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Biomedical subjects

S Martino

Publications and source records attributed to S Martino.

At least 19 recordsLinked to original sources
PubMed2005

A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease.

Therapy for neurodegenerative lysosomal Tay-Sachs (TS) disease requires active hexosaminidase (Hex) A production in the central nervous system and an efficient therapeutic approach that can act faster than human disease progression. We combined the efficacy of a non-replicating Herpes simplex vector encoding for the Hex A alpha-subunit (HSV-T0alphaHex) and the anatomic structure of the brain internal capsule to distribute the missing enzyme optimally. With this gene transfer strategy, for the first time, we re-established the Hex A activity and totally removed the GM2 ganglioside storage in both injected and controlateral hemispheres, in the cerebellum and spinal cord of TS animal model in the span of one month's treatment. In our studies, no adverse effects were observed due to the viral vector, injection site or gene expression and on the basis of these results, we feel confident that the same approach could be applied to similar diseases involving an enzyme defect.

Animals↗
PubMed2005

Histological and functional characteristics of peritoneal membrane in peritoneal sclerosis of PD patients.

BACKGROUND: Function and structure of peritoneal membrane (PM) are impaired on peritoneal dialysis (PD). Peritoneal sclerosis is a common finding in peritoneal biopsies (PB) of PD patients. The aim of this study was to examine the impact of peritoneal sclerosis on peritoneal function and clinical parameters in PD patients submitted to peritoneal biopsy. METHODS: A PB was performed on 31 PD patients during catheter removal due to malfunction or after drop-out from treatment. For each patient PM transport was evaluated by the last peritoneal equilibration test before PB. Each daily glucose load was calculated. Tissue was formalin-embedded and stained for histological and immunohistochemical studies. RESULTS: Patients with submesothelial sclerosis and those with impairment of submesothelial basement membrane and subendothelial vascular membrane were submitted to a larger daily glucose load. Peritoneal sclerosis > 50 microns was more frequent in high transporters, who were exposed to larger daily glucose load compared to medium-high transporters. Mesothelial loss is correlated to peritoneal sclerosis and vascular injuries. CONCLUSIONS: Peritoneal sclerosis is not constant in PD patients: it is related to the loss of mesothelium integrity, to the daily glucose load of PD treatment and to vascular injuries, but apparently not to the presence of inflammatory infiltrate. It remains a matter of debate how much the peritoneal sclerosis modifies the function of PM and how new more biocompatible PD solutions could reduce PM injury.

Actins↗
PubMed2004

Analysis of galactocerebrosidase activity in the mouse brain by a new histological staining method.

Gene therapy of galactocerebrosidase (GALC) deficient mice (Twitcher mutants) requires a fast and sensitive assay to detect transduced cells in vitro and in vivo. We have developed a new rapid histochemical method that specifically detects GALC activity in situ in neural cells using 5-Br-3Cl-beta-galactopiranoside (X-Gal) in the presence of taurodeoxycholic and oleic acids to enhance suspension of the substrate at low pH. Using this method, we observed robust X-Gal staining in diverse neuronal populations and interfascicular oligodendrocytes in sections from normal mouse brain. In contrast, sections of Twitcher brain did not show a specific staining pattern in neurons or glial cells. The availability of this new sensitive and rapid in situ detection assay is fundamental for the follow-up of Twitcher mice under gene or cellular therapies to correct central GALC deficiency.

Animals↗
PubMed2003

Successful unrelated cord blood transplantation in two children with severe combined immunodeficiency syndrome.

We describe the successful unrelated cord blood transplantation in two patients affected by a Zap-70 deficiency and an Omenn-like syndrome, respectively. The patients were hospitalised for recurrent infections at the age of 13 and 2 months, respectively. An unrelated cord blood unit was found for each. The conditioning regimen was cyclophosphamide, busulfan and antithymocyte globulin. The total number of infused cells was 15.1 x 10(7)/kg and 17 x 10(7)/kg, respectively. Neutrophil engraftment was achieved on days +15 and +23, and platelet count >50 x 10(9)/l was achieved on days +21 and +52, respectively. One patient presented acute Graft-versus-host disease (GVHD) grade I and the other grade III. Chimerism was mixed and full donor. Normal lymphoproliferative response to mitogens and alloantigens was detectable at 6 months for both. No chronic GVHD was observed in either. The patients are alive and well at 53 and 15 months after transplantation. In conclusion, umbilical cord blood represents a valid alternative source of haemopoietic stem cells.

Antilymphocyte Serum↗
PubMed2002

Restoration of the GM2 ganglioside metabolism in bone marrow-derived stromal cells from Tay-Sachs disease animal model.

The therapeutic potential of bone marrow-derived stromal cells for the therapy of Tay-Sachs disease is primarily related to the restoration of their own GM2 ganglioside storage. With this aim, we produced bone marrow-derived stromal cells from the adult Tay-Sachs animal model and transduced them with a retroviral vector encoding for the alpha-subunit of the lysosomal enzyme beta-hexosaminidase A (E.C. 3.2.1.52). Our results demonstrate that transduced Tay-Sachs bone marrow-derived stromal cells have beta-hexosaminidase A comparable to that of bone marrow-derived stromal cells from wild-type mice. Moreover, beta-hexosaminidase A in transduced Tay-Sachs bone marrow-derived stromal cells was able to hydrolyze the GM2 ganglioside in a feeding experiment, thus demonstrating the correction of the altered phenotype.

Animals↗
PubMed2001

Comparison of ELISA for tissue transglutaminase autoantibodies with antiendomysium antibodies in pediatric and adult patients with celiac disease.

BACKGROUND: Tissue transglutaminase (t-TG) is the main autoantigen recognized by the endomysium antibodies (EMA) observed in patients with celiac disease (CD). The aim of the study was to assess an ELISA method for t-TG antibodies (t-TGA) with respect to EMA IF assay in pediatric and adult patients. METHODS: t-TGA were analyzed by ELISA in 220 sera samples: 82 patients with biopsy-proven untreated CD (23 adults and 59 children), 14 CD children on gluten-free diet, 18 asymptomatic relatives of CD patients, and 106 age-matched control patients with gluten-unrelated gastrointestinal diseases (58 adults and 48 children). Serum IgA EMA were tested on umbilical cord sections in all patients. RESULTS: The great majority (92.7%) of untreated CD patients (both adults and children) were t-TGA positive (values ranging from 20.1 to > 300 AU). None of the child control patients and only two out of 58 (3.4%) of the adults with unrelated gastrointestinal diseases had serum t-TGA positivity; two out of 18 first-degree relatives with biopsy-proved silent CD were t-TGA (as well as EMA) positive. Finally, two out of 14 CD children, assuming a gluten-free diet, had serum t-TGA (as well as EMA). A highly significant correlation (P < 0.001) was observed between t-TGA concentrations and EMA. t-TGA showed a sensitivity of 87% and 95%, a specificity of 97% and 100% for adults and children, respectively. CONCLUSION: The method is highly sensitive and specific in the diagnosis of CD and is promising as a tool for routine diagnostic use and population screening, especially in children.

Adolescent↗
PubMed2001

In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice.

Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.

Animals↗
PubMed2001

Prediction of node-negative breast cancer outcome by histologic grading and S-phase analysis by flow cytometry: an Eastern Cooperative Oncology Group Study (2192).

Histologic evaluation and reporting of invasive breast cancer has effectively used Nottingham combined histologic grade (NCHG). This approach to predict outcome in invasive breast cancer has not been tested in multicenter cooperative trials. Histologic slides from selected breast cancer cases entered on node-negative Eastern Cooperative Oncology Group trials were assigned grades. Two pathologists evaluated cases for NCHG defined from differentiation, mitotic index, and nuclear grade. The study population consisted of separate samples from low- and high-risk strata, where low risk was estrogen receptor positive with a tumor size of less than 3 cm and high risk was estrogen receptor negative or tumor size greater than or equal to 3 cm. The rate of agreement was generally good, with 80% of cases classified the same for mitotic count and 76% of the cases classified the same for combined grade. There were no cases disagreeing from the lowest to the highest of the three categories. The median follow-up is 11.6 years, but for analysis of survival, this was truncated at 5 years. Mitotic index and combined grade as assessed by both pathologists showed significant associations with survival. High combined histologic grade was predictive for response to cyclophosphamide/methotrexate/5-fluorouracil (CMF) with survival differences at 5 years of 30% in the treated high-grade patients over the untreated patients. Overall, it is clear that pathologists can have close agreement in assignment of combined histologic grades, with highly significant prediction in univariate and borderline significance in multivariate analysis in prognostication of time to recurrence as well as survival. Thus, stratification used in these trials was highly prognostic as hoped, leaving a role for histologic grading in these relatively large tumors, more powerful than S-phase analysis in this series. In the subgroups of high-risk patients randomized between CMF and observation, there was a suggestion that the high-combined-grade group was predictive of treatment efficacy. We conclude that a combined histologic grade with defined criteria may be reliably assigned by practiced pathologists using readily available criteria, and that the measure may be of use in prognostication and prediction of therapeutic responsiveness when done in a technically ideal fashion.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group.

BACKGROUND: We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. METHODS: Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. RESULTS: The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem cells and 89 were assigned to receive conventional-dose chemotherapy. In an intention-to-treat analysis, we found no significant difference in survival overall at three years between the two treatment groups (32 percent in the transplantation group and 38 percent in the conventional-chemotherapy group). There was no significant difference between the two treatments in the median time to progression of the disease (9.6 months for high-dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional-dose chemotherapy). CONCLUSIONS: As compared with maintenance chemotherapy in conventional doses, high-dose chemotherapy plus autologous stem-cell transplantation soon after the induction of a complete or partial remission with conventional-dose chemotherapy does not improve survival in women with metastatic breast cancer.

Adolescent↗
PubMed2000

Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study.

Results of estrogen receptor (ER) and progesterone receptor (PgR) ligand-binding assays (LBAs) are strongly correlated with ER and PgR by immuno-histochemistry (IHC). To investigate whether ER and PgR by IHC are also strongly correlated with tamoxifen response, time to treatment failure (TTF) and overall survival (OS), the results of the 2 methods were directly compared in 205 patients with ER(+) metastatic breast cancer treated with daily tamoxifen (Southwest Oncology Group protocol 8228) with 9 years median follow-up. pS2, another estrogen-regulated molecule, was also analyzed. Tumors were scored for IHC from 0 to 5, according to the proportion of positively stained cells. These IHC scores for both ER and PgR were significantly associated with LBA levels (p < 0.001). There was a significant direct relationship between higher IHC ER, PgR and pS2 and increasing response to tamoxifen. TTF and OS were also significantly longer for patients with higher ER or PgR, but not pS2, IHC scores. Low, intermediate and high ER or PgR categories showed similar differences in response rates whether defined by LBA or IHC. In logistic regression models which included ER, PgR and pS2 by IHC; ER and PgR by LBA; and menopausal status, only ER (IHC) and pS2 (IHC) retained significance for predicting tamoxifen response (p = 0. 02 and p = 0.005, respectively), along with menopausal status (for PgR by IHC, p = 0.09). Increasing ER and PgR by IHC, as by LBA, are thus significantly associated with a progressively better response and longer survival in ER(+) metastatic breast cancer. pS2 is also predictive in this setting.

Antineoplastic Agents, Hormonal↗
PubMed2000

Delphi-panel analysis of appropriateness of high-dose chemotherapy and blood cell or bone marrow autotransplants in women with breast cancer.

BACKGROUND: There is controversy whether high-dose chemotherapy and a blood cell or bone marrow autotransplant is a better treatment than conventional-dose chemotherapy for women with local/regional or metastatic breast cancer. Subject selection and time-to-treatment biases make definitive comparison impossible. Recent results of randomized trials are contradictory. OBJECTIVE: Determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow autotransplant in women with breast cancer. PANELISTS: Nine breast cancer experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of 'breast cancer' and 'chemotherapy' and/or 'blood cell' or 'bone marrow transplants'. PROCESS: We used a modified Delphi-panel group judgement process. Clinical variables were permuted to define 2058 clinical settings. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional therapy on a 9-point ordinal scale (1: most inappropriate, 9: most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. CONCLUSIONS: In women with local/regional breast cancer autotransplants were rated: 1) appropriate in those with > or = 10 cancer-involved lymph nodes; 2) uncertain in those with 4-9 cancer-involved nodes; and 3) inappropriate in women with < or = 3 cancer-involved lymph nodes. In women with metastatic breast cancer autotransplants were rated: 1) appropriate in those with metastases to 'favorable' sites (skin, lymph node, pleura) and a complete or partial response to chemotherapy; 2) uncertain in women with metastases to 'unfavorable' sites (lung, liver, or central nervous system) and a complete response to chemotherapy or those with bone metastases and a complete or partial response or stable disease after chemotherapy; and 3) inappropriate in other settings.

Antineoplastic Agents↗
PubMed2000

The role of medical oncology in an interdisciplinary comprehensive breast center.

The management of patients with breast cancer requires physicians with diverse expertise and skills. The comprehensive care of such patients is best accomplished when all necessary health care providers work together using an interdisciplinary model. Such a close working relationship has advantages for the patient and the physician. The role of the medical oncologist has greatly expanded during the past 3 decades. Physician participation has become necessary at each step of a patient's diagnosis, treatment, and follow-up. This is best accomplished when all physicians who will provide care are part of an interdisciplinary breast center.

Breast Neoplasms↗
PubMed1999

The influence of margin width on local control of ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ is a non-invasive carcinoma that is unlikely to recur if completely excised. Margin width, the distance between the boundary of the lesion and the edge of the excised specimen, may be an important determinant of local recurrence. METHODS: Margin widths, determined by direct measurement or ocular micrometry, and standardized evaluation of the tumor for nuclear grade, comedonecrosis, and size were performed on 469 specimens of ductal carcinoma in situ from patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy, according to the choice of the patient or her physician. We analyzed the results in relation to margin width and whether the patient received postoperative radiation therapy. RESULTS: The mean (+/-SE) estimated probability of recurrence at eight years was 0.04+/-0.02 among 133 patients whose excised lesions had margin widths of 10 mm or more in every direction. Among these patients there was no benefit from postoperative radiation therapy. There was also no statistically significant benefit from postoperative radiation therapy among patients with margin widths of 1 to <10 mm. In contrast, there was a statistically significant benefit from radiation among patients in whom margin widths were less than 1 mm. CONCLUSIONS: Postoperative radiation therapy did not lower the recurrence rate among patients with ductal carcinoma in situ that was excised with margins of 10 mm or more. Patients in whom the margin width is less than 1 mm can benefit from postoperative radiation therapy.

Breast Neoplasms↗
PubMed1999

'Neo-FAC' (5-fluorouracil, doxorubicin, and cyclophosphamide) for poor-prognosis stage IV breast cancer: a Southwest Oncology Group Phase II Study.

The authors report a phase II pilot investigation in the Southwest Oncology Group examining a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) incorporating modulated 5-FU in patients with poor-prognosis stage IV breast cancer. Patients with poor-prognosis stage IV breast cancer were treated with this "neo-FAC" as front-line therapy. The regimen consisted of 5-fluorouracil by continuous ambulatory infusion pump at 200 mg/m2/day for 42 days, repeated at 56-day intervals; doxorubicin at 20 mg/m2/week intravenously to a maximum cumulative total dose (including adjuvant therapy, if any) of 500 mg/m2; cyclophosphamide 60 mg/m2/day taken orally; methotrexate 15 mg/m2/week intravenously beginning 1 week after termination of doxorubicin; and oral prednisone decreasing from 60 mg/day on a tapering schedule for a total of 7 weeks of treatment. Treatment was continued until progression, unacceptable toxicity, or patient refusal. Twenty-four patients were accrued to this study. Of these, two were ineligible, and the remaining 22 were evaluable for response. Ten patients experienced grade 3 toxicity, and six had grade 4. There were no treatment-associated deaths. Best responses were a complete response in one patient (5%) and partial responses in 6, for an overall response rate of 32% (7/22 evaluable patients). Overall survival in five pilot studies in the Southwest Oncology Group in this poor-prognosis population are relatively superimposable. The present regimen, with its relatively poor outcome and the expense and inconvenience of administering chemotherapy by ambulatory infusion pump, will not be pursued further.

Adult↗