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[Sequential chemotherapy of malignant non-Hodgkin's lymphoma of high degree of malignancy in stages III and IV].

A sequential combination chemotherapy was used in the treatment of advanced high-grade malignant non-Hodgkins' lymphomas (NHL) from July 1978 to August 1980. The lymphomas were classified according to the Kiel-classification. Cyclophosphamide, vincristine, bleomycin, prednisone (phase A) were followed by a combination of adriamycin, cytosine arabinoside, 6-thioguanine and prednisone (phase B). Patients received four cycles of both combinations. No maintenance therapy was given. 20 patients with centroblastic, lymphoblastic or immunoblastic NHL were included in the study. The overall remission rate was 95% (19 out of 20 patients). 15 (75%) patients entered complete remission. The median duration of complete remission was 28.7 months. The probable survival rate of the patients entering complete remission is 64.5% at two years. Clinical prognostic factors, bone marrow infiltration, extralymphatic organ involvement other than skin and a tumor mass greater than 10 cm in diameter in a single location significantly affected remission induction and survival. All patients with favourable prognosis are still alive in unmaintained complete remission 14 to 38 months after start of treatment. Patients with unfavourable prognosis had a complete response rate of 64% and a median survival of 14.8 months.

Adult↗

Serum levels of C-erbB-2 (HER-2/neu) in patients with malignant and non-malignant diseases.

The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 controls, 112 patients with benign diseases and 534 patients with malignancies. Using 15 U/ml as the cutoff, no healthy subjects, patients with benign diseases (excluding liver cirrhosis) or patients with no evidence of disease (45 patients) had serum levels higher than this limit. Abnormal c-erbB-2 levels were found in 38.5% (10 of 26) of the patients with liver cirrhosis and in 26.7% (8 of 30) of those patients with primary liver cancer. No differences were found between the c-erbB-2 serum concentrations in liver cirrhosis or primary liver cancer, suggesting the possible catabolism of this antigen in the liver. Abnormal levels of this antigen were found in 20% (56 of 278) of the patients with breast carcinoma (locoregional 7%, metastases 41.5%), in 21% (6 of 28) of ovarian carcinomas (stage I-II 0%, stage III-IV 42.8%), in 21% (3 of 14) of the colorectal tumors (locoregional 0%, metastases 30%), and in 13.3% (11 of 83) of the patients with lung cancer (locoregional 11.5%, metastases 16%). C-erbB-2 sensitivity in other patients with advanced disease was: 25% (9 of 36) in prostatic cancer, 22% (2 of 9) in gastric cancer, and 11% (1 of 9) in vesical tumors. When patients with liver metastases were excluded abnormal c-erbB-2 serum levels were only found in breast, lung, prostatic and ovarian carcinomas. C-erbB-2 sensitivity in patients with lung cancer was related to tumor histology with significantly higher value in non-small cell lung cancer (mainly adenocarcinomas) than in patients with small cell lung cancer (p < 0.013). C-erbB-2 concentrations in patients with breast cancer were significantly higher in patients with recurrence (mainly bone and liver metastases) and in patients with progesterone receptor-negative (< 15 fmol/mg) tumors (p < 0.01). In conclusion, c-erbB-2 is not a specific tumor marker and abnormal serum levels may be found in patients with liver pathologies. Its sensitivity suggests its possible application as a tumor marker in breast, ovarian, lung (mainly adenocarcinomas) and prostatic tumors.

Adult↗

Trilateral malignant lymphoma: primary malignant B-cell lymphoma of the eyes and brain. Diagnosis by transvitreal retinochoroidal biopsy.

A 59-year-old woman with therapy-resistant bilateral involvement of posterior uvea and retina of some months' duration was examined. Diagnostic vitrectomy was inconclusive, but subsequent transvitreal retinochoroidal biopsy gave ample material for the immunohistopathological diagnosis of a malignant B cell lymphoma. Despite systemic and intrathecal cytostatics and ocular X-ray therapy, central nervous system involvement was observed 2 months later. The ocular lesions regressed after treatment and have not recurred.

B-Lymphocytes↗

Divergent differentiation in malignant soft tissue neoplasms: the paradigm of liposarcoma and malignant peripheral nerve sheath tumor.

In tumors clonality does not always translate into morphologic uniformity. While most sarcomas exhibit only one line of histologic differentiation, a minority may display a strikingly diverse phenotype in addition to the main lineage. This phenomenon not only presents a diagnostic problem but also raises questions about the commitment of tumor cells toward a specific phenotype. Among sarcomas, malignant peripheral nerve sheath tumor (MPNST) and dedifferentiated liposarcoma are two entities in which divergent differentiation is a relatively frequent event. Diagnostically it is crucial to recognize the "primary" sarcoma in such tumors correctly and distinguish it from the "secondary" divergent elements. The presence of the latter could be the first morphologic clue to a specific sarcoma type. Even though it may be difficult to explain the pathogenesis of divergent differentiation, divergence still illustrates that the phenotype of a tumor cell is not set in stone but can be modulated or switched by a number of factors.

Cell Transformation, Neoplastic↗

Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Committee.

PURPOSE: To describe the outcome of infants with a histologically confirmed diagnosis of malignant mesenchymal tumor (MMT) included in the International Society of Paediatric Oncology studies MMT 84 and MMT 89. PATIENTS AND METHODS: One hundred two infants (< or = 12 months old) were included. Twenty-four children were less than 3 months old, and 16 were less than 1 month old. Sixty-four patients had rhabdomyosarcoma (RMS), 26 had undifferentiated sarcoma, and 12 had other histology. Clinical TNM stage was stage I (41%), II (39%), III (6%), and IV (14%). First-line treatment was ifosfamide, vincristine, dactinomycin, whereas the second-line combination consisted of either cisplatin and doxorubicin (in MMT 84) or vincristine, carboplatin, etoposide/teniposide (in MMT 89). Chemotherapy doses were adapted to age. Local therapy was conservative surgery as often as possible. RESULTS: After a median follow-up of 7.8 years (range, 0.1 to 13 years), 5-year overall survival (OS) and event-free survival rates were 66% and 55% for the total study population and 72% and 60% for nonmetastatic patients, respectively. Only two of 13 stage IV patients survived. Sixty-seven percent of newborn infants survived. Infants with alveolar subtype had a poorer survival than those with non-RMS MMT or nonalveolar RMS (5-year OS, 37% v 75% or 82%, respectively; P = .002). When compared with older children with MMT, young age does not seem to be an important prognostic factor. CONCLUSION: OS was satisfactory even when local treatment was not aggressive, although the prognosis was poor for infants with alveolar RMS or metastatic tumors. Chemotherapy toxicity was manageable with appropriate dose modification.

Age Factors↗

Malignant seminoma with metastasis, Sertoli cell tumor, and pheochromocytoma in a spotted dolphin (Stenella frontalis) and malignant seminoma with metastasis in a bottlenose dolphin (Tursiops truncatus).

Seminoma with metastasis was diagnosed in a spotted dolphin (Stenella frontalis) and an Atlantic bottlenose dolphin (Tursiops truncatus). Sertoli cell tumor and pheochromocytoma were also diagnosed in the spotted dolphin. The spotted and bottlenose dolphins were adult males that stranded and died on the coasts of northwest Florida and southeast North Carolina, respectively. Neoplasia is infrequently reported in cetaceans. This is the first report of seminoma, Sertoli cell tumor, and pheochromocytoma in a dolphin, the first report of three distinct neoplasms in a dolphin, and one of the few reports of malignant neoplasia in dolphins.

Adrenal Gland Neoplasms↗

HLA-G upregulation in pre-malignant and malignant lesions of the gastrointestinal tract.

HLA-G belongs to the nonclassical MHC class Ib group of molecules and has been implicated in mediating immune-responsiveness in various cancerous and non-cancerous cell types. We have examined HLA-G expression in a number of human gastrointestinal malignancies, including pancreatic ductal adenocarcinoma, ampullary cancer, biliary cancer, and colorectal cancer by immunolabeling analysis. We used indices of <5% (negative), 6-25%, 26-50%, 51-75%, and >75% (diffuse) to subclassify lesions based on percentage of positive cell labeling. Across all cancer subtypes, 52-79% of lesions demonstrated expression of HLA-G, with up to 33% of lesions demonstrating diffuse (>75%) expression. In addition, we utilized the neoplastic progression model of colorectal cancer to evaluate HLA-G protein expression in normal colon, tubulovillous adenomas, invasive cancer, and liver metastases arising from colorectal cancer. Focal HLA-G expression was detected in regions of normal colon adjacent to sites of adenomatous and cancerous lesions, as well as in all stages of cancer progression. Overall, the percentage of diffusely (>75%) labeled lesions appeared increased in preneoplastic and neoplastic conditions, as compared to normal colon. Specifically, tubulovillous adnenomas demonstrated pronounced diffuse labeling in 58% of lesions examined. No correlation with HLA-G expression and CD4+ or CD8+ T cells was identified. We propose that HLA-G expression is upregulated in a large percentage of gastrointestinal lesions and may serve to mediate immune-responsiveness in certain instances.

CD4-Positive T-Lymphocytes↗

International comparative study of childhood malignancy comparative study of pediatric malignancy between Kurume and Karachi (K-K Project 1991).

UNLABELLED: A study was undertaken to compare Pediatric Malignancy at Kurume (Japan) and Karachi (Pakistan) with reference to international data collected over the years, in order to identify essential differences between developed and developing conditions and factors influencing the etio-pathogenesis of pediatric cancer. The study was retrospective encompassing all types of cancer in children over a period of three years i-e 1988-1990. Essential factors related to present study were: 1. POPULATION: The population of Karachi is about 10 million while that of Kurume is only half a million. 2. Socio-economic conditions: The average socio-economic condition of people in Karachi is poor while in Kurume it appears to be good. 3. Educational status: Only 25% people in Karachi are educated beyond middle class while Kurume reveals a 100% education up to high school level. 4. Environmental conditions: The environmental conditions of Kurume and surrounding areas are very clean and free from pollution, sewage problems and traffic hazards. Karachi and its surroundings on the other hand pose very serious air and water industries! It was concluded that whereas genetic predisposition predominates, the environmental conditions, educational and socio-economic status of a society immensely influence the pattern and trends of pediatric carcinogenesis.

Adolescent↗

Semen cryopreservation for patients with malignant or non-malignant disease: our experience for 10 years.

PURPOSE: We report our experience in 10 years of sperm cryopreservation to reveal the present state of the cryopreservation project. MATERIALS AND METHODS: 42 germ cell tumor, 110 non-germ cell tumor and 2 non-malignant disease patients who visited our clinic for semen cryopreservation were retrospectively analyzed. RESULTS: Only 7 (20%) out of 35 unilateral testicular tumor patients who had received no chemotherapy met the WHO criteria for sperm concentration and motility. However, there were no patients with azoospermia. Three testicular tumor patients with previous chemotherapy and 4 retroperitoneal germ cell tumor patients had poor sperm concentrations and motilities. Twenty (52%) out of 38 non-germ cell tumor patients without previous chemotherapy met the WHO criteria. In contrast, only 9 patients (13%) met the WHO criteria among 72 patients with previous chemotherapy. Twenty-nine patients (40%) with chemotherapy were azoospermia. Totally, 74 (96%) of 77 tumor patients' semen without chemotherapy and 34 (45%) of 75 with chemotherapy were cryopreserved. Sperm from a patient with testicular torsion were cryopreserved. CONCLUSION: Most cancer patients without previous chemotherapy, regardless of underlying disease, had abundant motile sperm. However, half of the patients who had received chemotherapy did not have suitable sperm for freezing. It is important to inform young cancer patients of the cryopreservation project immediately after the diagnosis is made.

Adolescent↗

[Sentinel node--malignant melanoma and primary breast cancer. The significance of sentinel node in the treatment of malignant melanoma and primary breast cancer].

Dissection of regional lymph nodes plays an important role in surgical treatment of melanoma and breast cancer. However, the dissection of regional nodes is connected with a high morbidity and dissection in the 50-75% of the patients, who have no regional metastases, represents an overtreatment. No diagnostic procedures are available which could select patients who should have a regional lymph node dissection. The sentinel node (SN) is the first node in the lymphatic basin that drains the primary tumour. SN can be localized by means of dye or isotope or a combination. SN can be localized in melanoma or breast cancer patients in 98% of the operations. In 0-1% (melanoma) or 0-5% (breast cancer) SN was false negative. In some melanoma centers SN technique is an established routine. If the SN is normal, no regional lymph node dissection is needed. In breast cancer technical improvements must be achieved before SN examination can be used routinely. Future studies must clarify if examination of SN could have clinical significance in other malignant tumour diseases.

Axilla↗

Kinetics of chimerism during the early post-transplant period in pediatric patients with malignant and non-malignant hematologic disorders: implications for timely detection of engraftment, graft failure and rejection.

The monitoring of chimerism by PCR has become a routine diagnostic approach in patients after allogeneic bone marrow or peripheral blood stem cell transplantation. Nevertheless, a temporal correlation between molecular and hematologic assessment of engraftment has not been clearly established. To address this issue, and to determine the potential clinical implications of early kinetics of mixed chimerism, we have investigated 66 allogeneic stem cell transplantations (SCTs) in 58 pediatric patients suffering from different types of leukemia (n = 44) or non-malignant hematologic disorders (n = 14) by close molecular monitoring during the first days and weeks after transplantation. Patient- and donor-derived hematopoiesis were assessed at 1- to 3-day intervals in peripheral blood samples by PCR analysis of highly polymorphic microsatellite loci (STR-PCR). Detection of an increasing, and ultimately dominant donor-specific allelic pattern, which we defined as molecular engraftment, preceded hematologic engraftment by a median of 7 days (range 1-17 days) in all patients investigated. PCR analyses during the first days after transplantation facilitated detection of molecular engraftment according to the above definition by day +14 (range day +2 to day +14), thus permitting prediction of successful engraftment (upper limit of the two-sided confidence interval po = 6%) while the peripheral leukocyte counts were mostly below 200/microl. In three cases, however, the criteria for molecular engraftment were not fulfilled by day +14. These patients also failed to show hematologic engraftment, and required a second transplantation. Close monitoring by STR-PCR showed that graft rejection and autologous recovery can occur early and with very rapid dynamics. Molecular analysis of specific leukocyte subsets isolated by flow-sorting enabled sensitive assessment of changes in the pattern of chimerism which had escaped detection in assays using whole white blood cell (WBC) samples. This approach facilitated the identification of expanding or decreasing recipient cells, and permitted early detection of impending rejection or relapse. Moreover, monitoring of the dynamics of chimerism allowed rapid assessment of the response to therapy. Our observations provide support for the concept of initiating genotype analyses early after SCT and monitoring at rather short intervals to permit timely evaluation of clinically relevant processes, and to provide a basis for early implementation of treatment.

Adolescent↗

Large deletions of chromosome 9p in cutaneous malignant melanoma identify patients with a high risk of developing metastases. Hospital Clinic Malignant Melanoma Group, University of Barcelona.

Cutaneous malignant melanoma (CMM) is an aggressive tumour with a high metastatic potential. Deletions of chromosome 9p have been detected in CMM, some of which involve the CDKN2A/p14ARF genes. Loss of heterozygosity (LOH) of 16 microsatellite markers on 9p and mutations in the CDKN2A/p14ARF genes had been previously studied in 32 melanoma patients by our group. 9p deletions were detected in 15 primary tumours (45.5%) and are here correlated with the clinical outcome over 5 years and compared with classical prognostic factors. Eight of the 32 patients developed metastases (25%). The metastases were all detected within 768 days of the initial diagnosis. The patients without metastases were last monitored at least 1621 days after diagnosis. None of the 21 patients with more than eight microsatellites conserved developed metastases, whereas all of the eight patients who developed metastases had eight or more markers deleted. The sensitivity of this analysis to predict metastases was 100% (specificity 84%), whereas the sensitivity for the same sample using a Breslow thickness > 3 mm was 62.5% (specificity 68%). LOH of eight or more of the 9p microsatellite markers is therefore a useful prognostic factor to predict the development of metastases in the first 4.4-6.3 years (1621-2294 days).

Chromosome Deletion↗

Overexpression of JunB in undifferentiated malignant rat oral keratinocytes enhances the malignant phenotype in vitro without altering cellular differentiation.

Our study examined the expression of AP-1 family members in keratinocytes derived from the rat-4NQO model of oral carcinogenesis in which extremes of epithelial differentiation and tumour cell aggressiveness are evident. The constitutive expression of JunB was diminished in the undifferentiated, more aggressive tumour phenotype compared with the well-differentiated, less aggressive keratinocytes, whereas the expression of other AP-1 family members (c-jun, junD, c-fos, fra1, fra2 and fosB) was either very weak or variable. After transfection of the undifferentiated keratinocytes with junB cDNA, clonal populations were isolated that expressed similar levels of JunB protein as the well-differentiated cells. Both untransfected and transfected cell lines were keratin negative and vimentin positive. Increased expression of JunB in the transfected cells resulted in up-regulation of c-Jun and Fra1 and an enhanced AP-1 activity as demonstrated by transcriptional activation of the prototypic AP-1 dependent promoter, MMP-1. JunB transfected cells grew more quickly than vector-only controls and were refractory to the growth inhibitory effects of TGF-beta1. Over-expression of JunB resulted in the elevated expression of the AP-1 dependent proteinase, MMP-9, whereas the expression of the AP-1 independent enzyme, MMP-2, was unaffected. JunB transfected keratinocytes were highly invasive in an in vitro assay of tumour cell invasion compared with vector controls. The results indicate that increased expression of JunB above baseline levels in undifferentiated rat keratinocytes does not alter epithelial differentiation but enhances the malignant phenotype in vitro, possibly by altering the dynamics of the AP-1 complex.

3T3 Cells↗

Leucocytotoxicity in malignant and non-malignant colonic diseases.

The survival of cells from five different cultures of allogeneic malignant colonic carcinoma, two from normal adult colonic epithelium and eight from foetal colonic epithelium in the presence of leucocytes from patients with neoplastic and inflammatory disorders of the colon has been compared. Cytotoxicity assessed by the reduction of the number of adherent target cells in microplate wells compared with those surviving in wells treated with tissue culture medium alone was observed with leucocytes from donors in all categories examined including those from individuals without any known abnormality. Patients with ulcerative colitis were the only group to reveal consistent reactivity against cultures derived from all three sources, an observation which may reflect sensitization to organ-related antigens in this disease. In contrast, leucocytes from patients with bowel neoplasia showed reactivity for cells derived from colon carcinoma tissue, which was comparable to that of healthy donors. Evidence for tumour-specific cytotoxicity was therefore lacking in this study. It is suggested that the detection of tumour-associated antigens on cultured cells may be limited by a number of factors of which the wide variation in reactivity among controls and unspecified nature of the target cells are likely to be of greatest importance.

Antigens, Neoplasm↗

mRNA expression profile of matrix metalloproteinases and their tissue inhibitors in malignant and non-malignant prostatic tissue.

BACKGROUND: Increased expression of matrix metalloproteinases (MMPs) was found in various carcinomas. The aim of this study was to present a comprehensive mRNA expression profile of MMPs in benign and malignant prostatic tissue. MATERIALS AND METHODS: mRNA expression patterns of MMP-1, -2, -7, -9, -11, -14 and their tissue inhibitors (TIMPs) -1, -2 and -3 were studied in cancerous and non-cancerous parts of 17 prostates removed by radical prostatectomy. Competitive reverse transcritpion PCR was used for quantification of MMP and TIMP mRNA. RESULTS: Both decreased (MMP-2, MMP-11, MMP-14) and a tendency to increased (MMP-9) MMP values in cancerous compared to the non-cancerous samples were observed. Significantly reduced TIMP-2 and TIMP-3 values were remarkable. Relatively strong associations were found among the three TIMPs while only a significant correlation between MMPs was observed between MMP-2 and MMP-7. There were no significant correlations between MMPs and tumor grade and stage and serum prostate-specific antigen. Receiver operation characteristic analyses proved that MMP and TIMP mRNA and their ratios have an insufficient capability to differentiate between cancerous and non-cancerous tissue. The ratios of MMP-9 to all three TIMPs and the ratio of MMP-14 to TIMP-3 were significantly increased. CONCLUSION: These increased ratios support the view of an imbalance between MMP-9 activity and its inhibitory counterparts in cancerous tissue as an important step in the development of prostate carcinoma and implicate the rationale of using synthetic inhibitors of MMPs as potential therapeutic tools.

Adenocarcinoma↗

[Bronchopulmonary carcinoids: neoplasms with attenuated malignancy or true and proper malignant tumors?].

The authors, in reporting their series of 6 bronchopulmonary carcinoids, dwell upon the criteria used to classify such neoplasms pointing out the related diagnostic problems. The presence of metastases and/or local recurrences as well as the impossibility to define the aggressiveness of the tumor brought the authors to consider such tumors as malignant. They conclude for a surgical approach which should be conservative: segmentectomy and lobectomy in elective procedures, whereas pneumonectomy and endoscopic resection should be reserved to particular cases.

Adult↗