Drug insight: thalidomide as a treatment for multiple myeloma

Multiple myeloma (MM)--a malignancy of the bone marrow--remains incurable by current therapies, and there is an urgent need for new drugs based on a better understanding of the underlying disease biology. MM is characterized by monoclonal plasma cells that accumulate in the bone marrow, which provides a microenvironment that promotes tumor cell growth and survival and protection against various therapeutic agents. The MM cell interacts with bone marrow stromal cells and endothelial cells, as well as osteoblasts and osteoclasts. Our understanding of the tumor microenvironment has already prompted the development of new agents that are aimed at disrupting the multiple facets of these interactions. It has also enabled the development of a comprehensive and rational approach to preclinical evaluation of new agents, facilitating the translation of in vitro studies to in vivo tumor models and, subsequently, to clinical trials. In this review, we describe the preclinical studies that led to the development of clinical trials of thalidomide and its immunomodulatory derivatives as therapeutic agents for MM. These drugs, alone or in combination, have shown impressive activity at all stages of the disease, and these demonstrations of clinical benefit have in turn validated our model systems for drug discovery in MM. Integration of data from clinical trials and laboratory studies will allow the design of future clinical trials that combine thalidomide and its derivatives with other drugs, ultimately leading to more effective therapies and better outcomes in patients with MM.     

Hyperbilirubinemia in homozygous HbE disease is associated with the UGT1A1 gene polymorphism

Homozygous HbE [beta26(B8)Glu-->Lys] is a clinically mild disorder with no significant symptoms. However, we have frequently noted hyperbilirubinemia among patients with homozygous HbE in the Indian population, with jaundice being the major complaint at presentation. A study of the UGT1A1 gene polymorphism shows that the variant TA7 in the promoter region of the UGT1A1 gene is associated with hyperbilirubinemia in homozygous HbE patients.     

E2 sequence variations of HPV 16 among patients with cervical neoplasia seen in the Indian subcontinent

OBJECTIVES: Specific nucleotide variations in the E2 DNA sequence were looked for in samples with an intact human papillomavirus (HPV) 16 episomal E2 DNA. METHODS: Ninety-two women, 76 with invasive cervical carcinoma and 16 with cervical intraepithelial neoplasia (CIN) were recruited. HPV DNA typing was performed by polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). Intact episomal E2 DNA of HPV 16 was detected by PCR. Important nucleotide variations in samples with amplifiable E2 DNA were detected by RFLP. Nucleotide sequencing was performed on representative samples to confirm RFLP findings. RESULTS: A total of 89 (96.7%) women were positive for HPV DNA. Of these, 56 (63%) were positive for HPV 16, and of these, 38 (68%) were positive for intact episomal HPV 16 E2 DNA while 18 (32%) were negative. Samples with intact episomal HPV 16 E2 DNA sequences were grouped into four different digestion profiles I to IV based on RFLP patterns. Digestion patterns revealed absence of any sequence variations in samples with digestion profile I and presence of a 2983 A-G variation in those with profile II. Samples with digestion profiles III and IV revealed three variations in the hinge region (3516 C-A, 3538 A-C, 3566 T-G) and two in the DNA binding domain (3684 C-A, 3694 T-A) of the E2 sequence. Sequencing performed on representative samples confirmed RFLP findings. CONCLUSIONS: PCR-RFLP helped in the identification of important HPV 16 E2 sequence variations, circumventing the need for sequencing. The presence of the nucleotide variations in positions that could alter the biological and immunological functions of the E2 protein combined with its increased occurrence in this study bring out the importance of these variations.     

Comparison of the effect of diclofenac with hyoscine-N-butylbromide in the symptomatic treatment of acute biliary colic

BACKGROUND: Although non-steroidal anti-inflammatory drugs (NSAID) and spasmolytics have been used to relieve biliary colic, the role of these drugs in the natural history of biliary colic has not been clarified. The objective of the present study is to compare the efficacy of intramuscular diclofenac with intramuscular hyoscine in the treatment of pain of acute biliary colic, and to study their role in the natural history of biliary colic and in the prevention of cholelithiasis-related complications. METHODS: Seventy-two consecutive patients with biliary colic were enrolled in this prospective, randomized, double-blind study. They received either a single 75 mg intramuscular dose of diclofenac (n = 36) or similarly administered 20 mg of hyoscine (n = 36). Pain severity was recorded on a visual analogue scale 30 min, 1 h, 2 h and 4 h after injection of the drug. Patients were then followed closely for the next 72 h for persistence or relapse of pain, or development of acute cholecystitis, or drug related complications. RESULTS: Diclofenac provided much more rapid relief of pain than hyoscine, as shown by significantly lesser pain scores after injection of the drug. 91.7% of patients on diclofenac were completely relieved of pain at 4 h as compared to 69.4% with hyoscine (P = 0.037). Progression to acute cholecystitis was seen in only 16.66% of patients on diclofenac as compared to 52.77% on hyoscine (P = 0.003). CONCLUSIONS: In patients with biliary colic, diclofenac gives much faster and more effective pain relief in a significantly larger number of patients as compared with hyoscine. Most remarkably, diclofenac can prevent progression of biliary colic to acute cholecystitis in a significant number of patients.     

Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells

PURPOSE: Maspin, a unique member of the serine protease inhibitor family, shows tumor suppressing activity for breast cancer progression and metastasis. Few studies have directly linked maspin function to prostate cancer. We used prostate tumor cells derived from the TRAMP (transgenic adenocarcinoma of mouse prostate) prostate tumor model to study the tumor suppressive function of maspin in prostate cancer. MATERIALS AND METHODS: Maspin cDNA was introduced via a retroviral plasmid into TRAMP C2N prostate tumor cells, which are aggressive and invasive in nature. We investigated the tumorigenesis of these stable cell lines in vitro by assessing the growth rate, anchorage independence and adhesion to extracellular matrix proteins such as fibronectin and laminin. RESULTS: Stable cell lines expressing maspin had decreased tumorigenic potential, as assessed by anchorage independent growth in soft agar assay compared with controls. Maspin stable transfectants showed decreased metastatic potential, as evaluated by modified Boyden chamber assay and increased adhesion to fibronectin and laminin. CONCLUSIONS: Our study confirms that maspin has a tumor suppressive role not only in breast cancer, but also in prostate cancer. The data in this study suggest that maspin can decrease the tumorigenic and metastatic potential of prostate tumors, most probably by remodeling cell-extracellular matrix interactions or triggering extracellular matrix mediated signaling pathways that negatively regulate tumor migration and invasion.     

Genetics of familial dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by ventricular dilatation and impaired systolic function. DCM is the most common form of cardiomyopathy, and is also the commonest cause for heart failure and cardiac transplantation in adults and children. The frequency of familial occurrence of DCM had been significantly underestimated in the past, but extensive family studies showed that 35–45% of cases are familial. This recognition led to molecular genetic investigations that have further enhanced the understanding of the molecular pathogenesis of DCM. In this review, we discuss these new insights into the genetics of DCM which will have important implications for the diagnosis, risk stratification and treatment of DCM.     

Adjuvant chemotherapy for colon cancer

Colon cancer remains the third most common cancer, and cause of cancer-related death in the United States. Greater public awareness and acceptance of screening programs have contributed significantly to increasingly earlier detection of colon cancer and decreased mortality. Advances made in the understanding of this disease, both in terms of its clinical behavior and molecular pathogenesis, have translated into major improvements in its therapy. Several large randomized trials during the last two decades have helped the oncology community forge a successful multi-modality treatment strategy against colon cancer. These studies have defined the role of adjuvant therapy for colon cancer after curative surgery. Despite all the advances, a large number of patients continue to succumb to this disease, and the search for better therapies is still necessary. In this article, we discuss the evolution and the current state of adjuvant chemotherapy in colon cancer and briefly review new developments.     

Feasibility of day‐care open cholecystectomy: Evaluation in an inpatient model

Background : Open cholecystectomy is still a fairly frequently performed operation worldwide, and is used where laparoscopic surgery has failed or is contraindicated, and where some surgeons do not operate laparoscopically for technical reasons. In developing countries laparoscopic cholecystectomy is costly and is available only in a few centres. The present study was conducted to assess the feasibility of day‐care open cholecystectomy using an inpatient model. Methods : Thirty patients were subjected to open cholecystectomy. Intraoperative nasogastric decompression and local wound infiltration with 0.25% bupivacaine was carried out. Postoperatively patients were encouraged to be ambulant, pass urine and start oral fluids. Intravenous fluids and parenteral medication were stopped at 8 p.m. when patients were assessed for feasibility for discharge. All patients were reassessed the next morning for any adverse effects that could have occurred had the patients been discharged on the evening of surgery. Results : Prospectively, 73.3% of patients were considered to be dischargeable on the evening of surgery; but on reassessment the next morning, retrospectively, 93.3% of patients were actually dischargeable on the evening of surgery. A total of 76.6% of patients was actually discharged within 24 h of surgery. No patient required readmission. On follow up there were no complications that could be attributable to early discharge. A total of 83.3% of patients approved of day‐care open cholecystectomy. Conclusions : Day‐care open cholecystectomy is safe and feasible. In developing countries, where the use of laparoscopic surgery is limited due to resource constraints, day‐care open cholecystectomy can lead to substantial savings in health‐care resources.