were common, but IBS was not. Local dietary factors were associated with specific FGIDs, suggesting that diet may play a role in global variations of FGIDs.

Abusing science.

The perversion of science in the interest of ideology and greed is not a new phenomenon, but a public that is largely scientifically illiterate now is besieged by "alternative facts" and well-designed efforts to discredit legitimate science on topics ranging from vaccines to climate change. Here, we examine three topics rooted in biology and biomedicine-creationism, harms from tobacco, and opioid addiction-to show that those purveying misinformation employ a consistent pattern of intellectual dishonesty to delegitimize science that challenges their ideological positions. Individual scientists and the scientific community at large should confront and counter these attacks on the intellectual integrity that is at the heart of the scientific enterprise.

PRAS40 Phosphorylation Correlates with Insulin-Like Growth Factor-1 Receptor-Induced Resistance to Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells.

EGFR inhibitors have shown poor efficacy in head and neck squamous cell carcinoma (HNSCC) with demonstrated involvement of the insulin-like growth factor-1 receptor (IGF1R) in resistance to EGFR inhibition. IGF1R activates the PI3K-Akt pathway, which phosphorylates proline-rich Akt substrate of 40 kDa (PRAS40) to cease mTOR inhibition resulting in increased mTOR signaling. Proliferation assays separated six HNSCC cell lines into two groups: sensitive to EGFR inhibition or resistant; all sensitive cell lines demonstrated reduced sensitivity to EGFR inhibition upon IGF1R activation. Reverse phase protein microarray analysis and immunoblot identified a correlation between increased PRAS40 phosphorylation and IGFR-mediated resistance to EGFR inhibition. In sensitive cell lines, PRAS40 phosphorylation decreased 44%-80% with EGFR inhibition and was restored to 98%-196% of control by IGF1R activation, while phosphorylation was unaffected in resistant cell lines. Possible involvement of mTOR in this resistance mechanism was demonstrated through a similar pattern of p70S6K phosphorylation. However, addition of temsirolimus, an mTORC1 inhibitor, was insufficient to overcome IGF1R-mediated resistance and suggested an alternative mechanism. Forkhead box O3a (FOXO3a), which has been reported to complex with PRAS40 in the cytoplasm, demonstrated a 6-fold increase in nuclear to cytoplasmic ratio upon EGFR inhibition that was eliminated with concurrent IGF1R activation. Transcription of FOXO3a-regulated TRAIL and PTEN-induced putative kinase-1 (PINK1) was increased with EGFR inhibition in sensitive cell lines; this effect was diminished with IGF1R stimulation. IMPLICATIONS: These data suggest PRAS40 may play an important role in IGF1R-based therapeutic resistance to EGFR inhibition, and this likely occurs via inhibition of FOXO3a-mediated proapoptotic gene transcription.

Perivascular epithelioid cell tumor (PEComa) of the pterygopalatine fossa.

Perivascular epithelioid cell tumors (PEComas) are a rare group of mesenchymal tumors associated with tuberous sclerosis. These tumors are typically treated with resection and rarely recur or exhibit malignant behavior. A 78-year-old woman presented with an incidentally discovered pterygopalatine fossa/retroantral mass. Excisional biopsy was performed and revealed pathology consistent with PEComa. Upon review of the literature, there have been 43 reported cases of PEComa of the head and neck. There is only one previously reported case of PEComa in the skull base, and none reported in the pterygopalatine fossa. Of note, the previously reported case of skull base PEComa involved an aggressive tumor with widespread metastasis. Here, we report the first case of a PEComa of the pterygopalatine fossa/retroantral region, which was treated conservatively. This rare pathology should be considered in the differential diagnosis for atypical skull base tumors.

Antitumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma.

OBJECTIVES: The insulin-like growth factor-1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R-TKIs, OSI-906 and BMS-754807, were evaluated in HNSCC cell lines in vitro. METHODS: Clinical outcome data and tissue microarray immunohistochemistry were used to generate IGF1R expression-specific survival curves. Immunoblot, alamarBlue proliferation assay, trypan blue exclusion viability test, clonogenic assay, flow cytometry, and reverse phase protein array (RPPA) were used to evaluate in vitro responses to IGF1R-TKIs. RESULTS: For patients with stage III/IV OCSCC, higher IGF1R expression was associated with poorer overall 5-year survival (P = 0.029). Both BMS-754807 and OSI-906 caused dose-dependent inhibition of IGF1R and Akt phosphorylation and inhibited proliferation; BMS-754807 was more potent than OSI-906. Both drugs reduced HNSCC cell viability; only OSI-906 was able to eliminate all viable cells at 10 µM. The two drugs similarly inhibited clonogenic cell survival. At 1 µM, only BMS-754807 caused a fourfold increase in the basal apoptotic rate. RPPA demonstrated broad effects of both drugs on canonical IGF1R signaling pathways and also inhibition of human epidermal growth factor receptor-3 (HER3), Src, paxillin, and ezrin phosphorylation. CONCLUSION: OSI-906 and BMS-754807 inhibit IGF1R activity in HNSCC cell lines with reduction in prosurvival and proliferative signaling and with concomitant antiproliferative and proapoptotic effects. Such antagonists may have utility as adjuvants to existing therapies for HNSCC. LEVEL OF EVIDENCE: NA Laryngoscope, 130:1470-1478, 2020.

The potential for malignancy from atopic disorders and allergic inflammation: A systematic review and meta-analysis.

OBJECTIVE: While chronic inflammation is a well-established risk factor for malignancy, studies evaluating the relationship between allergic inflammation and cancer have revealed conflicting results. Here, we aimed to assess the association between allergic inflammation in the lung (asthma), skin (eczema) or oesophagus (eosinophilic oesophagitis; EoE) and cancer at the organ site. DESIGN: We conducted a systematic review of the literature to identify observational studies (case-control, cohort and cross-sectional) evaluating the association between asthma and lung cancer, eczema and skin cancer, or EoE and oesophageal cancer. Random-effects meta-analysis was performed to define pooled estimates of effects. DATA SOURCES: PubMed, EMBASE and Web of Science. ELIGIBILITY CRITERIA FOR SELECTION: Included studies evaluated the incidence of cancer. RESULTS: Thirty-two studies met the inclusion criteria, 27 in the lung, four in the skin and one in the oesophagus. Meta-analysis of the three studies with prospective data collection of asthma diagnosis revealed a positive association with incident lung cancer (OR 1.27, 95% CI 1.09-1.44); however, this result was not consistently supported by the larger dataset of retrospective studies (OR 1.37, 95% CI 0.90-1.83). Overall, studies in the lung displayed significant heterogeneity (I2 98%, P < .0001), but no significant effect modification on the association between asthma and lung cancer was identified for the variables of sex, smoking or study design. Meta-analysis could not be applied to the four papers reviewed in the skin, but three suggested an association between eczema and non-melanoma skin cancer, while the remaining study failed to identify an association between melanoma and eczema. A single study meeting inclusion criteria showed no association between EoE and oesophageal malignancy. CONCLUSIONS: The current data cannot exclude the possibility of an association between atopy and malignancy the lung, skin and oesophagus. The relationship between allergy and cancer should be explored further in prospective studies that any association identified between these conditions has the potential for significant public health implications.