An evaluation of the safety of continuing trastuzumab despite overt left ventricular dysfunction.

Background: The major limitation in the use of trastuzumab therapy is cardiotoxicity. We evaluated the safety of a strategy of continuing trastuzumab in patients with breast cancer despite mild, asymptomatic left ventricular impairment. Methods: Charts of consecutive patients referred to a cardio-oncology clinic from January 2015 to March 2017 for decline in left ventricular ejection fraction (lvef), defined as a fall of 10 percentage points or more, or a value of less than 50% during trastuzumab therapy, were reviewed. The primary outcome of interest was change in lvef, measured before and during trastuzumab exposure and up to 3 times after initiation of cardiac medications during a median of 9 months. Results: All 18 patients referred for decline in lvef chose to remain on trastuzumab and were included. All patients were treated with angiotensin converting-enzyme inhibitors or beta-blockers, or both. After initiation of cardiac medications, lvef increased over time by 4.6 percentage points (95% confidence interval: 1.9 percentage points to 7.4 percentage points), approaching baseline values. Of the 18 patients, 17 (94%) were asymptomatic at all future visits. No deaths occurred in the group. Conclusions: Many patients with mildly reduced lvef and minimal heart failure symptoms might be able to continue trastuzumab without further decline in lvef, adverse cardiac events, or death when treated under the supervision of a cardiologist with close follow-up.

Implementation and evaluation of a transit dosimetry system for treatment verification.

PURPOSE: To evaluate a formalism for transit dosimetry using a phantom study and prospectively evaluate the protocol on a patient population undergoing 3D conformal radiotherapy. METHODS: Amorphous silicon EPIDs were calibrated for dose and used to acquire images of delivered fields. The measured EPID dose map was back-projected using the planning CT images to calculate dose at pre-specified points within the patient using commercially available software, EPIgray (DOSIsoft, France). This software compared computed back-projected dose with treatment planning system dose. A series of tests were performed on solid water phantoms (linearity, field size effects, off-axis effects). 37 patients were enrolled in the prospective study. RESULTS: The EPID dose response was stable and linear with dose. For all tested field sizes the agreement was good between EPID-derived and treatment planning system dose in the central axis, with performance stability up to a measured depth of 18cm (agreement within -0.5% at 10cm depth on the central axis and within -1.4% at 2cm off-axis). 126 transit images were analysed of 37 3D-conformal patients. Patient results demonstrated the potential of EPIgray with 91% of all delivered fields achieved the initial set tolerance level of ΔD of 0±5-cGy or %ΔD of 0±5%. CONCLUSIONS: The in vivo dose verification method was simple to implement, with very few commissioning measurements needed. The system required no extra dose to the patient, and importantly was able to detect patient position errors that impacted on dose delivery in two of cases.

Distribution of Entamoeba histolytica Gal/GalNAc lectin-specific antibody response in an endemic area.

To demonstrate the dynamics of specific antibody isotypes against Entamoeba histolytica Gal/GalNAc adhesin and its correlation, if any, with the development of immunity, we evaluated subjects suffering from a spectrum of amoebic infections ranging from amoebic liver abscess (ALA) to asymptomatic cyst passers. The quantitative analysis of antibody levels was done in the sera by enzyme-linked immunosorbent assay. Gal/GalNAc adhesin-specific immunoglobulin G (IgG) was higher in ALA (and their follow-ups) and intestinal amoebiasis cases as compared with asymptomatic cyst passers (P < 0.05). Among the isotypes of IgG, high levels of IgG1 (60% of the total IgG concentration), suggestive of T-helper 2-type response, was associated with ALA cases. Intestinal amoebiasis cases and cyst passers had high percentage of IgG1 and IgG4 antibodies as compared with per cent IgG2 and IgG3 (of the total IgG), whereas follow-up cases of ALA had predominantly IgG2 and IgG3 isotypes of antibodies. Gal/GalNAc lectin-specific IgM antibodies were maximum in cases of intestinal amoebiasis. ALA cases and their follow-ups had significantly lower levels of Gal/GalNAc-specific IgM levels as compared with cyst passers (P < 0.05). Gal/GalNAc adhesin-specific IgA antibodies were raised maximally in intestinal amoebic infection cases. ALA cases and their 3-month follow-ups had significantly higher concentrations of lectin-specific IgA (P < 0.05) as compared with the healthy subjects.

Evaluation of newer diagnostic methods for the detection and differentiation of Entamoeba histolytica in an endemic area.

We evaluated the colorimetric polymerase chain reaction (PCR)-based method for the detection and differentiation of Entamoeba spp. and compared the efficacy of E. histolytica-specific antigen detection in faeces with the detection of specific antibodies to E. histolytica-specific antigen in faeces, by enzyme-linked immunosorbent assay. Faecal samples were obtained from patients attending hospital in Chandigarh, India, from March 2001 to February 2002. The PCR-based colorimetric method was found to be the most sensitive (100%) and it could differentiate between pathogenic and non-pathogenic Entamoeba spp. The present study also emphasized that the antigen detection system may prove to be a better diagnostic tool than the antibody detection system in endemic areas.

Splenectomy in a case of splenic vein thrombosis unmasks essential thrombocythemia.

We report a patient with splenic vein thrombosis (SVT) in whom splenectomy resulted in the unmasking of essential thrombocythemia (ET). He had portal hypertension with haematemesis, resulting in anaemia requiring repeated blood transfusions. Investigations revealed SVT. Following splenectomy, he suffered a transient ischaemic attack episode, associated with persistent thrombocytosis (> 2000 x 10(9)/l). Other myeloproliferative disorders were excluded and a diagnosis of ET was established. He responded to hydroxyurea but, due to financial constraints, he discontinued treatment and subsequently relapsed. The association of ET with SVT is rare and the diagnosis of ET was missed initially as the platelet count was normal prior to splenectomy.

Modulation of acid secretion in common bile duct ligation-related gastropathy in Wistar rats.

BACKGROUND: Portal hypertensive gastropathy is associated with fundic gland atrophy, resulting in a decrease in chief and parietal cells, and diminished acid secretion. METHODS: Acid secretion by isolated parietal cells was measured (acridine orange retention), along with the levels of various second messengers (intracellular Ca(2+), cyclic adenosine monophosphate and protein kinase C) in the common bile duct, ligated portal hypertensive rats and compared with sham-operated controls. RESULTS: There was a significant decrease in the response of isolated parietal cells to the secretagogues histamine and carbachol. This resulted in the blunted acid secretion in the common bile duct ligated group. In addition, all the second messengers studied were significantly decreased as compared with the sham-operated controls. CONCLUSION: These results suggest that the blunted acid secretory response in the portal hypertensive rat is caused by an alteration in the intracellular signal transduction mechanism.

Activity of brush border membrane enzymes in proximal jejunum of portal hypertensive rats.

PURPOSE: Malabsorption accompanies portal hypertension, especially when associated with chronic liver disease. The development of portal hypertension is accompanied by significant alterations in the splanchnic microcirculation. In this study, the effect of extrahepatic and intrahepatic portal hypertension on brush border membrane enzymes was estimated. METHODS: Portal hypertension was induced in rats by partial portal vein ligation (PPVL) (n = 6) and common bile duct ligation (CBDL) (n = 6), and the activity of sucrase, lactase, alkaline phosphatase, and leucine aminopeptidase (LAP) in the intestinal homogenate was measured. RESULTS: Intrasplenic pulp pressure (ISPP) (in cm of saline) was found to be elevated in PPVL (21.3 +/- 1.47) and CBDL animals (21.5 +/- 1.79) as compared with findings in their respective sham-operated controls (12.74 +/- 0.86, 11.83 +/- 1.04). Only sucrase and LAP activity was significantly elevated (P < 0.05) in the PPVL group. No changes were observed in the CBDL group. CONCLUSION: Only sucrase and LAP activities were increased in PPVL rats.

Budd-Chiari syndrome: our experience of 71 patients.

BACKGROUND: Hepatic venous outflow obstruction (Budd-Chiari syndrome) is frequently encountered as a cause of portal hypertension at our centre. METHODS AND RESULTS: We studied the clinical presentation, therapeutic modalities and outcome of 71 patients with hepatic venous outflow obstruction between 1992 and 1997. Twenty-seven patients presented with acute disease, while 44 had chronic presentation. Abdominal pain, distension, jaundice and upper gastrointestinal bleeding were the commonest presenting symptoms. The majority of patients had distended veins, hepatomegaly, splenomegaly, ascites and ankle oedema. The diagnosis was made on the basis of inferior vena cavography/functional hepatography and pulsed Doppler ultrasonography and/or liver biopsy in 39 patients and pulsed Doppler ultrasonography and/or liver biopsy in 32 patients. Pulsed Doppler ultrasonography accurately detected the site of the block in 31 of 39 patients (79.4%). The obstruction was in the hepatic vein in 20 patients, in the inferior vena cava in 10, and in both in 41 patients. Aetiologically, four had pregnancy-related disease, four tumour-related, three hypercoagulable states, 18 inferior vena cava membranes and 42 were idiopathic. Of 30 patients in whom liver biopsy was carried out, eight had centrizonal congestion and necrosis, 13 had mixed features and nine had established cirrhosis. Seven patients underwent a shunt operation and surgical membranotomy was carried out in one. Three patients (4.2%) died in the hospital. CONCLUSIONS: Hepatic venous outflow obstruction is a common problem; patients present with abdominal pain, distension, jaundice, distended veins, ascites and ankle oedema. Chronic presentation is more frequent. Pulsed Doppler ultrasound, venography and liver biopsy are very helpful in diagnosis.

Gastropathy and defense mechanisms in common bile duct ligated portal hypertensive rats.

Portal hypertensive gastropathy is associated with a broad spectrum of gastric mucosal damage inspite of decreased gastric acid secretion, suggestive of compromised endogenous protective mechanisms. To determine the mechanisms of damage in portal hypertensive gastropathy we measured lipid peroxidation, glutathione, antioxidant and lysosomal enzymes in gastric mucosal homogenates from male Wistar rats with elevated intrasplenic pulp pressure, eighteen days after common bile duct ligation. Thiobarbituric acid-reactive substances and lysosomal enzymes (beta-glucuronidase and acid phosphatase) were increased in the common bile duct ligated group as compared to the sham-operated group. The levels of antioxidant defense enzymes, superoxide dismutase, glutathione peroxidase, catalase and glutathione were decreased as compared to the sham-operated controls. Pre-operative vitamin E administration decreased mucosal lipid peroxidation increased the levels of antioxidant defense enzymes and lowered the lysosomal enzymes. The plasma vitamin E levels in this group were lower when compared to animals receiving it post-operatively. In conclusion, free radical and lysosomal enzyme mediated damage may play a role in portal hypertensive gastropathy.

Dilatation of benign oesophageal strictures: 10 years' experience with Celestin dilators.

BACKGROUND: Endoscopic dilatation is the first line of treatment for benign oesophageal strictures. There are limited data available on the use of Celestin dilators. METHODS: The efficacy and safety of Celestin dilators was evaluated retrospectively in 61 patients with benign oesophageal strictures. Three hundred and ninety-three dilatations using Celestin dilators were performed over a period of 10 years on an outpatient basis in patients with corrosive, peptic and other causes of benign oesophageal strictures. RESULTS: Initial success was achieved in all patients in the peptic and miscellaneous group and in 91% in the corrosive group of patients. Patients with corrosive strictures required significantly more dilatations for initial success compared with the peptic group (mean 5.82 vs 1.62 P < 0.1). At 6 months follow up after the initial success, 29% of the patients had an excellent response, 56% a good response and 15% a fair response. No patient had a poor response. During the long-term follow up of 10 years, overall dilatation requirement decreased significantly. (72 vs 27 vs 14% of patients requiring dilatation at 1, 5 and 10 years P < 0.05). The dilatation requirement also decreased significantly within the groups (P < 0.05). Patients with corrosive stricture required more frequent dilatations on follow up compared with the other two groups. Complications in the form of oesophageal perforation occurred in only two patients. There was no mortality. CONCLUSION: Oesophageal dilatation with Celestin dilators is an effective and safe modality for managing patients with benign oesophageal strictures.

Extrahepatic portal hypertensive gastropathy in Wistar rats: modulation of acid secretion in isolated parietal cells.

Stimulated acid secretion in portal hypertensive gastropathy is blunted and could be due to defective signal transduction in the parietal cell. Therefore, an attempt was made to study the levels of second messengers in parietal cells in experimental extrahepatic portal hypertensive gastropathy. Our aim was to measure acid secretion, intracellular free calcium, calcium transport, cyclic AMP, and ATP levels in the parietal cells isolated from the gastric mucosa of portal hypertensive rats. Acid secretion using acridine orange, intracellular free calcium using Fura-2/AM, calcium influx and efflux by 45CaCl2 and cyclic AMP by RIA kits were measured in unstimulated and histamine- and carbachol-stimulated isolated parietal cells in rats with partial portal vein ligation and sham operation. ATP was measured by HPLC. In portal hypertensive gastropathy, stimulated acid secretion was blunted, and there was a decrease in basal intracellular free calcium. Calcium influx and efflux were at a higher level, and there was a decrease in elevation of intracellular free calcium and cyclic AMP levels with secretagogues. There was also a decrease in ATP. In conclusion, there exists a low energy state in addition to multiple aberrations at the second messenger level in parietal cells in portal hypertensive gastropathy.

Acetylsalicylic acid-induced biochemical changes in gastric juice: a failure of adaptation?

BACKGROUND: Acetylsalicyclic acid (ASA) causes gastric mucosal damage which diminishes with continued use due to adaptation. METHODS: To determine the net effect of these processes on the gastric juice, we estimated acid, osmolality, bicarbonate concentration in nonparietal gastric juice, calcium, potassium and sodium in 18 patients (9 men; mean age 32 years, range 20-46) with irritable bowel syndrome, before and after 600 mg of ASA taken post-cibum thrice daily for 4 weeks. Osmolality was determined by an osmometer, acidity by titration, and Na+, K+ and Ca++ using a sodium-potassium-calcium analyzer; bicarbonate was derived from the two-component model of Feldman. RESULTS: Gastric juice K+ and Na+ increased significantly from mean (SE) 14.6 (0.5) and 197.5 (16.3) to 16.7 (0.4) and 256.8 (18.1) mEq/L, respectively. The other parameters remained unchanged. CONCLUSION: After four weeks of ASA ingestion there is a dichotomy of gastric mucosal injury and adaptation, with preservation of acid secretion but continued loss of Na+ and K+.

Sclerotherapy in noncirrhotic portal fibrosis.

Endoscopic sclerotherapy has emerged as an effective and safe mode of treatment for long-term management of esophageal varices due to cirrhosis of liver and extrahepatic portal venous obstruction. There are few studies that have evaluated the role of sclerotherapy in the management of esophageal varices in patients with noncirrhotic portal fibrosis (NCPF). We report our results of long-term sclerotherapy in patients with NCPF. Seventy-two consecutive patients (men 29, women 43; age 32.9 +/- 11.8 years) with recurrent variceal bleeding due to NCPF were entered into the sclerotherapy program. Forty-eight patients received intravariceal absolute alcohol and 24 patients received intravariceal sodium tetradecyl sulfate (STD). Variceal obliteration was achieved in 65 (90.3%) patients with a mean of 5.7 +/- 3.0 (range 1-14) sessions. These patients were followed-up for a mean of 21.4 +/- 20.4 (range 1-96) months. Thirteen (17.3%) patients had episodes of upper gastrointestinal bleeding during sclerotherapy. Rebleed after obliteration was seen in 6 (9.2%) patients. Sclerotherapy was associated with a significant reduction in bleeding rate (bleeds per month per patient) during sclerotherapy and after obliteration of varices as compared to presclerotherapy period (P < 0.000001 for both). Recurrence of esophageal varices after obliteration was seen in 9 (13.9%) patients with reobliteration of varices in five patients in whom sclerotherapy was attempted. Complications including esophageal ulcer and stricture formation were seen in 18 (25%) and 4 (5.6%) patients respectively; strictures were restricted to patients who received absolute alcohol. Two (2.77%) patients died of massive upper gastrointestinal bleed during follow-up. We conclude that sclerotherapy is an effective and safe modality in the prevention of variceal bleeds in patients with NCPF.

Diminution in parietal cell number in experimental portal hypertensive gastropathy.

Portal hypertensive gastropathy is a well-established clinical entity. Although stimulated acid secretion has been found to be decreased in portal hypertensive rats, the parietal cell mass has not been studied. Portal hypertension was produced in Wistar rats either by partial portal vein ligation (N = 16) or by common bile duct ligation (N = 23) and confirmed by intrasplenic pulp pressure measurement. The parietal cells were isolated and counted in a Neubaur hemacytometer. The parietal cell count was also done in microscopic sections at direct histopathological examination. The viable, isolated parietal cell count and parietal cell count on histopathological examination were significantly decreased in partial portal vein ligated rats. Similarly, in common bile duct ligated rats, the parietal cell count was decreased as compared to sham-operated rats. In experimental portal hypertensive gastropathy there is a decrease in parietal cell number.

Experimental extrahepatic obstruction of portal vein: documentation of histopathological alterations in liver and extrahepatic tissues.

The histopathology of the portal vein in human extrahepatic portal vein obstruction (EHPVO) in the form of cavernomatous transformation of the portal vein is well documented. However, a similar detailed histopathology has not been documented in experimental EHPVO, even though the model has been in existence for many years. An experimental model of EHPVO was created by partial ligation of the portal vein in 20 rats. A control group of 11 sham operated (SO) rats was also studied. Development of portal hypertension was confirmed by measurement of intrasplenic pulp pressure (19.7 + 7.1 cm normal saline vs 12.9 + 1.1 cm of normal saline in SO rats). Histopathological evidence included varices in the oesophagus and congestion in the submucosa and mucosa of the stomach and capillarization of sinusoids in the spleen. Animals were killed at 22-265 days post-ligation. While SO animals showed mild focal sinusoidal congestion and a normal portal vein, the experimental group of animals with EHPVO showed oedema around the portal vein, multiple dilated vascular channels near the hilum resembling cavernomatous transformation and severe sinusoidal congestion. Jejunum and kidneys showed congested veins in the experimental group. None of the SO animals showed this change. Thus experimental EHPVO does reproduce some histological changes observed in human EHPVO.

Sexual behaviour, drug use and hepatitis B infection in Chandigarh students.

BACKGROUND: The relationship of hepatitis B virus infection with drug use and sexual activity in Indian college students has not been studied earlier. METHODS: We studied this relationship in Chandigarh, using a prospective, cross-sectional questionnaire-based survey and blood tests for hepatitis B markers. The responders were assured of the confidentiality of their responses and blood test results. RESULTS: Of the 1311 students who participated, 192 (15%) were sexually active. Eight-four per cent of them were heterosexual, 7.3% homosexual and 8.7% bisexual. Thirty-seven per cent of heterosexuals and 36% of homosexuals had more than one partner. Condoms were used by 24% heterosexuals, 11% bisexuals and 7% homosexuals. Of the sera tested, 2.9% were hepatitis B surface antigen positive and 10.4% were positive for the antibody to hepatitis B surface antigen. Fifteen per cent consumed alcohol, but only 1.6% were addicted to other drugs. Two students were intravenous drug users. Eleven per cent had donated blood at least once and a third of these had suffered from jaundice in the past. CONCLUSION: The pattern of sexual behaviour, low condom use and the small but definite prevalence of hepatitis B virus infection in this population of students suggests that the human immunodeficiency virus infection may spread rapidly when it enters this community.

Duodenal ulcer. Calcium status in isolated parietal cells.

Although the etiology of duodenal ulcer is not known, its treatment with drugs that reduce acid secretion is well accepted. The central role of calcium in stimulus-secretion coupling resulting in acid secretion by gastric parietal cells is documented. However, the status of intracellular calcium in gastric parietal cells in the basal state in patients with duodenal ulcer is not known. Multiple endoscopic gastric mucosal biopsies from the corpus of the stomach of 52 patients were processed and isolated parietal cells were studied. Intracellular calcium was estimated using fura-2-acetoxymethyl ester. Influx and efflux were determined by using radioactive calcium. Acridine orange retention was used to assess acid production. Only calcium influx at 20 min was significantly (P < 0.01) more in patients with duodenal ulcer as compared to the control group. There was no difference between the groups in calcium influx at 0 and 60 min; calcium efflux at 0, 20, and 60 min; intracellular free calcium and acid secretion. We conclude that in the unstimulated state calcium homeostasis in isolated parietal cells of patients with duodenal ulcer shows only a minimal difference as compared to controls.

Atypical strain of hepatitis E virus (HEV) from north India.

Hepatitis E virus (HEV) infection was detected during an epidemic in North India. Virus particles present in the stool of an acutely ill patient (YAM-67) was transmitted intravenously into rhesus monkeys (M. mulata) and orally to a human volunteer. Virus-like particles (VLPs) of 32-34 nm were detected in the bile of monkeys and in the stools of the human volunteer by means of solid phase immune electron microscopy (SPIEM) with acute homologous and heterologous sera. The VLPs were confirmed to be HEV by a reverse transcription polymerase chain reaction (RT-PCR). Virus-like particles from human volunteer stools were passaged further into rhesus monkeys. A bimodal rise in aminotransferase levels were observed in the animals, and liver histopathology indicated mild to severe form of hepatitis. Further, SPIEM and RT-PCR analysis in monkey bile revealed presence of virus from 15 to 45 days post-inoculation. Rechallenge of the animals 6 months after recovery with the same viral inoculum failed to produce abnormal liver function tests indicating the presence of protective immunity during this period. The VLPs in the stool from the patient (YAM-67) with epidemic hepatitis were found to retain infectivity even after several cycles of freeze-thawing and exposure at 37 degrees C for 2 days. Moreover, these VLPs from the patient, human volunteer, and monkeys did not react with an anti-HEV chimpanzee serum from NIH, Bethesda, MD. These findings indicate that this North India isolate of HEV is an atypical strain of HEV. The present study further validates that the rhesus monkey is a suitable experimental model for HEV.

Hepatic outflow obstruction (Budd-Chiari syndrome). Experience with 177 patients and a review of the literature.

Budd-Chiari syndrome (BCS) may not be as uncommon as was once believed. Our study has substantiated the existence of 2 major clinical forms. The acute syndrome is invariably associated with extensive blockage of the major hepatic veins, resulting in congestive liver cell necrosis. In a small, but significant, number of patients the inferior vena cava (IVC) is also occluded. The important etiologic factors are related to hypercoagulability of blood. Immediate placement of a shunt improves survival. The chronic syndrome is characterized by portal hypertension and is associated with a variable abnormal vascular anatomy. The causes of the chronic syndrome are not clear, but a substantial number of cases are related to the presence of an IVC membrane. Shunt surgery is effective but procedures aimed at the primary pathology are likely to be even more so. The natural history of BCS should be viewed over a long period of time. The very long survival of several patients urges a more cautious approach to surgical remedies. Budd-Chiari syndrome probably represents a spectrum of disease caused primarily by a hypercoagulable state and having a varied presentation depending on the balance between rate of formation and the extent of the thrombosis and the body's own rate of thrombolysis and recanalization. The extent and efficacy of the individual's collateral circulation and the rate of development of liver fibrosis are other determinants. It is thus possible to view BCS as a continuum of a single pathogenetic spectrum. Pregnancy-related BCS in India probably has strong social determinants, and is usually acute and fulminant. We have, however, documented a chronic form not described earlier. Children usually do not have acute BCS, but chronic BCS in children and adolescents is similar to that in adults. Membranous obstruction of the inferior vena cava (MOVC) is common and was found even at a young age. The association of MOVC with hepatocellular carcinoma, however, did not appear to be as clear as was previously believed. There has been a wide geographical variability in the causes and manifestations of BCS. Our study has clearly shown that--Kipling's categorical statement to the contrary--East and West do meet in India, in the Budd-Chiari syndrome.