Induction of CD8 T-cell-Ifn-gamma response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma

Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-gamma secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-gamma responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization.     

Surface,core, and X genes of hepatitis B virus in hepatocellular carcinoma: an in situ hybridization study

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) and the seroprevalence of hepatitis B virus (HBV) in this disease state are significantly higher in South India than in North India. Because data on serologic studies do not project the actual association between the two parameters, this study was undertaken. METHODS: The prevalence of HBV genes in HCC patients was studied using nonisotopic in situ hybridization. Fifty patients from South India were diagnosed with HCC after performing ultrasound-guided fine-needle aspiration biopsies of liver lesions. The diagnosis was confirmed by cell block studies. Sections cut from paraffin-embedded cell blocks made out of the aspirates were probed with digoxigenin-labeled surface, core, and X regions of the viral genome. RESULTS: Nuclear integration of the surface gene was observed in 100% (50 of 50), the core gene was positive in 94% (47 of 50), and the X gene was present in 98% (49 of 50) of the cases. An episomal form of the virus was not found. Serum hepatitis B surface antigen was positive only in 48% (12 of 25) of the patients screened. CONCLUSIONS: We found molecular evidence that HBV is an important contributing factor in the etiology of HCC in South India. In HCC, the S gene of the virus was the most prevalent followed by the X and C genes. Only integrated forms of the viral DNA were observed. Nonisotopic in situ hybridization using multiple regions of the viral genome is a good technique for studying this association. It has an added advantage over polymerase chain reaction, of localization of signals in a tumor cell. Cell blocks made from fine-needle aspirates are ideal for in situ hybridization.     

Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active,irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2)

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.     

Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with a poor prognosis in several human malignancies. In addition, cancers overexpressing EGFR respond poorly to both chemotherapy and radiation therapy. Therefore, EGFR is a viable target for cancer therapy. This review will address how EGFR blockade modulates signal transduction, leading to alterations in the cell cycle progression with secondary inhibition of proliferation and differentiation of cancer cells. As a prototypical example, erlotinib (Tarceva), a reversible EGFR tyrosine kinase inhibitor will be discussed. This drug has demonstrated promising antitumor activity in Phase II trials in several solid tumors and definitive Phase III studies to demonstrate clinical benefit have completed accrual.     

Postasphyxiai Encephalopathy in Preterm Neonates

Objective : Perinatal asphyxia is an important determinant of infant neurological outcome. There are very few studies looking exclusively at postasphyxial encephalopathy in preterm neonates.Methods : We studied the neurologic and sonographic abnormalities in 40 preterm babies with severe birth asphyxia during their hospital stay and till 3 months corrected age.Result : 87.5 % of the asphyxiated preterm babies had neonatal neurologic abnormality, compared to only 17% of the control babies (p < 0.0001). Generalised hypotonia and reduced activity were the commonest abnormalities (observed in 85% of asphyxiated babies) while depressed sensorium (60%) and seizures (35%) were seen in more severe cases. White matter disease (WMD-including periventricular flare, cerebral edema and periventricular leucomalacia) was significantly more frequent in the study cases (34.5% in study casesvs 7.5% in controls, p < 0.0001) as was grade 3/4 intraventricular hemorrhage(IVH) (25% in study cases vs 2.5% in controls, p < 0.0001). There was 11 fold higher mortality among the asphyxiated babies (23 deaths in study casesvs 2 in controls, p < 0.0001).Conclusion :The survivors had a significantly higher incidence of both mild and severe neurological abnormalities at corrected age of 3 months among the asphyxiated babies. There was a good correlation between the severity of the neonatal encephalopathy as well as the sonographic findings and the outcome.     

Anterior stromal puncture in bullous keratopathy: a clinicopathologic study

PURPOSE: We report our experience of anterior stromal puncture (ASP) in symptomatic chronic corneal edema patients awaiting penetrating keratoplasty (PK) and hypothesize the mechanism of action of ASP in bullous keratopathy (BK). METHODS: We reviewed the medical records of 28 patients with BK who underwent ASP between November 1996 and September 1999 with at least 1 month of follow-up. In all these patients, approximately 200 punctures were given with a bent 26-gauge needle sparing the peripheral cornea. Patients were examined on days 1 and 7, 1 month, and every 3 months after the procedure. The symptoms, corneal findings, and visual acuity of the patients at last follow-up were noted and compared with the preprocedure findings. For 11 patients who underwent PK, histopathologic study of corneal buttons was performed and a clinicopathologic correlation was attempted. RESULTS: Of the 28 patients, there were 15 men and 13 women with a mean age of 61.1 years. The clinical diagnosis was pseudophakic BK in 11 (39.3%), aphakic BK in 11 (39.3%), Fuchs' dystrophy in 4 (14.3%), failed graft in 1 (3.6%), and chronic corneal edema of unknown etiology in 1 (3.6%). The follow-up ranged from 1 to 33 months with a mean of 9.5 +/- 7.5 months. Symptomatic relief was noted in all. Twenty patients (71.4%) had complete relief, whereas eight patients (28.6%) experienced mild symptoms such as tearing and occasional pain. Visual acuity improved in 7 patients (25%), decreased in 12 (42.8%), and remained the same in 9 (32.4%). Objective evidence of scarring after ASP was noted in all patients. Complete regression of epithelial bullae and epithelial edema was found in 10 (35.7%) and partial regression in 18 (62.25%) patients. There was no progression or appearance of new blood vessels except in one patient (3.6%). Histologically, puncture marks and superficial stromal scarring were noted in all corneal buttons. Adhesion of epithelium with varying degrees of subepithelial fibrosis was seen in six, whereas in the remaining five buttons, there was complete denudation of the epithelium. Vascularization was seen in five and inflammation in two buttons. Clinicopathologic correlation revealed that symptomatic patients had persistent edema and loose adhesion of the epithelium to the stroma, resulting in detachment. CONCLUSIONS: ASP is a simple, safe, and cost-effective outpatient procedure for symptomatic relief in patients with BK. The possibility of decreased visual acuity after the procedure should be explained to all patients. Although ASP promoted subepithelial fibrosis in all cases, its subsequent adhesion is variable and probably has clinical relevance. Further studies could be directed toward identifying specific mediators that promote epithelial-stromal interaction and firm anchoring of epithelium to the underlying stroma.     

Impression cytology-proven corneal stem cell deficiency in patients after surgeries involving the limbus

PURPOSE: To report three cases of limbal stem cell deficiency (confirmed by impression cytology) that followed multiple pterygium surgeries and therapeutic penetrating keratoplasty. METHODS: The first case, after multiple pterygium surgeries, presented with corneal scarring and thickened epithelium with vascularization sparing the central cornea in the right eye and involving the entire cornea in the left eye. The second case presented with superficial scarring and extensive vascularization after failed therapeutic graft performed for a large perforated corneal ulcer. The third case was a clear graft performed for a progressing fungal ulcer with signs of conjunctivalization inferotemporally. Limbal stem cell deficiency was clinically suspected in all of these cases. RESULTS: Goblet cells with mucin globules were found on the corneal surface by impression cytology in all three cases. CONCLUSIONS: We report three cases of limbal stem cell deficiency (proven by impression cytology) that followed multiple pterygium surgeries and therapeutic penetrating keratoplasty. Surgical insult to the limbus is the predisposing factor for stem cell damage in these cases. Involvement of the limbus by infection and use of intensive medications are probable contributing factors for stem cell damage in cases of therapeutic penetrating keratoplasty.     

Trigonella foenum graecum (fenugreek) seed extract as an antineoplastic agent

The antineoplastic effect of Trigonella foenum graecum seed extract has been evaluated in the Ehrlich ascites carcinoma (EAC) model in Balb-C mice. Intra-peritoneal administration of the alcohol extract of the seed both before and after inoculation of EAC cell in mice produced more than 70% inhibition of tumour cell growth with respect to the control. Treatment with the extract was found to enhance both the peritoneal exudate cell and macrophage cell counts. The extract also produced a significant antiinflammatory effect. We report here the antiinflammatory and antineoplastic effects, of Trigonella foenum graecum seed extract.     

Growth hormone levels in relation to birth weight and gestational age

Growth hormone levels were measured in 33 umbilical cord blood samples collected from babies born at JIPMER Hospital during April and May-1998. The study was done to evaluate the growth hormone profile in relation to birth weight and gestational age. There was statistically significant difference in the cord blood growth hormone levels between babies weighing > 2500 gms (28.1 ± 12.83 ng/dl) and low birth weight babies (76.8 ± 55.7 ng/dl). The difference in growth hormone levels between term babies weighing >2500 gms and preterm babies (72.5 ± 29.4 ng/dl) was also statistically significant. However, there was no significant difference in the cord blood growth hormone levels between term low birth weight and preterm babies. Growth hormone levels were higher in preterm babies and low birth weight babies as compared to term babies weighing >2500 gms indicating that growth hormone has an important role to play in intrauterine growth along with other growth promoting factors.     

Invasive nosocomial aspergillosis associated with heart failure and complete heart block following recovery from dengue shock syndrome.

OBJECTIVE: To report a case of invasive aspergillosis, associated with complete heart block and heart failure, in an immunocompetent child recovering from dengue shock syndrome. DESIGN: Case report and literature review. SETTING: Pediatric intensive care unit in a tertiary care center. PATIENT AND RESULTS: A 9-yr-old boy was admitted to our pediatric intensive care unit with dengue shock syndrome, for which he was successfully managed. During the recovery phase, the child developed recurrence of fever and signs of congestive heart failure. Thereafter, he developed complete heart block and died. Myocardial biopsy revealed myocarditis and invading fungal elements with branching septate hyphae suggestive of Aspergillus. A renal biopsy specimen also showed glomerular invasion with Aspergillus and patchy necrosis. This suggested the diagnosis of invasive aspergillosis. CONCLUSIONS: This case highlights an unusual manifestation of invasive aspergillosis in a critically ill immunocompetent child.