Management of gastrointestinal carcinoid tumours - 10 years experience at a district general hospital

Background

There is paucity of guidelines regarding management of gastrointestinal carcinoid tumours in district hospitals.

Methods

This study was undertaken at a district hospital to analyse the management pathway of gastrointestinal carcinoid tumours.

Results

Over a period of 10 years there were 35 patients, with an estimated annual incidence of 2.5 per 100,000 population. After a median follow up of 24 months, 22 (63%) patients were alive and disease free. Only 56% patients were referred to the regional neuro-endocrine multidisciplinary team.

Conclusions

Management of patients with carcinoid tumours in district hospitals needs streamling with increased utilisation of regional neuroendocrine multidisciplinary teams.Key Words: Gastrointestinal carcinoid tumours, neuro-endocrine tumours, district hospital     

Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists

Cannabinoid 1 (CB1) receptors have the ability to change conformation between active (R*) and inactive (R) receptor states. Herein, we further characterize these receptor states using series of saturation radioligand binding studies and their differential displacement binding by various CB1 receptor ligands. Binding experiments were carried out in naïve rat/dog whole brain membranes using radioligands [³H]CP55,940 (for R* state) & [³H]SR141716A (both R* and R states) and various agonist, antagonist & inverse agonist ligands at CB1 receptors. In the saturation binding experiments, of the total number of CB1 receptor binding sites (R* + R) in the rat and dog whole brain membranes, only about 18.3 and 11.6% were in the active (R*) state recognized by [³H]CP55,940, respectively. In the competitive binding studies, all the CB1 receptor agonists investigated had significantly very high affinity for the active R* state recognized by [³H]CP55,940 and lower affinity for the inactive R state mainly recognized by [³H]SR141716A in the presence of a non-hydrolyzable analogue of GTP [Gpp(NH)p]. In contrast, various CB1 receptor antagonists/inverse agonists had similar nanomolar affinities at both [³H]CP55,940 and [³H]SR141716A recognized binding states. These results clearly characterize the significant differences between the active R* and inactive R binding states of CB1 receptors in naive rat and dog brain. In addition, these results also demonstrates that the CB1 agonists and antagonists/inverse agonists can be differentiated by their relative affinities at active (R*) and inactive (R) binding states of the CB1 receptor.     

Perioperative outcomes associated with robotic Ivor Lewis esophagectomy in patient’s undergoing neoadjuvant chemoradiotherapy

Background

Neoadjuvant chemoradiotherapy (NCR) for the treatment of esophageal cancer has been associated with increased perioperative morbidity and mortality. Minimally invasive procedures utilizing robotic techniques have been shown to reduce perioperative complications and length of hospitalization (LOH). The purpose of this study is to compare perioperative outcomes between patients undergoing NCR and robotic-assisted Ivor Lewis esophagectomy (RAIL) versus upfront RAIL.

Methods

A database of esophagectomy patients was queried to identify RAIL patients. Differences in perioperative outcomes were analyzed between NCR and non NCR patients.

Results

Eighty-nine patients were identified who underwent RAIL Seventy-seven patients (87%) had NCR and 22 patients did not (13%). The median age was 66 (range, 44-83). The median age of the patients treated with NCR was younger {69 [44-83] vs. 64 [46-81] years respectively, P=0.05}. The patients who underwent NCR had a higher BMI then those who went straight to esophagectomy (31 vs. 27; P=0.001). There were no conversions to open laparotomy or thoracotomy in either group. There were no statistically significant differences in the mean operative times and estimated blood loss (EBL) between both groups. Complications occurred in 17 (19.1%) patients. There were no statistically significant differences in the rates of any complications between patients receiving NCR and those that did not receive NCR (P=0.11). There were no deaths in either group. The total number of days in hospital and total number of intensive care unit (ICU) days were also similar in both groups (P=0.25). There was no statistically significant difference in the mean number of lymph nodes harvested in the patients treated with NCR compared with those treated without NCR.

Conclusions

We have demonstrated that RAIL is a safe and feasible option for patients with esophageal cancer. The administration of NCR to RAIL did not result in an increase in perioperative morbidity and mortality. The number of lymph nodes harvested and the completeness of resection was also similar between patients who received NCR and those who did not. Longer follow-up is required in order to determine long term oncologic outcome.     

Stability-indicating HPTLC method for simultaneous determination of nateglinide and metformin hydrochloride in pharmaceutical dosage form

A stability indicating high performance thin layer chromatography (HPTLC) method was developed and validated for determination of two anti-diabetic drugs, nateglinide and metformin hydrochloride in co-formulations. Study was performed on pre-coated silica gel HPTLC plates using chloroform:ethyl acetate:acetic acid (4:6:0.1 v/v/v) as the mobile phase. A TLC scanner set at 216 nm was used for direct evaluation of the chromatograms in the reflectance/absorbance mode. Method was validated according to ICH guidelines. The correlation coefficients of calibration curves were found to be 0.996 and 0.995 in the concentration range of 200–2400 and 500–3000 ng band⁻¹ for nateglinide and metformin, respectively. The method had an accuracy of 99.72% for nateglinide and 100.08% for metformin hydrochloride. The method had the potential to determine these drugs simultaneously from dosage forms without any interference of the tablets excipients. Nateglinide and metformin hydrochloride were also subjected to acid, base, oxidation, wet, heat and photo-degradation studies. The degradation products obtained were well resolved from the pure drugs with significantly different R_f values. As the method could effectively separate the drugs from its degradation products, it can be used for stability-indicating analysis.     

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3^ser461 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158-induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co-immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158-mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX-resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.     

Massive retinal gliosis: an unusual case with immunohistochemical study

Massive retinal gliosis (MRG) is a rare, benign intraocular condition that results from the proliferation of well-differentiated glial cells. Immunohistochemically, these cells show positivity for glial fibrillary acid protein (GFAP), neuron specific enolase (NSE), and S-100 protein. We encountered a case of a 45-year-old female with loss of vision in the left eye. She had a history of trauma to that eye two years ago. Enucleation was carried out, because malignancy was suspected due to retinal calcification. On the basis of light microscopy and immunohistochemistry (IHC) performed on the enucleated eye, it was diagnosed as massive retinal gliosis.