Significance of MYB and NTRK Expression in Head and Neck Adenoid Cystic Carcinoma.

BACKGROUND/AIM: Adenoid cystic carcinoma (ACC) is an aggressive neoplasm even though it has low-grade histological appearance and slow growth. The aim of this study was to identify the immunohistochemical and molecular characteristics of ACC, as well as their correlation with the clinical course of patients. PATIENTS AND METHODS: This is a retrospective multicenter analysis. We included 50 patients diagnosed with ACC in the head and neck between 2000 and 2021. The expression of MYB proto-oncogene transcription factor (MYB), neurotrophic tyrosine kinase receptor (NTRK), human epidermal receptor-2 (HER-2), and Ki-67 was examined through immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). We also performed a clinical follow-up of the patients. RESULTS: The median age of the patients was 58.5 years; moreover, 54% of the patients were male. Compared with female patients, male patients were at a higher risk of both recurrence and death. No HER-2-positive cases were revealed. MYB expression was positive in 28 (56%) cases. However, MYB expression did not significantly affect survival. NTRK expression was positive in eight (16%) cases. NTRK-positive patients had worse overall survival (OS) than NTRK-negative patients (p=0.0246). Additionally, the percentage of NTRK-stained cells was negatively correlated with disease-free survival (p=0.0016) and OS (p=0.0027). CONCLUSION: There was no correlation between MYB positivity and survival. Contrarily, NTRK-positive patients had worse survival, indicating that NTRK is a negative prognostic factor. Tropomyosin receptor kinase inhibitors can be used to treat these patients. Furthermore, MYB-targeted inhibitors are promising therapeutic agents.

Transforming growth factor-ß inhibition and endothelin receptor blockade in rats with monocrotaline-induced pulmonary hypertension.

Transforming growth factor-ß (TGF-ß) inhibition is an investigational therapy for pulmonary arterial hypertension with promising results in experimental studies. The present work compared this approach with endothelin-receptor blockade and evaluated the effects of combined administration. Pulmonary arterial hypertension was induced by single monocrotaline injection (60 mg/kg) in 75 Wistar rats and 15 rats served as controls. Intervention groups consisted of treatment with an antibody against TGF-ß-ligand, bosentan, both or none, initiated four weeks after monocrotaline injection. Right ventricular systolic pressure, pulmonary vascular remodeling, and exercise tolerance were evaluated eight weeks after monocrotaline injection. Either treatment, alone or in combination, lowered mortality. Comparable efficacy was found in the three treatment groups in terms of right ventricular systolic pressure (~45% decrease) and hypertrophy (~30% decrease), as well as exercise capacity. The three treatment groups equally ameliorated pulmonary vascular remodeling, evidenced by decreased vessel-wall thickness (in vessels 50-200 µm) and a smaller number of pre-capillary arterioles (< 50 µm) with a muscularized media. Treatment either with an antibody against TGF-ß or with endothelin receptor blockade are equally effective in experimental pulmonary hypertension. Their combination provides no added benefit, indicating common mechanisms of action.

Chronic skeletal muscle ischemia preserves coronary flow in the ischemic rat heart.

Chronic skeletal muscle ischemia confers cytoprotection to the ventricular myocardium during infarction, but the underlying mechanisms remain unclear. Although neovascularization in the left ventricular myocardium has been proposed as a possible mechanism, the functional capacity of such vessels has not been studied. We examined the effects of chronic limb ischemia on infarct size, coronary blood flow, and left ventricular function after ischemia-reperfusion. Hindlimb ischemia was induced in 65 Wistar rats by excision of the left femoral artery, whereas 65 rats were sham operated. After 4 wk, myocardial infarction was generated by permanent coronary artery ligation. Infarct size was measured 24 h postligation. Left ventricular function was evaluated in isolated hearts after ischemia-reperfusion, 4 wk after limb ischemia. Neovascularization was assessed by immunohistochemistry, and coronary flow was measured under maximum vasodilatation at different perfusion pressures before and after coronary ligation. Infarct size was smaller after limb ischemia compared with controls (24.4 ± 8.1% vs. 46.2 ± 9.5% of the ventricle and 47.6 ± 8.7% vs. 80.1 ± 9.3% of the ischemic area, respectively). Indexes of left ventricular function at the end of reperfusion (divided by baseline values) were improved after limb ischemia (developed pressure: 0.68 ± 0.06 vs. 0.59 ± 0.05, P = 0.008; maximum +dP/dt: 0.70 ± 0.08 vs. 0.59 ± 0.04, P = 0.004; and maximum -dP/dt: 0.86 ± 0.14 vs. 0.72 ± 0.10, P = 0.041). Coronary vessel density was markedly higher (P = 0.00021) in limb ischemic rats. In contrast to controls (F = 5.65, P = 0.00182), where coronary flow decreased, it remained unchanged (F = 1.36, P = 0.28) after ligation in limb ischemic rats. In conclusion, chronic hindlimb ischemia decreases infarct size and attenuates left ventricular dysfunction by increasing coronary collateral vessel density and blood flow.

Chronic skeletal muscle ischemia in rats decreases the inducibility of ventricular tachyarrhythmias after myocardial infarction.

BACKGROUND: Chronic hind-limb ischemia confers cytoprotection after coronary occlusion, but it is unclear whether it ameliorates substrate formation for ventricular tachyarrhythmias (VTs). MATERIALS AND METHODS: Chronic hind-limb ischemia was generated by femoral artery excision in 50 rats, while 25 animals were sham-operated. Left coronary artery ligation was performed after 3 weeks and infarct size was measured 24 hours thereafter. The inducibility of VTs was assessed by programmed electrical stimulation (PES) 4 weeks post-ligation. A score was assigned, based on protocol stage and tachyarrhythmia duration. Monophasic action potentials (MAP) were recorded prior to and 4 weeks after ligation. RESULTS: The infarct size was smaller (p=0.000079) in the ischemic rats (25.7±2.1%) than in the controls (41.7±2.2%), accompanied by a lower (p=0.029) arrhythmia score (1.05±0.38 versus 2.70±0.68, respectively). The action potential duration (APD) was shorter (p<0.05) in the ischemic rats prior to ligation and remained stable after 4 weeks. CONCLUSION: Chronic hind limb ischemia limits infarct size and decreases inducible ventricular tachyarrhythmias.

Interposition of a reversed jejunal segment enhances intestinal adaptation in short bowel syndrome: an experimental study on pigs.

BACKGROUND: Interposition of a reversed intestinal segment as a factor facilitating intestinal adaptation has been experimentally investigated. Controversy exists about its efficacy in terms of body weight improvement, direction of luminal changes, and underlying mechanisms. This study aims to provide a comprehensive approach. METHODS: The pigs were randomly allocated to two groups: (1) short bowel (SB) group (n=8) and (2) short bowel reverse jejunal segment (SB-RS) group (n=8). On postoperative d 3, 30, and 60, intestinal transit time was measured; body weight and serum albumin were measured on baseline, as well as on postoperative d 30 and 60. After sacrifice, histopathologic and immunohistochemical (PCNA, activated caspase-3) evaluation followed. RESULTS: Transit time was numerically longer in SB-RS group at all time points; the difference reached statistical significance on d 60. No statistically significant differences were observed concerning body weight or serum albumin. In the SB-RS group, a statistically significant increase in muscle thickness, crypt depth, villus height, and PCNA immunostaining, and a decrease in caspase-3 positive (+) cell count were documented both at the jejunal and ileal level. CONCLUSIONS: The reversed jejunal segment seemed able to enhance intestinal adaptation at a histopathologic level, as well as to favorably modify transit time. These putatively beneficial actions were not reflected upon body weight. The decrease in apoptosis was caspase-3-dependent.

Transforming growth factor-ß inhibition attenuates pulmonary arterial hypertension in rats.

The role of transforming growth factor-ß in the pathogenesis of pulmonary arterial hypertension is unclear. We examined the effects of T9429, an antibody against transforming growth factor-ß receptors, on hemodynamic, histological and functional parameters in the rat model of monocrotaline-induced pulmonary hypertension. One week after monocrotaline injection (60 mg/kg) in 28 Wistar rats, T9429 (0.1mg/kg daily) was administered intraperito-neally in 19 rats (268±10g) via an osmotic mini-pump for 7 days. One week thereafter, right ventricular systolic pressure, pulmonary vascular remodeling and exercise tolerance were evaluated. Compared to the monocrotaline group (25.5±1.9mmHg), right ventricular systolic pressure was lower (p=0.0014) in the monocrotaline+antibody group (18.4±0.8mmHg). This was translated into attenuated right ventricular hypertrophy (p=0.0063) and longer (p=0.0155) exercise duration (2.08±0.29min versus 6.19±1.02min). Pulmonary arterial wall thickness (in vessels 50 -200µm) was comparable between the two groups, but the monocrotaline+antibody group displayed lower number (p<0.0001) of pre-capillary arterioles (<50µm, in 20 randomly selected fields) with a muscularized media (23.33±3.15 versus 6.64±0.75). Our results suggest that transforming growth factor-ß receptor blockade improves vascular remodeling and attenuates pulmonary hypertension, a finding with potential therapeutic implications.

Adenosquamous carcinoma of the pancreas: a case report.

Adenosquamous carcinoma of the pancreas is a rare variant of pancreatic exocrine carcinoma. We report a case of 70 year old man who came to our hospital with abdominal pain, anorexia and jaundice. Imaging of the abdomen showed a mass in the region of the head of the pancreas. Histological evaluation of the pancreatic tumor showed an adenosquamous carcinoma which was extensively infiltrative with perineural invasion, involvement of peripancreatic lymph nodes and all the thickness of the duodenum wall. The tumor exhibited a biphasic malignant growth identified as well to moderate differentiated adenocarcinoma and well to poorly differentiated squamous cell carcinoma.

Merkel cell carcinoma of the upper extremity: case report and an update.

BACKGROUND: Merkel cell carcinoma is a rare but aggressive cutaneous primary small cell carcinoma. It is commonly seen in elderly affecting the head, neck, and extremities. Macroscopically may be difficult to distinguish MCC from other small cells neoplasms especially oat cell carcinoma of the lung. CASE PRESENTATION: It is presented a case report concerning a 72 years old male with a MMC on the dorsal aspect of the right wrist. The patient underwent a diagnostic excisional biopsy and after the histological confirmation of the diagnosis a second excision was performed to achieve free margins. No postoperative radiation or adjuvant chemotherapy was given and within 9 years follow up no recurrence was reported. CONCLUSION: Although most cases present as localized disease treatment should be definitive due to high rates of local or systemic recurrence. Treatment includes excision of the lesion, lymphadenectomy, postoperative radiotherapy and chemotherapy depending on the stage of the disease. Even when locoregional control is achieved close surveillance is required due to high rates of relapse.