Primary combined small cell carcinoma of larynx with lateralized histologic components and corresponding side-specific neck nodal metastasis: report of a unique case and review of literature

Combined small cell carcinoma (neuroendocrine) of the larynx has been rarely reported in the literature, and included in the current WHO classification. We hereby report an unusual case of combined carcinoma of the larynx; composed mainly of small cell neuroendocrine carcinoma nearly confined to the right side (mainly involving supraglottis extending to glottis) with synchronous minor in-situ and invasive squamous cell carcinoma component located on the left side of larynx (mainly glottis). Interestingly, this side-specific distribution of tumor was recapitulated in its metastatic nodal spread; so that right cervical lymph nodes showed only metastatic small cell carcinoma and left cervical lymph nodes only metastatic squamous cell carcinoma. To the best of our knowledge, the present case is the seventeenth reported case of a combined small cell carcinoma of larynx, second case in which individual tumor components were lateralized on either side of larynx, and the first case in which this side-specificity of tumor was reflected in its metastatic neck nodal spread. This report emphasizes the value of accurate pathologic diagnosis including diversity in differentiation and localization of laryngeal tumors, and underscores the need for thorough pathologic examination of bilateral laryngeal tumors. The pre-operative diagnostic yield of small cell carcinoma (pure or combined) can be enhanced by including deeper submucosal biopsies on laryngoscopy in all those cases in which the extent of disease on imaging is disproportionately larger than the apparent mucosal involvement on laryngoscopy. This approach can facilitate selection of neoadjuvant or palliative chemo-radiotherapy in large or unresectable tumors.     

A polyclonal antibody to the prepore loop of transient receptor potential vanilloid type 1 blocks channel activation

Transient receptor potential vanilloid type 1 (TRPV1) can be activated by multiple chemical and physical stimuli such as capsaicin, anandamide, protons, and heat. Capsaicin interacts with the binding pocket constituted by transmembrane regions 3 and 4, whereas protons act through residues in the prepore loop of TRPV1. Here, we report on characterization of polyclonal and monoclonal antibodies to the prepore loop of TRPV1. A rabbit anti-rat TRPV1 polyclonal antibody (Ab-156H) acted as a full antagonist of proton activation (IC(50) values for pH 5 and 5.5 were 364.68 +/- 29.78 and 28.31 +/- 6.30 nM, respectively) and as a partial antagonist of capsaicin, heat, and pH 6 potentiated chemical ligand (anandamide and capsaicin) activation (50-79% inhibition). Ab-156H antagonism of TRPV1 is not affected by the conformation of the capsaicin-binding pocket because it is equally potent at wild-type (capsaicin-sensitive) rat TRPV1 and its T550I mutant (capsaicin-insensitive). With the goal of generating monoclonal antagonist antibodies to the prepore region of human TRPV1, we used a recently developed rabbit immunization protocol. Although rabbit polyclonal antiserum blocked human TRPV1 activation, rabbit monoclonal antibodies (identified on the basis of selective binding to Chinese hamster ovary cells expressing human TRPV1) did not block activation by either capsaicin or protons. Thus, rabbit polyclonal antibodies against rat and human TRPV1 prepore region seem to partially lock or stabilize the channel in the closed state, whereas rabbit anti-human TRPV1 monoclonal antibodies bind to the prepore region but do not lock or stabilize the channel conformation.     

MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's disease

BACKGROUND: To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohn's disease (CD). METHODS: A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case-control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid-dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. RESULTS: A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6-12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8-22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8-fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82-3.9; P = 0.14). CONCLUSIONS: The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy.     

An 11‐country study to benchmark the implementation of recommended nutrition policies by national governments using the Healthy Food Environment Policy Index, 2015‐2018

The Healthy Food Environment Policy Index (Food‐EPI) aims to assess the extent of implementation of recommended food environment policies by governments compared with international best practices and prioritize actions to fill implementation gaps. The Food‐EPI was applied in 11 countries across six regions (2015‐2018). National public health nutrition panels (n = 11‐101 experts) rated the extent of implementation of 47 policy and infrastructure support good practice indicators by their government(s) against best practices, using an evidence document verified by government officials. Experts identified and prioritized actions to address implementation gaps. The proportion of indicators at “very low if any,” “low,” “medium,” and “high” implementation, overall Food‐EPI scores, and priority action areas were compared across countries. Inter‐rater reliability was good (GwetAC2 = 0.6‐0.8). Chile had the highest proportion of policies (13%) rated at “high” implementation, while Guatemala had the highest proportion of policies (83%) rated at “very low if any” implementation. The overall Food‐EPI score was “medium” for Australia, England, Chile, and Singapore, while “very low if any” for Guatemala. Policy areas most frequently prioritized included taxes on unhealthy foods, restricting unhealthy food promotion and front‐of‐pack labelling. The Food‐EPI was found to be a robust tool and process to benchmark governments' progress to create healthy food environments.     

Depression as a risk factor for mortality after acute myocardial infarction

The ENRICHD clinical trial, which compared an intervention for depression and social isolation to usual care, failed to decrease the rate of mortality and recurrent acute myocardial infarction (AMI) in post-AMI patients. One explanation for this is that depression was not associated with increased mortality in these patients. The purpose of this study was to determine if depression was associated with an increased risk of mortality in a subsample of the ENRICHD trial's depressed patients compared with a group of nondepressed patients recruited for an ancillary study. Three hundred fifty-eight depressed patients with an acute AMI from the ENRICHD clinical trial and 408 nondepressed patients who met the ENRICHD medical inclusion criteria were followed for up to 30 months. There were 47 deaths (6.1%) and 57 nonfatal AMIs (7.4%). After adjusting for other risk factors, depressed patients were at higher risk for all-cause mortality (hazard ratio 2.4, 95% confidence interval 1.2 to 4.7) but not for nonfatal recurrent infarction (hazard ratio 1.2, 95% confidence interval 0.7 to 2.0) compared with nondepressed patients. In conclusion, depression was an independent risk factor for death after AMI, but it did not have a significant effect on mortality until nearly 12 months after the acute event, nor did it predict nonfatal recurrent infarction.