Faculty Bibliography

PURPOSE/OBJECTIVE:Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined. EXPERIMENTAL DESIGN/METHODS:We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901). RESULTS:PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo. CONCLUSIONS:PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo.

Chronic administration of colchicine remains a mainstay of therapy for patients with Familial Mediterranean Fever (FMF). As this medication is a strong CYP3A4 inhibitor, it has the potential to interact with many routinely used medications. One such medication is clarithromycin, itself a strong inhibitor of the same enzyme, and a typical choice for triple therapy eradication of H. pylori. Various sequelae of colchicine-clarithromycin interaction have been documented and can be expected by prescribing physicians, with rhabdomyolysis, though rare, being among the most serious. Review of cases from a tertiary academic medical center and full PubMed/MEDLINE literature review. Despite the prevalence of diseases treated with clarithromycin and the expected drug interaction with colchicine, only two cases in the literature document clinical rhabdomyolysis due to colchicine-clarithromycin interaction. In neither case, however, were patients undergoing treatment for FMF. Herein, we describe the first two cases in the literature of clinical rhabdomyolysis in FMF patients under colchicine therapy after administration of clarithromycin as part of therapy treating H. pylori infection.

OBJECTIVE:To report on a patient with bilateral meningoencephalocele complicated by bilateral asymptomatic superior semicircular canal dehiscence and discuss dilemmas associated with his successful surgical treatment. STUDY DESIGN/METHODS:Case capsule report. SETTING/METHODS:Tertiary academic medical center. PATIENT/METHODS:A 56-year-old man with 6 years of progressive conductive hearing loss and recent spontaneous cerebrospinal fluid leak from the right ear diagnosed as having bilateral large temporal bone meningoencephalocele (ME) and concomitant bilateral asymptomatic superior semicircular canal dehiscence (SSCD). RESULTS:The right ME was repaired through the middle fossa approach, and the right SSCD was plugged. To avoid the risk associated with bilaterally plugging the SSCDs, the left ME was sealed by subtotal petrosectomy, blind sac closure of the external auditory canal, plugging of the eustachian tube orifice, and obliteration of the residual space with an abdominal fat graft. The herniated brain and meninges were amputated, and the tissue present in the attic was not disrupted. Hearing was reconstructed with a two-staged Bone-anchored Hearing Aid procedure to avoid the risk of cerebrospinal fluid leaking through the skin defect of the Bone-anchored Hearing Aid abutment. CONCLUSION/CONCLUSIONS:Temporal bone ME can be associated with asymptomatic SSCD. We illustrate an example of how patients with bilateral pathologies can be managed effectively with good vestibular, auditory, and cosmetic results.

Surgical resection of extracranial head and neck schwannomas (ECHNS) may be associated with major morbidity, but some ECHNSs can be safely treated expectantly. The aim of this study is to present a large case series and an algorithm for therapeutic decision-making in the management of ECHNS. The clinical records of patients diagnosed and treated for ECHNS between 1999 and 2012 at The Tel Aviv Sourasky Medical Center were reviewed retrospectively. All relevant demographic and medical data were extracted, among them presenting symptoms, surgical approaches, nerve of origin, complications and follow-up. A total of 53 patients with ECHNS were included in this clinical study. There were 29 males and 24 females whose mean age was 49.2 years, and all were treated surgically. The schwannomas originated from the brachial plexus, sympathetic chain, vagus nerve, trigeminal nerve, lip, hypoglossal nerve and larynx. Intracapsular enucleation was performed in 32 (60 %) patients, and the remaining 21 (40 %) patients underwent complete excision of the tumor with the involved nerve segment. Thirty-two patients (60 %) had postoperative neurological deficits. This study provides an algorithm to serve as a guideline in the decision-making process for this patient population. Although there is abundant evidence regarding the efficacy of radiotherapy for acoustic schwannoma, the value of radiotherapy as a treatment alternative for patients with ECNHS, especially those unsuitable for surgery, has not been established and further studies are warranted.

BACKGROUND:Insulin resistance increases during adolescence in those with type 1 diabetes mellitus (T1DM), complicating glycemic control and potentially increasing cardiovascular disease (CVD) risk. Metformin, typically used in type 2 diabetes mellitus (T2DM), is a possible adjunct therapy in T1DM to help improve glycemic control and insulin sensitivity. OBJECTIVE:We hypothesized that metformin would improve metabolic parameters in adolescents with T1DM. DESIGN, SETTING, AND PARTICIPANTS/METHODS:This randomized, double-blinded, placebo-controlled trial included 74 pubertal adolescents (ages: 13-20 yr) with T1DM. Participants were randomized to receive either metformin or placebo for 6 months. Glycated hemoglobin (HbA1c), insulin dose, waist circumference, body mass index (BMI), and blood pressure were measured at baseline, 3 and 6 months, with fasting lipids measured at baseline and 6 months. RESULTS:Total daily insulin dose, BMI z-score and waist circumference significantly decreased at 3 and 6 months compared to baseline within the metformin group, even among normal-weight participants. In the placebo group, total insulin dose and systolic blood pressure increased significantly at 3 months and total insulin dose increased significantly at 6 months. No significant change was observed in HbA1c at any time point between metformin and placebo groups or within either group. CONCLUSIONS:Low-dose metformin likely improves BMI as well as insulin sensitivity in T1DM adolescents, as indicated by a decrease in total daily insulin dose. The decrease in waist circumference indicates that fat distribution is also likely impacted by metformin in T1DM. Further studies with higher metformin doses and more detailed measurements are needed to confirm these results, their underlying mechanisms, and potential impact on CVD in T1DM youth.

Kikuchi-Fujimoto disease (KFD) is an unusual cause of lymphadenopathy and fever. Pregnancy associated with KFD presents as a diagnostic dilemma for clinicians. The diagnosis can be confirmed with invasive biopsies or non-invasive gene analysis. We report a case of a 24-year-old woman at 18 weeks' gestation with a neck lump and histologically confirmed KFD.

BACKGROUND:Hyperhomocysteinemia is associated with increased cardiovascular risk, but treatment with folic acid has no effect on outcome in unselected patient populations. OBJECTIVES/OBJECTIVE:To confirm previous observations on the association of homozygosity for the TT MTHFR genotype with B12 deficiency and endothelial dysfunction, and to investigate whether patients with B12 deficiency should be tested for 677MTHFR genotype. METHODS:We enrolled 100 individuals with B12 deficiency, tested them for the MTHFR C677T polymorphism and measured their homocysteine levels. Forearm endothelial function was checked in 23 B12-deficient individuals (13 with TT MTHFR genotype and 10 with CT or CC genotypes). Flow-mediated dilatation (FMD) was tested after short-term treatment with B12 and folic acid in 12 TT MTHFR homozygotes. RESULTS:Frequency of the TT MTHFR genotype was 28/100 (28%), compared with 47/313 (15%) in a previously published cohort of individuals with normal B12 levels (P = 0.005). Mean homocysteine level was 21.2 ± 16 μM among TT homozygotes as compared to 12.3 ± 5.6 μM in individuals with the CC or CT genotype (P = 0.008). FMD was abnormal ( 6%) in 9/13 TT individuals with B12 deficiency (69%), and was still abnormal in 7/12 of those tested 6 weeks after B12 and folic treatment (58%). CONCLUSIONS:Among individuals with B12 deficiency, the frequency of the TT MTHFR genotype was particularly high. The TT polymorphism was associated with endothelial dysfunction even after 6 weeks of treatment with B12 and folic acid. Based on our findings we suggest that B12 deficiency be tested for MTHFR polymorphism in order to identify potential vascular abnormalities and increased cardiovascular risk.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:The goal of this study was to present a classification based on the degree of pneumatization of the sphenoid sinus in the coronal plane that can be used to instruct preoperative planning for endoscopic endonasal surgery (EES). STUDY DESIGN/METHODS:Observational anatomical study. METHODS:The geometry of sphenoid sinus pneumatization was characterized (n = 204 hemisinus) on high-resolution computed tomography scans, and its associations with the location of the foramen rotundum (FR) and the vidian canal (VC) were measured. Based on these findings, we propose a simple classification of pneumatization of the sphenoid sinus relevant for EES. RESULTS:The lateral recess of the sphenoid sinus was pneumatized lateral to the FR in the coronal plane in 54% of patients. The distance separating the FR and the VC correlated strongly with the depth of the lateral recess. Based on these findings, we propose three types of pneumatization: type I, where the pneumatization extends from the midline to the medial edge of the VC (25%); type II, where the pneumatization reaches the medial edge of the FR (39%); and type III, where the pneumatization extends beyond the medial border of the FR (37%). CONCLUSIONS:The proposed sphenoid sinus pneumatization classification in the coronal plane is simple and reproducible. It predicts the distance between vidian and maxillary nerve, determines the size of the surgical window to access the middle cranial fossa transnasally, and instructs on the potential risk to neurovascular structures during surgery.