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We present a 24-year-old combat veteran who underwent extensive work-up for elevated aminotransferases, including liver biopsy, with no underlying pathology identified. Subsequent investigations showed elevated creatinine kinase and aldolase. The patient was later diagnosed with biopsy-proven dysferlin-deficient muscular dystrophy. Persistent transaminase elevation despite negative liver work-up should prompt clinicians to consider extrahepatic sources of enzyme elevation. Promptly correlating aminotransferase elevation with musculoskeletal pathology may present an opportunity for clinicians to detect myopathies such as muscular dystrophy in their preclinical stages.

Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.

A 79-year-old female was evaluated in consultation for painless jaundice. Past medical history was signifi cant for obstructive jaundice secondary to distal bile duct stricture from a benign pancreatic head mass status postpancreaticoduodenectomy. She later developed recurrent cholangitis and during surgical exploration was found to have a left hepatic duct bifurcation stricture that was resected. Four years later the patient presented with fatigue, weight loss, and painless jaundice. Laboratory investigation showed elevated total bilirubin of 9.4 mg/dL, alanine aminotransferase 645 IU/L, aspartate aminotransferase 1088 IU/L, and alkaline phosphatase 183 IU/L. Endoscopic retrograde cholangiopancreatography (ERCP) was performed to evaluate for possible recurrent biliary stricture. A pediatric colonoscope was utilized to access the aff erent jejunal limb with the hepaticojejunostomy. Th e aff erent limb was intubated and the colonoscope was advanced freely with excellent visualization of the intrahepatic bile ducts at the anastomosis site (Fig. 1). Th e site of previous hepatic duct stricture was identifi ed (Fig. 2) with no recurrence of stricture noted. Assessment of biliary strictures remains diffi cult and direct visualization of bile ducts is traditionally obtainable through cumbersome fl exible cholangioscopes or newer ‘SpyGlass’ (Boston Scientifi c, USA) cholangioscopy [1]. Bile duct visualization in post-surgical patients is less well characterized and there is limited evidence available regarding the role of ERCP in post-pancreaticoduodenectomy patients [2,3]. Current indications for ERCP in post-Whipple patients include: evaluation of suspected biliary obstruction; recurrent pancreatitis; or persistent pain thought to be biliary or pancreatic in origin [3]. In post-pancreaticoduodenectomy patients, accessing the aff erent limb to evaluate for bile duct abnormalities may be an underutilized endoscopic technique.

Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ET(A)) and endothelin B (ET(B)) receptors, and is secreted in high concentrations in many different cancer environments. Although ET(A) receptor activation has an established nociceptive effect in cancer models, the role of ET(B) receptors on cancer pain is controversial. EDNRB, the gene encoding the ET(B) receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral squamous cell carcinoma lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ET(B) mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ET(B) receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.

Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.