Persistence of transcriptionally silent BCR-ABL rearrangements in chronic myeloid leukemia patients in sustained complete cytogenetic remission.

Persistence of BCR-ABL rearrangements was demonstrated by D-FISH technique in chronic myeloid leukemia (CML) patients in complete cytogenetic response (CCR) after allogeneic bone marrow transplantation (BMT) or interferon-alpha therapy (IFN-alpha). Samples from bone marrow aspirate or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, fluorescent interphase in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement remains unexpressed in a small percentage of cells whatever the treatment (IFN-alpha or BMT), and this in spite of the negativity of the RT-PCR-based classical molecular remission criterion. These data corroborate those obtained by other investigators and point to the need for follow-up of CML patients in CCR over an extensive period, at the DNA level to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse and guide the therapeutic decision. Experimental models suggesting the persistence of positive BCR-ABL cells are discussed and tentative explanations of tumor "dormancy" are proposed.

Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma.

1q rearrangement is a remarkably frequent secondary chromosomal change in both non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), where it is associated with tumor progression. To gain insight into 1q rearrangement-associated disease mechanisms, we used fluorescence in situ hybridization (FISH) to search for recurring 1q breaks in 35 lymphoma samples (31 NHL patients and 4 lymphoma-derived cell lines) as well as 22 MM patients with cytogenetically determined 1q abnormalities. Strikingly, dual-color FISH analysis with chromosome 1 centromere and 1q12-specific probes identified constitutive heterochromatin band 1q12 as the single most frequent breakpoint site in both NHL and MM (39% and 89% of 1q breaks, respectively). These rearrangements consistently generated aberrant heterochromatin/euchromatin junctions and gain of 1q12 material. A further 30% of NHL 1q breaks specifically involved two other novel, closely spaced sites (clusters I and II) within a 2.5 Mb region of proximal 1q21 (D1S3620 to D1S3623). A possible association between these sites and NHL subtype was evident; the cluster I rearrangement was frequent in follicular and diffuse large cell lymphoma, whereas the cluster II rearrangement was more frequently observed in diffuse small-cell lymphoma (2/2 marginal zone lymphomas, 1/2 atypical chronic lymphocytic leukemias, and 1 lymphoplasmacytic lymphoma in this series). Candidate oncogenes bordering this interval (BCL9 and AF1Q) were not rearranged in any patient except one (AF1Q). This study provides the first evidence of involvement of 1q12 constitutive heterochromatin in the pathogenesis of NHL and MM and indicates proximal 1q21 to be of specific pathological significance in NHL.

Interphase FISH: a rapid method for detecting malignant plasma cells in multiple myeloma patients submitted to autologous transplantation.

Fluorescence in situ hybridization (FISH) on interphase nuclei has been shown to be an efficient method for detecting aneuploidy in multiple myeloma (MM). The aim of this study was to test the feasibility of FISH techniques for detecting malignant cells in the harvests of MM patients submitted to autologous transplantation. As trisomy 9 (T9) is a frequent event in MM, we used it as a genetic marker of malignant plasma cells. T9 was detected in 45 out of 55 MM bone marrow samples (81.8%) using a chromosome 9 centromeric (C9C) probe. Twenty-four of the 55 MM patients were subjected to high-dose therapy followed by autologous unselected progenitor cell transplantation. Trisomy 9 was detected in 20 patients and was used as a marker of malignant cells. Upon karyotypic analysis, three of the four remaining patients without T9 showed an unbalanced translocation leading to a complete trisomy of the long arm of chromosome 1 (T1q). We thus used a 1q juxtacentromeric probe, pUC1.77, as another genetic marker of malignant plasma cells in these three further patients. FISH with C9C or pUC1.77 probes was performed on the harvests of these 23 patients and detected clonal cells in 11 transplants. The disease-free survival from graft was significantly longer for the patients who had no malignant cells in their transplant (P=0.009). The median disease-free survival was 23 months in these patients, as compared to 12 months in the patients whose transplant was contaminated. As almost all MM are cytogenetically abnormal, FISH with adequate probes represents a simple, quantitative tool for rapid detection of malignant cells in the harvests. Our results also suggest that the presence of MM cells in the transplant may be predictive of poor outcome.

Deletion 7q in B-cell low-grade lymphoid malignancies: a cytogenetic/fluorescence in situ hybridization and immunopathologic study.

Ten cases presenting a simple karyotype and del(7q) as a primary event were selected out of 353 patients referred as B-cell low-grade malignant lymphoproliferative disorders. Chromosome 7-specific painting probes confirmed the deletion that was tentatively assigned to bands q31q35. Chromosome 7 was involved in an interstitial deletion in seven cases, in an unbalanced translocation in two cases, and in a ring chromosome in one case. Common clinical/hematological features included advanced age, marked splenomegaly, and peripheral blood monoclonal IgM(D) lymphocytosis. Regardless of morphologic entity, most cases shared lymphoplasmacytoid features. Deletion 7q may delineate a variety of low-grade B-cell lymphoid disorders characterized by a common clinical history and immunopathologic similarities. The cytogenetic pattern and the ongoing work on molecular mapping of this deletion suggest that the loss of a putative tumor-supressor gene at 7q31q32 may constitute an early event in their pathogenesis.

Familial adenomatous polyposis--which operation?

Familial adenomatous polyposis (FAP) syndromes are well recognized entities that benefit from surgical treatment which should not be delayed. Screening of first degree relatives is important. The aim of removing the colorectal mucosa with significant potential of malignant transformation can be achieved by means of three distinct procedures: pan-proctocolectomy and ileostomy, subtotal colectomy with ileorectal anastomosis, restorative proctocolectomy with ileoanal anastomosis. In a series of eight patients with FAP we performed mostly subtotal colectomy with ileorectal anastomosis. Of five patients who underwent a form of subtotal colonic resection, one was lost from follow up and two developed carcinoma in the remaining rectal mucosa, which necessitated completion of the resection with proctectomy and permanent ileostomy. Nevertheless, in the increasing number of patients amenable to regular outpatient supervision, there are strong points for recommending sphincter-saving operations.

Polipoza adenomatoasa familiala--care operatie? [Familial adenomatous polyposis--which operation?].

Familial adenomatous polyposis (FAP) syndromes are well recognized entities that benefit from surgical treatment which should not be delayed. Screening of first degree relatives is important. The aim of removing the colorectal mucosa with significant potential of malignant transformation can be achieved by means of three distinct procedures: panproctocolectomy and ileostomy, subtotal colectomy with ileorectal anastomosis, restorative proctocolectomy with ileoanal anastomosis. In a series of eight patients with FAP we performed mostly subtotal colectomy with ileorectal anastomosis. Of five patients who underwent a form of subtotal colonic resection, one was lost from follow up and two developed carcinoma in the remaining rectal mucosa, which necessitated completion of the resection with proctectomy and permanent ileostomy. Nevertheless, in the increasing number of patients amenable to regular outpatient supervision, there are strong points for recommending sphincter-saving operations.

Molecular diagnosis of t(11;14) in mantle cell lymphoma using two-colour interphase fluorescence in situ hybridization.

t(11;14) is observed in up to 70% of mantle cell lymphoma (MCL) cases and is therefore an important diagnostic element. In routine practice, detection of t(11;14) by conventional cytogenetic techniques is hindered by the low yield and quality of tumour metaphases. Molecular techniques (Southern blot, PCR) are unable to detect a large number of 11q13 breakpoints due to scattering over distances up to 1 Mb. Using 23 MCL patients with karyotypically determined t(11;14) and eight negative controls, we have devised a two-colour interphase FISH assay for detection of the 14q + chromosome. We chose an 11q13 probe telomeric to the major 11q13 translocation cluster sites and an IGH probe centromeric of the 14q32 breakpoints. This method detected the translocation in all 23 t(11;14) positive patients, with an overall average of 60% nuclei showing colocalized signals. Widespread application of this technique will constitute an important diagnostic aid in clinical management of MCL patients. Since FISH is a convenient method for retrospective analysis of large numbers of patient specimens, this method should contribute to an accurate estimation of t(11;14) frequency in MCL and other chronic B-cell malignancies and consequently to their better nosological characterization.

Experimental and clinical correlation in acute pancreatitis pathogenesis.

Pathological aspects in 100 cases of operated A.P. different in severity are not strictly related to aetiological conditions. Clinical observations have suggested some components of pathogenesis: obstruction of bilio-pancreatic inflow in duodenum at the beginning of the attack, bilio-pancreatic reflux on cholangiograms, strong secretory digestive stimulation before attack. Some experimental animals models (dogs) which can mimic pathogenic mechanism (obstruction of pancreatic flow, common bilio-pancreatic duct, closed duodenal loop, acute cholecystitis) have revealed characteristic pathological changes depending on the initiating process. Our conclusion that severity of pathological changes in A.P. are determined by the initiating mechanisms which may differ in some aetiological condition or may be common for different ones.

[The clinical, diagnostic and therapeutic characteristics in antral gastric cancer]. / Particularitati clinice, diagnostice si terapeutice în cancerul gastric antral.

This paper is part of a comprehensive study on subphrenic digestive cancer carried out between 1984 and 1988, representing the experience of the III-rd, I-st, IV-th and emergency surgical clinics of Iasi (1530 cases). The peculiarities of gastric cancer with antral site in 231 out of a total of 612 cases, representing the experience of the III-rd Surgical Clinic, are presented. Clinically, the relative early occurrence of the symptoms, the need for an endoscopic examination and biopsy for all gastric ulcer lesions, for the antral ones particularly, are mentioned. The treatment is surgical, but it has to be associated with adjuvant therapy. For the antral site, the oncological subtotal gastrectomy was the surgery of choice (157 cases), the need of restoring the transit in a gastrojejunal manner being underlined. Total gastrectomy was performed in 12 cases.

[The diagnosis and treatment of benign tumors of the subdiaphragmatic digestive tract]. / Diagnosticul si tratamentul tumorilor benigne ale tubului digestiv subdiafragmatic.

One hundred twenty-two benign tumors of subdiaphragmatic digestive tract admitted in the interval 1975-1988 at the III-rd Surgical Clinic of Iasi are reported. Out of these patients 120 required surgical treatment, the remainder of 2 being treated conservatively (diffuse intestinal angiomatosis, Peutz-Jeghers' syndrome). The clinical evolution being atypical, the surgical intervention was required, in most of the cases, due to hemorrhagic and occlusive complications. Histologically, the polyps and schwannomas were prevalent. The diagnostic difficulties, especially in the cases with jejuno-ileal localization, are mentioned.

[Voluminous malignant nonsecreting tumors of the adrenal cortex ruptured in thoracic-lumbar injuries]. / Tumori maligne nesecretante voluminoase de corticosuprarenala rupte prin traumatism toraco-lombar.

Based on two cases of nonsecreting malignant adrenal tumors the authors make some clinical and therapeutical considerations. These tumors are rare, have a longer evolution without significant clinical manifestations, may reach considerable size and may become complicated, most frequently by intratumoral hemorrhages and necroses, which usually favour an infection, and more rarely by their rupture. The diagnosis is based on the clinical and laboratory findings. The treatment is surgical, associated with chemotherapy and radiotherapy. The survival interval is long, sometimes exceeding 10 years.