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Biomedical subjects

M Mohiuddin

Publications and source records attributed to M Mohiuddin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Current and emerging treatments for pancreatic cancer.

The worldwide annual pancreatic cancer death rate equals its estimated annual incidence. Surgery has been considered the only curative modality for this disease, but only 5 to 15% of patients are candidates for potentially curative resection. Evidence that postoperative adjuvant treatment improves outcome has been limited to a single randomised trial of a well tolerated split-course chemoradiation regimen. More intensive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative adjuvant ('neoadjuvant') chemoradiation in these patients. Although experience suggests that such an approach is feasible, its ultimate impact awaits further evaluation. Combined modality therapy has produced the most promising results in patients with unresectable or locally advanced disease. However, only modest improvements in median survival and minimal increases in long term survival have so far been achieved. This observation has encouraged many investigators to devise innovative methods of delivering therapy, including radioisotope implantation and intraoperative radiation therapy (IORT). Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. IORT may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by the radiobiological disadvantage associated with single dose boost therapy. Although new radiosensitising drugs are being tested, the problem of distant metastasis remains significant. New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil. Investigations into the optimal integration of different therapeutic modalities, along with continued advances in surgery, radiation and systemic therapy, should lead to the increased use of modern multimodality interventions. In turn, this will lead us towards further improvements in outcomes for patients with pancreatic carcinoma.

Antimetabolites, Antineoplastic↗
PubMed1997

Critical issues in the evolving management of rectal cancer.

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.

Combined Modality Therapy↗
PubMed1996

Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats.

BACKGROUND: Vesnarinone (VES) has been used for treatment of patients with congestive heart failure. In addition to inotropic effects, it seems to have immunosuppressive action. We tested the hypothesis that VES suppresses graft rejection, inotropic dysfunction caused by early rejection, and chronic coronary obstruction in a heterotopic rat cardiac transplantation model. METHODS: (1) To study acute rejection, hearts from Lewis-Brown Norway (LBN) rats were transplanted into Lewis rats, which were treated with or without VES (50 or 100 mg/kg/day orally). (2) In a functional study, LBN hearts with or without VES (100 mg/kg/ day) were isolated and perfused on day 3 after transplantation to assess inotropic response to isoproterenol (3 x 10(-8) M). (3) To study chronic rejection, Lewis hearts were transplanted into Fisher 344 rats, which were treated with or without VES (50 mg/kg/day) for 90 days. Coronary obstructive disease was assessed by morphometric analysis. There were five to six animals in each group. RESULTS: (1) VES (100 mg/kg/day) prolonged LBN heart survival (11.7 +/- 0.7 vs. 9.6 +/- 0.7 days in control; P < 0.05). (2) Left ventricular developed pressure was depressed in transplanted hearts regardless of VES treatment (84 +/- 12, 90 +/- 8 vs. 144 +/- 16 mmHg in untransplanted hearts; P < 0.01). The developed pressure after administration of isoproterenol in VES-treated hearts (184 +/- 20 mmHg) was higher than transplanted hearts without VES (118 +/- 16 mmHg; P < 0.05), and similar to untransplanted hearts (203 +/- 27 mmHg; P = NS). (3) Transplanted hearts treated with or without VES showed similar grades of rejection (2.0 +/- 0.3 vs. 2.6 +/- 0.2; P = NS), intimal area (6,996 +/- 3,186 vs. 13,441 +/- 5,165 microns2; NS), and coronary luminal obstruction (45 +/- 16% vs. 67 +/- 14%; NS). CONCLUSIONS: VES produces mild prolongation in survival of rat heart grafts, but has no significant effect on chronic graft atherosclerosis. VES preserves the positive inotropic effects of isoproterenol that are otherwise deteriorated by early acute rejection.

Acute Disease↗
PubMed1996

EGR-1 induction is required for maximal radiosensitivity in A375-C6 melanoma cells.

Exposure to ionizing radiation leads to induction of the immediate-early gene, early growth response-1 (Egr-1). Previous studies have suggested distinct cell type- and inducer-specific roles for EGR-1 protein in cellular growth inhibition. The present study was undertaken to determine the functional role of EGR-1 in growth inhibition caused by exposure of tumor cells to ionizing radiation. Exposure to ionizing radiation caused induction of EGR-1 protein in human melanoma cells A375-C6. Inhibition of either the function of EGR-1 protein by stable transfection with a dominant-negative mutant or the expression of EGR-1 by transient transfection with an antisense oligomer resulted in a diminished growth-inhibitory response to ionizing radiation. Because previous studies have suggested that mutations in the tumor-suppressor gene p53 confer radio-resistance, we examined the p53 status of A375-C6 cells. Interestingly, both the parental and the transfected A375-C6 cells showed trisomy for wild-type p53 alleles. Exposure to ionizing radiation resulted in induction of p53 protein that localized to the nucleus in A375-C6 cells. These data suggest that inhibition of EGR-1 function confers radio resistance despite the induction of wild-type nuclear p53. Thus, EGR-1 is required for the growth-inhibitory response to ionizing radiation in A375-C6 cells.

Cell Division↗
PubMed1996

Prognostic significance of tumor fixation of rectal carcinoma. Implications for adjunctive radiation therapy.

BACKGROUND: This study was conducted to assess the prognostic significance of adjunctive radiation in the surgical management of rectal carcinoma patients with tumor fixation. METHODS: Two hundred and ninety-seven patients with a histologic diagnosis of adenocarcinoma of the rectum were treated with high dose preoperative radiation ( > or = 45 Gray [Gy]) followed by surgical resection of the tumor (Group A). One hundred and seventy-four patients underwent initial curative surgery (Group B) followed by selective postoperative radiation (45-50 Gy) for those with pathologic T3, T4, or N+ (B2, C) cancers (N = 143). The two patient groups were compared by presenting clinical stage of the disease to assess the prognostic significance of tumor fixation on results of adjunctive therapy. Follow-up ranged from 24 months to 180 months. RESULTS: The 5-year actuarial survival of Groups A and B was similar, 69% and 61% respectively. Survival was significantly better for Group A patients with fixed cancer (57% vs. 33%, P = 0.003). Survival was also better for patients in Group A with tumors located in the distal rectum (70% vs. 56%, P = 0.02). The local recurrence rate for patients with tumors located in the distal rectum was 17% for Group A and 19% for Group B (P = 0.74). The local recurrence rate for fixed cancers was 23% and 50% for Group A and Group B respectively (P = 0.0009). The incidence of small bowel complications (Grade 3 or 4) was lower for patients undergoing preoperative radiation compared with patients treated with postoperative radiation, (4% vs. 13%, P < 0.05). CONCLUSIONS: When special considerations of sphincter-preserving surgery are not an issue, mobile rectal carcinoma may be effectively treated with surgery and selective postoperative radiation. However, fixed tumors, especially those located in the distal rectum, are better treated with high dose preoperative radiation.

Adenocarcinoma↗
PubMed1996

C-Ki-ras mutations in peripheral blood of pancreatic cancer patients: a marker for early tumor metastasis.

PURPOSE: To determine the incidence of circulating minimal malignant clone (CMMC) (harboring c-Ki-ras-2 mutation) in peripheral blood (PB) samples of untreated pancreatic cancer using polymerase chain reaction (PCR) analysis of c-Ki-ras-2 oncogene. METHODS AND MATERIALS: Experiments were carried out in fresh tumor, peritoneal washings (PW), and PB samples of untreated pancreatic adenocarcinoma patients (both resectable and unresectable). Samples were taken from 16 patients diagnosed with pancreatic adenocarcinoma for the PCR analysis of mutated c-Ki-ras oncogene. Five tumor samples, 15 PB samples, and 3 PW samples were analyzed for point mutation of the c-Ki-ras gene at codon 12. RESULTS: Out of five tumor samples analyzed for c-Ki-ras mutation, four were positive at the 12th codon. Out of total 15 PB samples, nine were positive for the c-Ki-ras point mutation at the 12th codon. All the positive PB samples showed a base substitution from GGT to GAT in the second position of the 12th codon. Out of three PW samples, two showed mutation at the second position from GGT to GAT similar to their PB and tumor samples. CONCLUSION: Our study indicated the presence of the tumor cells (CMMC) in PB of pancreatic adenocarcinoma that can be identified by PCR analysis of c-Ki-ras oncogene. Patients with presence of CMMC in PB and mutation in PW had aggressive tumors that responded poorly to treatment.

Adenocarcinoma↗
PubMed1996

Expression and mutation of H-ras in uterine cervical cancer.

In cervical cancer, abnormalities of ras genes have not been fully investigated. We studied the expression and mutation of H-ras oncogene in cervical cancer to investigate their relationship and usefulness as an independent prognostic indicator. Twenty-seven paraffin-embedded resection specimens of cervical cancer (21 squamous, 3 adeno, 2 adenosquamous, and 1 small cell) were examined by immunohistochemistry using a mAb H-ras p21 and by PCR and allele-specific oligonucleotide hybridization using H-ras codon 12 and 61 amplimers and oligonucleotide probes. A strong immunoreaction was noted in 10 cases (37%) and weak immunoreaction in an additional 6 cases (22%). H-ras codon 12 mutations were detected in 6 of 27 cases (22%) and all of the mutations were guanine to adenine transitions. There was no mutation in codon 61. Cases with codon 12 mutations included all 3 squamous, 2 adeno, and I adenosquamous carcinoma. Only 3 of 16 (19%) cases with positive staining and 3 of 11 (27%) cases with negative staining showed mutations. No correlation was found between ras gene alterations and patient survival time. Our findings indicate that expression and mutation of H-ras oncogene occur in cervical cancer but their determination adds no useful prognostic information.

Adult↗
PubMed1996

Tolerance to cardiac allografts requires a time lag between intrathymic treatment and transplantation.

Permanent tolerance to an experimental heterotopic cardiac allograft can be achieved by pretreatment with antilymphocyte serum (ALS) and intrathymic inoculation of donor cells. Most successful experimental protocols have employed a time lag of 2 to 3 weeks between intrathymic pretreatment and transplantation, which makes this treatment strategy impractical for clinical heart transplantation. In these experiments we modified the standard protocol by giving ALS 24 hr prior to both intrathymic injection of donor cells and heterotopic transplantation. Seven Lewis rats had intraperitoneal injection of 1 ml of ALS and 24 hr later underwent intrathymic injection of 5 X 10(7) donor Lewis-Brown Norway (LBN) splenocytes and heterotopic cardiac transplantation using an LBN donor. Mean graft survival was 24.4 days, significantly longer than the 7.8-day graft survival observed in untreated Lewis recipients (n = 5) (P < 0.02). However, graft survival was not different from that observed in Lewis rats pretreated with ALS alone (n = 5) (25.8 days, P = NS). Permanent graft survival was produced in two rats receiving only A-LS and in one rat receiving both ALS and intrathymic inoculation. In these experiments it appears that prolongation of graft survival may have been due to the effect of A-LS alone. These results suggest that there is a critical time period between intrathymic inoculation and transplantation that is needed for permanent tolerance to be induced consistently. This may be due to the kinetics of the effects of ALS on alloreactive T-lymphocytes or to a time-dependent requirement for antigen processing in the thymus.

Animals↗
PubMed1996

Fetal inoculation with donor cells in cardiac xenotransplantation.

BACKGROUND: In utero fetal inoculation with allogeneic cells has produced subsequent tolerance to experimental cardiac allografts. We attempted to extend this observation to a model of xenogeneic cardiac transplantation. METHODS: Lewis rat fetuses were inoculated with Golden Syrian hamster thymocytes (n = 5) or whole spleen cells (n = 5) on the tenth day of intrauterine life. Six weeks after the birth of pretreated fetuses, heterotopic cardiac transplantation using a hamster donor was performed. Three to 4 weeks after parturition, we performed heterotopic cardiac transplantation using hamster donors in the female Lewis rats whose fetuses had been treated in utero. RESULTS: Animals treated in utero with either thymocytes or whole spleen cells had graft survival of 3 days, not different from that in untreated Lewis rats (n = 5) (p = not significant). Maternal Lewis rats whose fetuses were treated with thymocytes (n = 5) or whole spleen cells (in = 4) had markedly reduced survival of xenogeneic cardiac grafts (range, 3 to 20 hours; mean, 15 hours; p < 0.01; and range, 5 to 15 minutes; mean, 10 minutes; p < 0.01, respectively). Female Lewis rats without intrauterine inoculation (n = 5) had expected xenograft survival time (3 days) (p = not significant). Immunohistochemical staining of hyperacutely rejected grafts showed deposits of immunoglobulin M as well as immunoglobulin G and complement. In normally rejected xenografts, no immunoglobulin M was detected. CONCLUSIONS: These studies reveal the surprising observation that fetal exposure to xenogeneic cells sensitizes the maternal rat without tolerizing the fetal rat as observed in an allograft model. In addition, whole spleen cells produce a more vigorous hyperacute rejection than thymocytes, suggesting that B cells or macrophages may be the sensitizing agents. The accelerated rejection observed has the characteristics of an immunoglobulin M antibody-mediated hyperacute rejection response with deposition of complement.

Animals↗
PubMed1996

Differential dose delivery for cancers of the head and neck.

A technique was developed for the treatment of head and neck cancers that employs differential dose delivery to primary and nodal areas while simultaneously correcting the dose delivered through various thickness of tissue in the field(s). Our technique modulates the intensity of the static lateral fields in three dimensions utilizing data acquired from a pre-treatment CT scan. This technique has been used to treat patients with various cancers of the head and neck. All patients tolerated treatment well with no observed increase in acute normal tissue reactions.

Head and Neck Neoplasms↗
PubMed1996

Induction of tolerance to an experimental cardiac allograft through intrathymic inoculation of class II major histocompatibility complex disparate antigens.

Indefinite donor-specific tolerance to a cardiac allograft can be induced through pretransplantation intrathymic injection of donor spleen cells and a single intraperitoneal injection of antilymphocyte serum. This study was designed to determine whether this phenomenon was reproducible with grafts differing in either class I major histocompatibility complex only or class II MHC only. Donors of cells and hearts in all experiments were RP rats. Class I MHC disparate grafts were performed by placing an RP heart into a Lewis recipient, and class II disparate grafts were performed with RP donors and Wistar Furth recipients. Lewis (n = 10) and Wistar Furth (n = 10) recipients underwent intraperitoneal injection of 1 ml antilympocyte serum and intrathymic injection of 5 x 10(7) RP spleen cells. Three weeks later, heterotopic cardiac transplantation was done with a heart from an RP rat. Control rats had no pretreatment or received antilympocyte serum alone. Without pretreatment, RP hearts survived 7 to 9 days (mean 8 days) in Lewis recipients (n = 5) and 9 to 14 days (mean 12 days) in Wistar Furth recipients (n = 5). Antilymphocyte serum alone produced slight prolongation of graft survival. Lewis rats pretreated with class I disparate RP splenocytes and antilympocyte serum had graft survivals of 8 to 27 days (mean 14 days), not significantly different from the results with antilympocyte serum alone. Class II disparate RP grafts placed in pretreated Wistar Furth rats had significant prolongation of graft survival, with four of five grafts surviving longer than 60 days (p < 0.01 vs antilympocyte serum alone). These results suggest that a disparity at the class II locus of the major histocompatibility complex is critical for the induction of cardiac allograft tolerance after intrathymic inoculation of allogeneic cells.

Animals↗
PubMed1996

T-cell receptor expression in C57BL/6 mice that reject or are rendered tolerant to bm1 cardiac grafts.

To study the molecular immunologic features of allograft rejection and tolerance induction by intrathymic pretreatment we developed a murine model of cardiac transplantation. In this model the transplant recipient was the C57BL/6 mouse with its major histocompatibility phenotype H-2b. Donors of cells for intrathymic pretreatment and of hearts for grafting were mice of the bm1 mutation. The bm1 mutation involves substitution of three amino acids in one of the alpha helixes of the class I H-2Kb molecule. Because of the discrete molecular configuration of the transplant antigen we hypothesized that there would be limited heterogeneity of receptor expression on C57BL/6 T cells responding to bm1 cardiac grafts and that intrathymic pretreatment would alter the T-cell repertoire of graft recipients by causing elimination of T cells responsible for graft rejection. Mice were given 0.3 ml of antilymphocyte serum intraperitoneally and had intrathymic injection of 25 x 10(6) bm1 splenocytes 12 to 21 days before transplantation with a bm1 cardiac graft. Flow cytometric analysis of lymph node and spleen cells was used to study the V beta T-cell repertoire of graft recipients. Cells were stained with monoclonal antibodies to CD3 and 13 V beta regions (n = 5, each group) of T cells in naive, sensitized, and tolerant animals. Untreated C57BL/6 mice (n = 9) rejected bm1 cardiac grafts a mean of 20.4 days after transplantation. Twelve mice pretreated with antilymphocyte serum and intrathymic bm1 cells had permanent graft survival (> 100 days, p < 0.0001). Animals treated with antilymphocyte serum alone (n = 5) or pretreated animals undergoing third-party BALB/c grafts (n = 4) rejected grafts in the normal time frame. There was significant alteration of percentage receptor expression of V beta 5.1, 7, 12, 13, and 17a in sensitized and tolerant mice. Of interest, V beta 7 expression was increased in the sensitized mice (3.8% to 8.3%,p = 0.005) and was virtually eliminated in tolerant mice (p = 0.005). In conclusion, these data suggest that V beta 7 is a critical receptor in the C57BL/6 response to subcutaneous bm1 cardiac grafts. Pretreatment of graft recipients with one dose of antilymphocyte serum and intrathymic bm1 cells appears to produce permanent tolerance to bm1 grafts with elimination of T cells expressing receptor chain V beta 7.

Animals↗
PubMed1996

Durability of donor-specific and organ-specific heart transplant tolerance induced by intrathymic pretreatment with allogeneic spleen cells.

Permanent acceptance of an experimental cardiac allograft can be achieved in the rat by pretreating the recipient with antilymphocyte serum and intrathymic donor lymphocytes. We investigated the durability and specificity of the tolerance produced by this pretreatment in a rat model of heterotopic heart transplantation with Lewis-Brown Norway donors and Lewis recipients. Pretreated Lewis rats received 1 ml antilymphocyte serum intraperitoneally and 5 x 10(7) Lewis-Brown Norway splenocytes intrathymically, followed 21 days later by Lewis-Brown Norway cardiac transplantation. The first Lewis-Brown Norway cardiac allograft survived long term (mean 140 days) in pretreated recipients who were given no subsequent immunosuppression. After 60 days with a beating Lewis-Brown Norway allograft, tolerant Lewis recipients underwent a second cardiac allograft with either a Lewis-Brown Norway heart or a third-party Wistar-Furth heart. The second Lewis-Brown Norway cardiac allograft was not rejected (mean survival 76 days), but that from the third-party Wistar-Furth donor was rejected in a normal fashion (mean survival 10.4 days). The presence of second grafts did not affect survival of first grafts. Tolerant Lewis recipients of two Lewis-Brown Norway heart grafts underwent subsequent transplantation with Lewis-Brown Norway skin. Skin allograft survival in this group (mean 8.4 days) was not different from that in Lewis recipients without pretreatment. Rejection of skin grafts had no effect on the heart grafts. These data suggest that tolerance to cardiac allografts produced by intrathymic pretreatment is durable and extends to a second heart graft from a genetically identical donor. Tolerant rats reject third-party hearts and primary donor skin grafts normally, and tolerance to previously placed heart grafts is not abrogated by this rejection. Non-major histocompatibility complex skin antigens not present on cardiac cells may account for the tissue specificity of the tolerance produced by intrathymic treatment in this model.

Animals↗
PubMed1996

Combined liver radiation and chemotherapy for palliation of hepatic metastases from colorectal cancer.

PURPOSE: To report the effects of boost dose radiation on palliation, survival, and toxicity in patients undergoing palliative treatment for hepatic metastases from colorectal cancers and to assess the potential benefits of higher doses of radiation to partial liver volumes. MATERIALS AND METHODS: Forty-five patients with hepatic metastases from colorectal cancers were treated with a course of palliative irradiation. Eligible patients included those with radiographically or histologically proven liver metastases. All patients but one received chemotherapy, either pretreatment (one patient) and/or concurrently with radiation (43 patients) via intravenous or hepatic intraarterial infusion. Patients were divided into two groups based on whether or not boost radiation was given. Thirty-three of the 45 patients (group 1) received whole-liver irradiation at doses that ranged from 8 to 31 Gy at 2.0 to 3.0 Gy per fraction (median dose, 21 Gy). The remaining 12 patients (group 2) received liver irradiation to 20 to 30 Gy followed by a boost dose to the area of dominant disease for a total dose of 33 to 60 Gy. The extent of liver involvement was similar between the two groups. Palliation, overall survival, and toxicity were analyzed with respect to radiation dose. RESULTS: There was no increase in acute effects observed in treating partial liver volumes to higher doses in conjunction with systemic chemotherapy. No cases of radiation-induced hepatitis or nephritis were documented. Hematologic toxicity (> or = grade 3) was observed in four patients with thrombocytopenia, three with leukopenia, and two with anemia. Pain was relieved in 71% and hepatomegaly in 59% of group 1 patients, as compared with 100% and 89%, respectively, of group 2 patients. Other symptoms such as nausea, fever, fatigue, and jaundice were palliated in 35% of group 1 and 90% of group 2 patients. The median survival time for group 1 patients was 4 months (range, 1 week to 26 months), which is consistent with that reported in the literature. The median survival time for group 2 patients was 14 months (range, 2 to 32 months) (P=.01). CONCLUSION: Standard hepatic irradiation followed by boost radiation to partial liver volumes in combination with chemotherapy is well tolerated without significant acute/late morbidity. Higher radiation doses to partial liver volumes offers improved palliative benefit and may prolong survival without an increase in morbidity.

Adult↗