Low Protein Z levels in patients with plasma cell neoplasms are inversely correlated with IL-6 levels.

Patients with multiple myeloma (MM) have an increased thrombotic risk, but pathogenesis remains uncertain. Low levels of Protein Z (PZ), a vitamin K-dependent plasma protein, are associated with venous as well as arterial thrombosis. The purpose of this study was to analyze PZ levels in patients with plasma cell neoplasms. PATIENTS AND METHODS: The study consisted of 64 plasma cells neoplasm patients and 42 healthy individuals. Clinical investigations included measurement of plasma PZ and IL-6 levels. RESULTS: PZ levels in patients with plasma cell neoplasms were significantly lower compared to healthy controls in the entire cohort (1392±659 vs.2010±603ng/mL, P<0.01), as well as in specific disease subgroups; symptomatic MM (1428±652ng/mL, p<0.01), smoldering MM (1437±883ng/mL, p=0.045) and monoclonal gammopathy of undetermined significance (MGUS) (1247±593ng/mL, p=0.01). PZ was negatively correlated with IL-6 levels in MM patients (r=-0.7, P<0.01). There was no significant difference in PZ levels between patients with or without thrombotic event. CONCLUSION: Plasma cell neoplasm patients have low levels of PZ. This is presumably related to the increased IL-6 production by the bone marrow microenvironment, and could have a potential role in the increased thrombotic tendency in those patients.

Successful treatment of prolonged agranulocytosis caused by acute parvovirus B19 infection with intravenous immunoglobulins.

A 21-year-old previously healthy male presented with prolonged fever of 3 weeks duration and profound agranulocytosis that did not respond to treatment with granulocyte-stimulating factors. A bone marrow biopsy demonstrated an absence of myeloid lineage. Acute parvovirus B19 infection was diagnosed by the presence of both IgM and IgG anti-parvovirus antibodies. Two days treatment with intravenous immunoglobulins (IVIg) resulted in complete recovery. The role of treatment with immunoglobulins in acute and persistent parvovirus infection is discussed.

Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Release from apoptosis correlates with tumor progression in the AKR lymphoma.

Disturbance of apoptosis is an established factor in tumorigenesis. The role of apoptosis in tumor progression is not yet clear. In the present study we compared the tendency to spontaneous apoptosis (and the proliferative capacity) of tumor cells derived from primary (PT) and metastatic tumor (MT) cells of several AKR lymphoma variants. Apoptosis-related gene expression was also compared. Our results indicate that release from apoptosis has a role in the tumor progression of this T cell lymphoma. At the cellular level, a markedly lower apoptotic tendency was observed in MT than in PT cells. The existence of macrophages only in PT also supports the presence of apoptotic cells in local but not in MTs. By contrast, proliferative capacity does not determine tumor aggressiveness in this system. At the molecular level, we found a higher staining intensity for bcl-2 in MT than in PT cells, suggesting that bcl-2 might be responsible for the reduced apoptosis in MT compared to PT cells. Evidence for p53 overexpression was found in the MT cells of one of the variants but in none of the PT. Comparison of Fas receptor, unexpectedly showed an increased expression in MT versus PT cells, possibly indicating resistance to Fas-induced apoptosis in the MT cells.

Sensitivity to thermochemotherapy of AKR lymphoma and B16 melanoma variants of malignancy.

Drug resistance, which so often accompanies tumor progression, has been shown to be related to changes in membrane properties which may result in decreased drug accumulation in the tumor cell. A correlation between sensitivity to thermochemotherapy and degree of malignancy was found in the AKR lymphoma system. Hyperthermia increased adriamycin (ADR) uptake and concomitantly its cytotoxicity to AKR lymphoma cells. Moreover, these effects were more pronounced on a variant of high malignancy (HM) than on a low malignancy (LM) one. Fluorescent microscopy, as well as cytofluorometry, indicated that lymphoma cells treated by ADR at 43 degrees C were more permeable to the cytotoxic agent than those exposed to the chemotherapeutic substance at 37 degrees C. Cytofluorometry indicated the presence of a minor cell subpopulation with low ADR uptake in the HM variant, not found in the LM one. Fluorocytometry also showed that the temperature-dependent increased ADR uptake was more marked in the HM than in the LM variant, explaining the differential effect of thermochemotherapy on the two lymphoma variants. However, correlation between degree of malignancy and sensitivity to thermochemotherapy is not a general feature. In contrast to the results obtained in the AKR lymphoma system, in the B16 melanoma the low malignancy variant, F1, was more markedly affected by the combined treatment than the F10 variant. The increased cytotoxic effect of ADR by supranormal temperatures in the F1 variant was shown to be due to an augmented drug uptake. The results suggest that drug resistance in late stages of tumor progression can be overcome by an agent acting on the cell membrane. However, the data also indicate the necessity of assaying cancer treatment modalities, including those designed to circumvent drug resistance, on various tumor system models.

Role of immune response as determinant of tumor progression in function of host age in the B16 melanoma.

Aging constitutes the major cause for the development of most neoplastic diseases. However, tumors in aged people present with a lower degree of aggressiveness than in young patients. The reasons for this paradoxical behavior are not clear. We attempted to verify whether the immune system has a role in the relation between host age, immune response and tumor progression. We compared the growth rate of B16 melanoma and a highly malignant variant, the B16/Col/R, in young and aged mice that have or have not undergone splenectomy. The following results were obtained: (1) Splenectomy stimulated growth in the parental melanoma in both young and aged mice, indicating a protective role of the spleen against this tumor at all ages; (2) Spleen ablation provoked inhibition of the highly-metastatic variant growth in young mice, suggesting a stimulatory role of the spleen in this case; (3) By contrast, in aged mice inoculated with the B16/Col/R variant, splenectomy enhanced tumor growth, indicating a defensive role of the spleen. Age favors a positive host response against the aggressive clone of the melanoma. Differential host response in young versus aged mice can explain, in this tumor system, the difference in tumor progression rate as a function of age.

Different stages of tumor development are unequally affected by pretreatment of tumor cells with a polysaccharide.

Pretreatment with the polysaccharide levan of Lewis lung carcinoma and AKR lymphoma cells affected unequally different stages of tumor development. While levan pretreatment sharply reduced the evolution of tumors from subcutaneously inoculated cells, no such inhibition was observed with pretreated cells inoculated intravenously. Since levan is known to affect the cell membrane, it is concluded that different cell membrane properties may be involved in the various stages of tumor progression.

AKR lymphoma malignancy variants differing at late phase of metastasis.

The biological behavior of two AKR lymphoma variants, the TAU-39 and TAU-38, of low (LM) and high (HM) malignancy, respectively, has previously been described. In the present study an attempt was made to determine the phase in the metastatic process in which these variants differ. Two types of findings suggest that the two variants differ in the late phase of the process; (a) no difference in the degree of invasiveness of the primary tumor to the surrounding tissues has been found between the two variants, both being highly invasive; (b) comparison of malignant behavior in the "spontaneous metastasis" versus the "experimental metastasis" tests showed a similar ranking of malignancy of the two variants.

Metastatic potential and multidrug resistance correlation in the B16 melanoma system.

The question of whether metastatic potential and drug resistance are related phenotypes was addressed by comparing the biological behavior of the parental B16 melanoma and a multidrug resistant variant derived from it, the B16/Col/R. A more pronounced metastatic spread to lungs was observed in mice inoculated i.v. with the B16/Col/R variant than in those bearing the parental line. In addition, in the mice injected with the drug resistant melanoma, unusual tumor masses were observed. Large abdominal and spinal cord growths were seen with the MDR variant but not encountered in mice inoculated with the original B16 melanoma. We further attempted to test the capacity of the two cell types to perform several cellular functions relevant to the metastatic process. The B16/Col/R cells displayed a higher aggregability and cell motility than did the B16 cells. Adherence to endothelial cells was higher in the parental line than in the B16/Col/R, possibly supporting a more efficient extravasation of the variant cells. The drug resistant variant displayed a higher capacity to grow locally in kidney, spleen, cecum and peritoneum, as compared to the parental melanoma, indicating a higher ability of homing and growth in these potential target organs for metastasis. A correlation between metastatic potential and multidrug resistance appears therefore to exist in the system examined.

A model for cancer treatment in advanced compared to early cancer.

Loss of sensitivity to drugs following tumor progression constitutes the main reason for failure of treatment in advanced cancer. In view of the dynamic nature of neoplasms, models of tumor progression should be used for the testing of drugs. In the present study, two variants of malignancy of AKR lymphoma were used as a model of tumor progression to test various treatment modalities. The two variants, TAU-39 (of low-malignancy) and TAU-38 (of high-malignancy) differed in the pattern of local tumor growth as well as in the rate of metastatic spread and mice killing capacity. The efficiency of chemotherapy, immunotherapy and hyperthermia on the two variants was compared. The low-malignancy tumor was more sensitive to adriamycin than the high-malignancy one. Administration of levan-activated macrophages at the tumor site inhibited the growth of TAU-39. However, growth of the high-malignancy variant was stimulated by macrophages. Hyperthermic treatment was, in contrast to the other treatments, more effective against the high - than against the low-malignancy tumor. Models of tumor progression used in tests for antitumoral drugs may help in the discovery of treatment modalities effective also for advanced stages of cancer.

Aberrant adrenal tissue in the wall of a hernial sac.

An aberrant adrenal, which is a supplementary to the normal adrenal, was found in the apex of hernial sacs in ten out of 350 operated children. This tissue contains adrenal cortex, which tends to atrophy and disappear during childhood, but uncommonly may persist into adult life. Rarely it may secrete abnormally or undergo neoplastic changes. The embryological development is discussed, and the literature briefly reviewed.

Congenital hypertrophic pyloric stenosis: a long-term follow-up of 41 cases.

From 1946 to 1977, 228 infants were operated on for congenital hypertrophic pyloric stenosis in the Tel-Aviv Municipal Medical Center, all by the method of Fredet-Ramstedt. An evaluation was made of the late morbidity in 41 patients, ranging in age from 15 to 30 years. The emphasis is on gastrointestinal diseases and their possible connection to the operation. Twenty-four of 41 patients had gastrointestinal symptoms, including dyspepsia, diarrhea, constipation, and abdominal pains. X-ray examination of the stomach was performed in 31 patients, in order to examine the structure and function of the stomach. Five patients showed clear signs of ulcer disease, four in the duodenum and one in the stomach. Another five patients showed mild deformation of the duodenal bulb, and two showed signs of gastritis. No correlation was found between the severity of the congenital pyloric stenosis and the presence of later illness or disturbances.

Testicular feminization syndrome.

The testicular feminization syndrome is an uncommon condition with a familial background. The clinical features of a typical case are presented, as well as its management. It is emphasized that these patients and their parents must be treated with the greatest sensitivity when the condition is explained to them.

Lipoma of the colon. A report of 22 cases.

A series of 22 cases of lipomas of the colon is presented. Fourteen patients had small (mean size, 12.5 mm), asymptomatic colon lipomas which were diagnosed incidently. In four of these patients, more than one lipoma was found. Eight patients had one larger (mean size, 70.5 mm) symptomatic lipoma. The symptomatic patients were older (mean age, 64.3 years) than the asymptomatic patients (mean age, 54.7 years). While small lipomas do not generally give symptoms, it seems that the symptoms of larger lipomas are mainly due to mechanical interference in colonic passage or ulceration of the mucosa that covers the lipoma.

Solcoderm as alternative conservative treatment for acute anal fissure: a controlled clinical study.

Acute anal fissure is a common malady that results in morbidity. If a patient is not responsive to conservative treatment, the current recommended treatments are either anal dilatation or lateral internal sphincterotomy. Both operations promise relatively good results, but the recurrence rates are about 16 per cent and 7 per cent, respectively. This fact, together with possible postoperative complications and costs, justifies trying conservative treatment before referring patients for surgery. The authors treated a study group of 25 patients with a topical application of Solcoderm. Another group of 25 patients concurrently treated with the usual conservative treatment served as the control group. Analysis of the early and late results proved Solcoderm to be simple to use, safe, without systemic side effects, cost-effective, and with statistically significant better outcome. Consequently, the authors believe that this method of treatment is justified in cases of acute and fissure and should be attempted before operation.

Brown-bowel syndrome.

Extensive brownish discoloration of the small bowel is rare and has been described mainly in association with malabsorption disorders. It is related to deficiency of the fat soluble vitamin E. Vitamin E is an antioxidant substance that prevents peroxidation of unsaturated fatty acids. Vitamin E deficiency may result in oxidized lipids, which when polymerized with polysaccharides form the brown, PAS-positive pigment termed ceroid or lipofuscin. The deposition of pigmented granules in the effected tissues accounts for the brownish discoloration. We present three patients ultimately found to have "brown bowel syndrome (BBS)," in which the symptoms, preoperative findings, and respective diagnoses were different. In all three patients, serum Vitamin E levels were found to be extremely low.

Abdominal operations without nasogastric tube decompression of the gastrointestinal tract.

The routine use of nasogastric (NG) drainage during and after abdominal surgery was examined. One hundred and fifty patients who underwent various abdominal operations with a Levine tube served as a control group (retrospective group). The tubeless study group (prospective group) of 150 patients was randomly and blindly divided into three equal subgroups. Subgroup A patients were operated on without any NG tube. The tube in subgroup B patients was inserted after induction of anesthesia and removed one hour after the operation. The tube in subgroup C was inserted as in subgroup B, but was taken out 12 hours after the operation. The total number of complications in the intubated group was significantly higher than in the tubeless group (P less than 0.01). High temperature, atelectasis and miscellaneous complications were more frequent in the control group than in the study group (P less than 0.01). Other complications such as nausea, vomiting, bronchopneumonia, and gastric dilatation, as well as the resolution of the postoperative ileus and hospital stay, were not of statistical significance. Fewer miscellaneous complications (P less than 0.05) and less patient discomfort were found in subgroup A than in the other tubeless subgroups. Complications in the study group were easily controlled by conservative treatment and no serious complications resulted. Therefore, the routine use of NG suction as adjunctive therapy following abdominal operations is not advocated by this study.

Percutaneous drainage of subcapsular splenic hematoma: an experimental model in dogs.

Preservation of the spleen in patients with posttraumatic subcapsular hematoma is still controversial. To determine the best therapeutic approach for this type of splenic injury, we designed an experimental model of subcapsular hematoma of the spleen in dogs. A total of 23 subcapsular hematomas were caused in 19 dogs, which were followed both clinically and ultrasonographically for 12 weeks. Fifty-seven per cent of the hematomas resolved spontaneously; those that persisted (43%) were aspirated percutaneously with ultrasound guidance, after which they were all resolved. Our results support a conservative approach. When the hematoma does not resolve spontaneously, percutaneous ultrasound-guided aspiration may be considered.

Traumatic rupture of the intestine in patients with inflammatory bowel disease.

Three young patients suffering from inflammatory bowel disease were admitted to our hospital during the past year for extensive intestinal rupture caused by disproportionately minor trauma. There was almost no concomitant intra-abdominal injury. We believe that a minimal direct or acceleration/deceleration trauma to a preexisting diseased intestine might have caused extensive damage that was not apparent on admission. It was concluded that these patients should be carefully monitored and that their relative intestinal vulnerability should be borne in mind during diagnosis of and therapeutic planning for their condition.

Biological behavior and cell properties of new AKR lymphoma malignancy variants.

The AKR lymphoma-leukemia is a T lymphocyte neoplasm, most suitable as a model for human T cell malignancies. We have been interested in the process of tumor progression in the AKR lymphoma system. In the present study, two newly isolated variants, the TAU-42 and TAU-44, were characterized with respect to their biological behavior, by comparing them to a previously studied low-malignancy variant, the TAU-39. While the TAU-44 variant formed large s.c. local tumors, the TAU-42 variant formed only small growths or none at all. The TAU-42 lymphoma was found to have the highest malignant potential: it displayed very marked dissemination to spleen, lymph nodes, liver and lungs. The TAU-44 variant had an intermediate degree of metastatic potential but presented a predilection for spread to lymph nodes and spleen and was sometimes found to metastasize to peculiar organs, such as heart and pancreas. Cells derived from the different lymphoma variants varied in their immunophenotype: the highly malignant variant cells expressed more CD4 antigen than the low-malignancy one. The opposite was observed with regard to CD8. The variant cells also differed in their migrating capacity, the more malignant one exhibiting a higher motile activity. Studies on the tumor progression model of AKR lymphoma might contribute to the elucidation of the features determining the aggressiveness of T lymphocytic malignancies.