Matrix Metalloproteinase Inhibitors: Applications in Oncology

Matrix metalloproteinases (MMP) are a group of zinc dependentenzymes which include the interstitial collagenases, stromelysins,gelatinases and membrane-type metalloproteinases. They are involvedin the remodelling and turnover of the extracellular matrixproteins. They play a role in wound healing and the pathogenesis ofarthritis. In malignancies they play a role in tumor invasion,metastasis and angiogenesis. A number of synthetic matrixmetalloproteinase inhibitors (MMPIs) have been developed forclinical use. In preclinical tumor models they have shown promisingactivity in achievinginhibition of MMPs and reducing tumor growth and metastatic spread.Some have also shown additive or synergistic effects with cytotoxicagents. Phase I and II studies in human subjects have defined themain side effects of these agents as beingmusculoskeletal pains or arthralgias. As they are cytostatic agentsrather than cytotoxic in activity conventional measurements ofradiological response for assessment are not applicable in trials.Biological activity has been demonstrated in certain cancers by theeffects on levels of tumor markers as surrogate markers of tumorresponse and also by a fibrotic stromal reaction seen in tumortissue. Newer agents have been developed withselective inhibition of certain MMPs in an attempt to reduce theside effects. A number of phase III human clinical trialsevaluating MMPs are being carried out at present but onlyone has been formally reported so far. This study suggested thatmarimastat had no survival advantage when compared to chemotherapywith gemcitabine in advanced pancreatic carcinoma. Current trialsare assessing efficacy of MMPIs in maintenance of remission afterother modalities of therapy or in combination with cytotoxicagents. MMPs have also been demonstrated to play an important rolein the articular cartilage destruction seen in both rheumatoidarthritis and osteoarthritis. The use of MMPIs in both exvivoand in vivomodels have shown promising resultsand trials are in process to assess their potential role in thecontrol of articular destruction. The true therapeutic role ofMMPIs await the results of these randomized studies.     

Breastfeeding and weaning practices in rural communities of Kelantan

A survey of infant-feeding and weaning practices of 566 mothers, systematically sampled from 15 rural villages, randomly selected in the district of Tumpat, Kelantan was carried out. Almost all mothers (97.3%) breastfed their children, reinforcing the previously reported high incidence of breast-feeding among rural Malaysian mothers. One hundred and seventeen (21.3%) of the 551 children breastfed were also given mixed feeding with infant fomulae as well. Weaning started before 4 months of age in 28.3% of the children and after 6 months of age in 12.8% of the children. The 3 most common type of food used in weaning were Nestum (45.0%), rice porridge or paste (42.6%) and wheat porridge or cakes (11.5%). Forty eight children (12.1%) discontinued breastfeeding once weaning was initiated. The main reasons for initiating weaning was mothers' perception that there was insufficient milk and that the child was always hungry (55.7%). Most mothers were also given advice by the health clinic staff on weaning, including the timing and the suitable weaning foods to give. All of the mothers were able to name at least one commercial weaning food product available in their community.     

Plasma melphalan and prednisolone concentrations during oral therapy for multiple myeloma

Summary Nine patients with myeloma were studied over 13 oral administrations of 10 mg melphalan and 5–10 mg prednisolone. Plasma melphalan concentrations were estimated by high-pressure liquid chromatography, prednisolone concentrations by quantitative thin-layer chromatography. The mean plasma half-life of unchanged melphalan was 0.9±0.5 (SD) h. The lag-time before melphalan was detected in the plasma varied from 1 to 4 h, the mean peak concentration was 96±21 ng/ml, and the mean area under the plasma concentration by time curve was 160±78 ng h/ml. This variability was consistent with observations made elsewhere following much higher oral doses of melphalan and illustrates the relatively wide interindividual variability of absorption. Observations made in the same subjects on two separate occasions showed lower variability. The melphalan elimination rate was not significantly affected by moderate impairment of creatinine clearance (to 31 ml/min). Absorption of prednisolone in five of these patients was apparently normal and unaffected by concurrent administration of melphalan.     

The surgical treatment of carcinoma of the colon and rectum: an index of quality care and sociologic and geographic distribution.

A comparative experience of 474 patients with primary carcinoma of the colon and rectum has been evaluated in several hospital settings, with particular respect to patient populations, geographic distribution, and surgical characteristics. The differences and similarities are interpreted with caution but may provide a format by which significant objective determinants become the basis for subsequent assessment of quality care in an illness which is prevalent and amenable to relatively standardized operative management. No difference in quality of medical care provided was detectable across the sociologic and geographic boundaries studied. Notable increases in extent of neoplasm and severity of co-existent illness in the urban, "indigent" population adversely influenced both short and long-term mortality rates.     

Controlled trial of frusemide as an antiepileptic drug in focal epilepsy

1 The antiepileptic activity of oral frusemide (120 mg daily) was compared with that of an identical placebo in a double-blind crossover trial in fourteen patients with severe focal epilepsy who were receiving long-term therapy with established antiepileptic drugs.

2 A statistically significant reduction in the frequency of focal fits was seen with the active drug.

3 Marked drowsiness occurred in three patients during frusemide therapy, causing their withdrawal from the trial.

4 A slight, but significant, rise in serum phenobarbitone concentrations was observed during frusemide therapy, but no change was seen in serum primidone or phenytoin concentrations.

5 Frusemide significantly lowered plasma sodium and potassium concentrations, and increased plasma bicarbonate.

     

Electrogustometry: strengths,weaknesses, and clinical evidence of stimulus boundaries

Electrogustometry is well established as a clinical tool for the estimation of taste detection thresholds. Nevertheless, the user is sometimes unaware of the impact of superficially minor procedural and psychophysical factors upon the reliability and comparability of threshold estimates. The inherent strengths and limitations of the procedure are outlined, and aspects of the control and specification of the stimulus that moderate threshold measures are discussed. In addition, threshold estimates from two individuals with severe unilateral taste loss are used to illustrate the level at which anodal dc current may elicit common, rather than taste, sensation. Where chorda tympani section is complete and historical (older than 7–14 days), very high stimulus levels, conservatively over 5 µA/mm² (100 µA linear current with a 5‐mm diameter electrode), are required to activate trigeminal responses.     

Abdominal cerebrospinal fluid pseudocyst

A case of an abdominal cerebrospinal fluid (CSF) pseudocyst in a patient with a ventriculoperitoneal shunt is reported to illustrate this known but rare complication. In the setting of a VP shunt, the frequency of abdominal CSF pseudocyst formation is approximately 3.2%, often being precipitated by a recent inflammatory or infective process or recent surgery. Larger pseudocysts tend to be sterile, whereas smaller pseudocysts are more often infected. Ultrasound and CT each have characteristic findings.     

Acute rejection-associated tubular basement membrane defects and chronic allograft nephropathy

BACKGROUND: Acute rejection is a major risk factor for chronic allograft nephropathy, although the link(s) between these events is not understood. The hypothesis of this study is that alterations in tubular basement membranes (TBMs) that occur during acute rejection may be irreversible and thereby play a role in the development of chronic allograft nephropathy. METHODS: Fourteen renal transplant patients were selected, each having had two or more biopsies performed (42 total). All biopsies were scored for acute and chronic rejection using Banff 1997 criteria. The initial biopsy showed only acute interstitial rejection (type I rejection). No biopsies contained significant chronic arterial lesions of chronic vascular rejection. The entire cortex was examined on Jones methenamine silver-stained sections at x400 for interruption in TBM staining. The number of tubules with TBM abnormalities was counted, and the renal cortical area was measured by image analysis. Periodic acid-Schiff/immunoperoxidase stain was performed on 12 acute rejection biopsies stained for laminin, cytokeratin 7, CD3, CD20, and CD68. Controls consisted of 11 biopsies (8 negative for rejection and 3 acute tubular necrosis). RESULTS: Numerous TBM alterations in silver staining were identified as being associated with acute rejection and tubulitis, consisting of abrupt TBM discontinuities and/or extreme attenuation with segmental or complete absence of TBM. A loss of TBM matrix proteins was confirmed by absent laminin staining in areas of acute rejection and tubulitis. There was herniation of tubular cells into the interstitium through TBM defects confirmed by cytokeratin staining. The TBM defects were spatially associated with inflammatory cells, particularly macrophages. When the biopsies were divided into two groups, <10 and> 10 TBM breaks/mm2, there were statistically significant morphologic and clinical correlations. The number of TBM disruptions correlated with the serum creatinine at the time of biopsy, a combined Banff t + i score, the difference in tubular atrophy between the initial and most recent biopsy and the difference between the nadir creatinine and most recent creatinine. CONCLUSION: Damage to TBM develops in acute rejection as a consequence of interstitial inflammation and tubulitis. These lytic events correlate with the later development of clinical and morphologic evidence of chronic injury in the absence of arterial injury of chronic rejection. We suggest that chronic allograft nephropathy may have an inflammatory interstitial origin.     

Cell-mediated immune response is better preserved by laparoscopy than laparotomy

BACKGROUND: This study compares the effects of carbon dioxide pneumoperitoneum versus laparotomy on cellular-mediated immune response in a murine model. METHODS: Sixty-eight female C3H/He mice were sensitized to keyhole limpet hemocyanin (KLH) and to a mouse mammary carcinoma cell line (MC2) before surgery. Animals were randomized into 4 groups: group I, anesthesia (control); group II, pneumoperitoneum with carbon dioxide; group III, extraperitoneal wound; group IV, laparotomy. All animals were challenged subsequently with KLH and MC2 tumor cells. Delayed-type hypersensitivity skin reaction (DTH) to KLH was measured on postoperative days (PODs) 1, 2, 4, and 5. Tumor growth was assessed weekly as an indicator of postoperative cellular immune response. RESULTS: Compared with preoperative values, postoperative DTH skin reactions were significantly less for all PODs in groups III and IV (P < .05), on POD 1 and 4 in group II (P < .05) and POD 4 for group I (P < .05). Group IV showed significantly fewer DTH skin reactions for all PODs compared with groups I and II (P < .05) and all PODs except on day 2 compared with group III (P < .05). Tumor growth was significantly increased at postoperative week 2 (n = 3/17 mice) and 3 (n = 4/17 mice) in group IV, when compared with groups I and II (P < .05). CONCLUSIONS: Cellular immunity is preserved after carbon dioxide pneumoperitoneum compared with extraperitoneal incisions and laparotomy as measured by DTH and the ability to reject an immunogenictumor.     

Supraventricular arrhythmia: A complication of 5-fluorouracil therapy

5-Fluorouracil is an S-phase-specific, synthetic pyrimidine antimetabolite, which is used as a cytostatic agent for a variety of malignant lesions, either singly or in multidrug regimens. Gastrointestinal toxicity and myelosuppression are the most common adverse reactions, but, of late, clinical cardiotoxicity has been reported in both prospective and retrospective studies. We present our experience of clinical cardiotoxicity in five patients.