Biomedical subjects

Avi Stein

Publications and source records attributed to Avi Stein.

6 recordsLinked to original sources

PubMed2005

Hyperbaric oxygen therapy for radiation-induced haemorrhagic cystitis.

OBJECTIVE: To assess the efficacy of hyperbaric oxygen (HBO) for treating haemorrhagic cystitis. PATIENTS AND METHODS: From February 1997 to April 2004, seven patients with radiation-induced haemorrhagic cystitis were treated with HBO; they received a mean (range) of 30 (18-57) HBO treatments and the follow-up was 24 (3-53) months. RESULTS: The haematuria resolved completely in all seven patients shortly after treatment; one had an improvement but died from complications relating to cancer shortly after completing treatment, and two had recurrence of gross haematuria. They were re-treated with HBO until the haematuria resolved. CONCLUSIONS: Radiation-induced haemorrhagic cystitis can be treated successfully with HBO primarily or after failure of standard regimens. This method was well tolerated even in patients debilitated by advanced cancer and blood loss. Long-term remission is possible in most patients, and re-treatment effectively manages recurrent bleeding.

Adult↗

PubMed2004

Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells.

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.

Animals↗

PubMed2003

Molecular analysis of transitional cell carcinoma using cDNA microarray.

The incidence of transitional cell carcinoma (TCC), the fourth most common neoplasm diagnosed in men, is rising. Despite the development of several noninvasive diagnostic tests, none have gained full recognition by the clinicians. Gene expression profiling of tumors can identify new molecular markers for early diagnosis and disease follow-up. It also allows the classification of tumors into subclasses assisting in disease diagnosis and prognosis, as well as in treatment selection. In this paper, we employed expression profiling for molecular analysis of TCC. A TCC-derived cDNA microarray was constructed and hybridized with 19 probes from normal urothelium and TCC tissues. Hierarchical clustering analysis identified all normal urothelium samples to be tightly clustered and separated from the TCC samples, with 29 of the genes significantly induced (t-test, P<10(-5)) in noninvasive TCC compared to normal urothelium. The identified genes are involved in epithelial cells' functions, tumorigenesis or apoptosis, and could become molecular tools for noninvasive TCC diagnosis. Principal components analysis of the noninvasive and invasive TCC expression profiles further revealed sets of genes that are specifically induced in different tumor subsets, thus providing molecular fingerprints that expand the information gained from classical staging and grading.

Adult↗

PubMed2003

Validation of the novel indices of nuclear pleomorphism, polarity and spatial distribution in the grading of urothelial carcinoma.

OBJECTIVE: To evaluate the role of the novel histomorphometric variables of pleomorphism, orientation and variability of spatial cytologic organization to objectively quantify histopathologic grade in urothelial carcinoma. STUDY DESIGN: As a validation model, we chose 51 papillary urothelial carcinomas. Thirty-six (70%) were low and 15 (29%) high grade tumors (World Health Organization grading system). Thirty-one cases (61%) were noninvasive, 12 (23%) exhibited lamina propria invasion, and 8 (16%) invaded the deep smooth muscle. Histomorphometric measurements were performed on noninvasive areas only. Pleomorphism was characterized by the anisokaryosis index (AIX), based on the autocorrelation function applied to classic nuclear shape descriptors. Additional indices of pleomorphism included standard deviations (sd) and coefficients of variation of these shape descriptors. Loss of polarity was assessed by the orientation index (ORX), based on Fourier transformation. Intraepithelial nuclear spatial distribution index (NSDX) was also computed. RESULTS: Low grade tumors exhibited less pleomorphism, higher orientation indices and a more homogeneous spatial distribution than did high grade tumors (area-AIX: P = .004, ORX: P < .0001, NSDX: P = .001). Multivariate analysis revealed the significant discriminators of grade to be nuclear size and orientation (size: max-diam, P < .0001; width: P < .0001; orientation: ORX: P < .0001). A discriminant score combining these independent variables distinguished between low and high grades in 98% of cases. The method was successfully validated using a testing sample of 40 new patients (accuracy, 94%). Lamina propria invasion was independently predicted by nuclear pleomorphism (width-sd: P = .0001, sensitivity = 64%, specificity = 91%). Muscle invasion was independently predicted by nuclear area (P < .0001) and pleomorphism (area-sd: P < .0001, max-diam-sd: P < .0001, width-AIX: P < .0001, sensitivity = 87%, specificity = 100%). CONCLUSION: These novel morphometric methods may serve as more objective methods of histopathologic grading and may contribute to the development of automated systems for quantitative grading of stratified and transitional epithelial neoplasms.

Aged↗

PubMed2002

Interleukin-2, interferon-alpha, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma: a prospective phase II study: the experience of Rambam and Lin Medical Centers 1996-2000.

BACKGROUND: The current study evaluated the efficacy and toxicity of interleukin-2 (IL-2), interferon-alpha (IFN-alpha), 5-fluorouracil (5-FU), and vinblastine (VBL) in the treatment of metastatic renal cell carcinoma (MRCC). METHODS: Sixty-two MRCC patients, median age 63 years, received immunochemotherapy. Eastern Cooperative Oncology Group performance status was 1 for 45 patients and 2 for 17 patients. Fifty-four patients underwent nephrectomy prior to treatment. Sites of disease were lungs, lymph nodes, bone, kidney, and liver. Treatment consisted of IL-2 10 MIU/m(2) subcutaneous (SC), three times per week, Weeks 1-4; IFN-alpha 6 MIU/m(2) SC, once per week, Weeks 1-4 and 9 MIU/m(2), three times per week, Weeks 5-7; 5-FU 600 mg/m(2) and VBL 6 mg/m(2), intravenous bolus, Day 1 of Weeks 5 and 7. RESULTS: In a median followup of 34 months, 62 patients were evaluated for tumor response. Four patients achieved complete response for 26+, 34+, 51+, and 56+ months, respectively; 14 patients achieved partial response for a median of 14 months; and 20 patients achieved stable disease for a median of 9 months. Seven patients (5 partial response, 2 stable disease) underwent complete resection of residual tumor. Five patients remained alive with no evidence of disease for 27, 32, 36, 42, and 48 months, respectively. Nine patients achieved long-term complete response for a median of 36 months. Three-year survival rate for the entire group and for 11 complete responders was 88%. Common side effects were flu-like symptoms, nausea, headache, and depression. Four patients were excluded because of treatment intolerance, and one patient died after nephrectomy. CONCLUSIONS: Immunochemotherapy is effective and well-tolerated by patients with MRCC. Surgical intervention for resection of residual disease is justified.

Adult↗

PubMed2002

Activated status of tumour-infiltrating lymphocytes and apoptosis in testicular seminoma.

Testicular seminoma is characterized by a prominent lymphoid infiltrate and an excellent prognosis. Cytotoxic T-lymphocytes (CTLs) infiltrating seminoma tumour nests constitute a major subset of the lymphoid infiltrate. The objective of this study was to determine whether CTLs express markers of cytotoxic potential and activity and whether the number of activated CTLs correlates with the extent of apoptosis in testicular seminomas, as opposed to non-seminomatous testicular germ cell tumours (NSTGCTs). Twenty cases of pure seminoma as well as 20 cases of NSTGCTs including 16 mixed germ cell tumours (MGCTs) were studied. Immunohistochemistry for the cytotoxic markers TIA-1 (cytotoxic potential) and granzyme B (cytotoxic activity) and the T-cell markers CD3 and CD8 was performed on formalin-fixed, paraffin-embedded sections. The apoptotic index (AI) was determined by the TUNEL method. The number of CD3(+), CD8(+), TIA-1(+), and granzyme B(+) cells in tumour cell nests was markedly increased in testicular seminomas, compared with NSTGCTs (p<0.01). Activated granzyme B(+) cells numbered 25.6+/-5.2 per high power field in seminomas and 8.9+/-3.2, 8.1+/-3.9, and 0.4+/-0.2 for embryonal carcinomas, yolk sac tumours, and immature teratomas, respectively. Double immunohistochemical staining for granzyme B and CD8 revealed that 82.6+/-8.5% of granzyme B-expressing cells were CD8(+). The tumour cell AI was significantly increased in embryonal carcinoma, compared with the seminoma, yolk sac tumour, and immature teratoma subgroups (6.7+/-1.3, 2.3+/-0.3, 3.0+/-1.1, and 2.3+/-1.1, respectively, p<0.001). TUNEL/CD3 double immunostaining revealed that a significant proportion of the apoptotic seminomatous tumour cells were in direct contact with one or more CD3(+) lymphocytes (47.2+/-6.2%). The number of activated granzyme B(+) CTLs showed a strong linear correlation with the AI in the seminoma group (r=0.71, p<0.0001) but not in other subgroups. TUNEL/granzyme B double immunolabelling revealed that a proportion of activated granzyme B(+) lymphocytes (20%) were often seen in close contact with apoptotic tumour cells. The presence of increased numbers of activated cytotoxic lymphocytes in testicular seminomas suggests that apoptotic tumour cell death in this neoplasm may be triggered by cytotoxic granule effectors. This phenomenon may be one of the key host immune mechanisms leading to the excellent prognosis in this tumour.

Adult↗