Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference.

Peritoneal mesothelioma is a rare cancer of the peritoneum with about 250 new cases diagnosed each year in the United States. It is the second most common site for mesothelioma development and accounts for 10-20% of all mesotheliomas diagnosed in the United States. A meeting sponsored by the NIH Office of Rare Diseases was held in Bethesda, Maryland on September 13 and 14, 2004. The objective of this meeting was to review the epidemiology, biology and current surgical and medical management of peritoneal mesothelioma. In addition, the meeting also discussed clinical and pre-clinical evaluation of novel treatments for mesothelioma as well as ongoing laboratory research to better understand this disease. This report summarizes the proceedings of the meeting as well as directions for future clinical and basic research.

[Effects of hip arthroplasty followed by by inpatient rehabilitation on physical function and quality of life]. / Effekte der Hüftarthroplastik und der nachfolgenden stationären postoperativen Rehabilitation auf körperliche Funktion und Lebensqualität.

The aim of the present study was to investigate the effects of hip arthroplasty followed by an inpatient rehabilitation. Moreover, the relationships among functional status, quality of life and satisfaction with life or health status were examined. Patients were assessed before hip arthroplasty, at the start and at the end of the inpatient rehabilitation. Functional status was measured by using the WOMAC questionnaire and quality of life with the Medical Outcome Survey Short Form 36 (SF-36). Satisfaction was determined with a specific questionnaire (FLZ). Hip arthroplasty followed by an inpatient rehabilitation resulted in significant and clinically highly important improvements of functional status, quality of life and satisfaction with health and life.

Accurate lymph node assessment prior to trimodality therapy for esophageal carcinoma.

PURPOSE: The diagnosis of esophageal carcinoma has historically been associated with a poor prognosis. Recently, investigators have reported improved outcomes for this patient population with the use of trimodality therapy. These results have fueled the debate regarding which patients may benefit from this aggressive treatment course. This retrospective analysis was conducted in order to evaluate the importance of regional lymph node involvement, determined by surgical staging before the initiation of therapy. PATIENTS AND MATERIALS: Between July 1991 and June 1999, 45 patients underwent surgical staging with thoracoscopy and/or laparoscopy followed by induction chemoradiation and surgical resection. All patients underwent consultation in our thoracic multidisciplinary clinic. Thoracoscopy included nodal sampling from American Thoracic Society levels 5, 6, 8, and 9 within the mediastinum. Laparoscopy included inspection of the liver and nodal sampling from the lesser curvature and the celiac axis. Preoperative chemoradiation consisted of two cycles of 5-fluorouracil (1000 mg/M2) and cisplatin (100 mg/M2) weeks 1 and 4 with 50.4 Gy. Radiotherapy was delivered at 1.8 Gy/fraction with 39.6 Gy being delivered to the large-field and 10.8 Gy to a small-field boost. The routine surgical procedure was an Ivor-Lewis esophagectomy performed 4 to 6 weeks after completion of induction therapy. RESULTS: The median follow up was 24 months for all patients. The median overall survival was 23 months, with 1-, 2-, and 3-year survivals of 64%, 42%, and 34%, respectively. Thirty patients had pathological evidence of lymph node disease before therapy. The pathological complete response rate for the entire group was 51%. Node-positive patients had a path complete response rate of 14%, as compared with 59% for those who were NO. The median survival for these two groups was 15 months versus 35 months. Patients whose nodes were cleared by chemoradiation had a 3-year survival of 40%, whereas all patients with persistent nodal disease were dead by 2 years. Twenty-one patients have experienced recurrence of their disease. Thirteen patients had evidence of distant metastasis only, three local only, and five with both. CONCLUSION: Trimodality therapy offers patients with esophageal cancer an opportunity for long-term survival. Our experience has shown that minimally invasive pretreatment surgical staging provides useful information that can predict complete response and can help in the selection of appropriate patients for aggressive therapy.

The use of concurrent chemotherapy with high-dose radiation before surgical resection in patients presenting with apical sulcus tumors.

PURPOSE: Patients presenting with apical sulcus tumors have historically been treated with preoperative radiotherapy followed by surgical resection. Since 1991, we have delivered an induction regimen consisting of combination chemotherapy and high-dose radiation in an attempt to improve tumor responses and increase survival for this patient population. PATIENTS AND MATERIALS: This retrospective analysis consisted of 23 (13 men and 10 women) consecutive patients who completed trimodality therapy. The median age was 53 years. Histologies included adenocarcinoma (nine patients), squamous cell (five patients), large cell (three patients), and undifferentiated non-small cell lung carcinoma (six patients). Pretreatment stages were T3NO (14 patients), T3N2 (two patients), T3N3 (one patient), T4NO (five patients), and T4N2 (one patient). Preoperative therapy consisted of daily radiotherapy (median dose, 59.4 Gy) delivered at 1.8 Gy/day and concurrent combination chemotherapy consisting of either two cycles of cisplatin and etoposide or weekly carboplatin and paclitaxel. Surgical resection typically included lobectomy with chest wall resection. RESULTS: All 23 patients were available for analysis of response and survival. The median follow-up was 53 months. The median number of days between completion of induction therapy and surgery was 56 days. Postoperative complications included prolonged atelectasis (two patients), pulmonary embolism (one patient), subarachnoid-pleural fistula (one patient), and deep vein thrombosis in the subclavian vein (one patient). The pathological complete response rate to induction therapy was 46% for the entire group. An additional 38% had evidence of tumor regression at the time of surgery. The 5-year disease-free and overall survivals were 36% and 49%, respectively. The median overall survival was 33 months. The median overall survival for those who achieved a pathological complete response has not been reached. Analysis of factors including age, sex, histology, differentiation, stage of disease, and radiation dose failed to identify any predictors of response or survival. CONCLUSION Concurrent chemotherapy and high-dose radiation can be safely delivered before surgery in patients presentingwith apical sulcus tumors. Our results compare favorably to other institutional series and support the further investigation of this approach in prospective trials.

Phase I study of docetaxel and topotecan in patients with solid tumors.

PURPOSE: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. METHODS: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 micrograms was administered subcutaneously (s.c.) on days 5-14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. RESULTS: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9-18 weeks). Administration of TOPO on days 1-4 and DOC on day 4 resulted in increased neutropenia. CONCLUSIONS: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 micrograms s.c. on days 5-14. The alternative schedule with DOC given on day 4 and TOPO on days 1-4 is not recommended.

The "comparative growth assay": examining the interplay of anti-cancer agents with cells carrying single gene alterations.

We have developed a "comparative growth assay" that complements current assays of drug effects based on cytotoxicity. A co-culture of two cell lines, one of which is fluorescently labeled, is exposed to a cytotoxic agent and the proportion of fluorescent cells is compared with that of a baseline unexposed co-culture. For demonstration purposes, two HCT116 cell lines (an hMLH1 homozygous and an hMLH1 heterozygous mutant), altered by insertion of vector alone or the same vector carrying an insert for the expression of enhanced green fluorescent protein (EGFP), were exposed to numerous "anti-cancer" agents. The assay was further validated in a system of two cell lines differing only in the expression of the breast cancer resistance protein (BRCP). The assay allowed the estimation of the duration of action of a particular agent. Assessment of the agent's differential activity over a given time in culture could be expressed as a selection rate, which we chose to describe on an "average selection per day" basis. We conclude that this assay: 1) provides insight into the differential dynamic effects of chemotherapeutic agents or radiation; and 2) allows, through the use of matched cell lines, the investigation of critical physiologic features that govern cell sensitivity.

Disseminated growth of murine plasmacytoma: similarities to multiple myeloma.

Murine plasma cell tumors share a number of common features with human multiple myeloma, suggesting their possible use as a model for this disease. However, one major difference between the two is the peritoneal localization of murine tumors as opposed to bone marrow residence of malignant plasma cells in early stages of multiple myeloma. We have thus examined the ability of murine plasmacytoma to produce disseminated growth similar to that seen in myeloma or other lymphoid neoplasias. Of four murine cell lines evaluated, all were demonstrated to effect highly metastatic disease involving multiple organs, although variation was observed between lines. A temporal analysis was accordingly performed with the S107 line to assess the pattern of cellular localization. Both light microscopy and PCR analysis revealed that engraftment of plasma cells occurs first in the bone marrow, followed by dissemination to other sites including the spleen, lung, and liver. Cells passaged in vivo through the bone marrow display an entirely different metastatic pattern with no homing preference to bone marrow or any other organ, suggesting the occurrence of a phenotypic change. Microscopic osteolytic lesions were observed adjacent to plasma cell tumor masses in the bone marrow, indicating early stages of bone disease. These findings demonstrate previously unrecognized similarities between the murine and human diseases and suggest the use of this in vivo model for experimental approaches to the treatment of human disease.

Mutations in beta-catenin are uncommon in colorectal cancer occurring in occasional replication error-positive tumors.

Beta-catenin has been identified as an oncogene in colon cancer and melanoma. Phosphorylation of sites in exon 3 of beta-catenin leads to degradation of this protein. These sites are primary targets for activating mutations. The frequency with which oncogenic mutations at these sites are found in colorectal cancer is unknown, as is the frequency of their occurrence in other malignancies. We analyzed 92 colorectal cancers (CRCs) and 57 cancer cell lines (representing a diversity of tumor types) to determine the frequency of activating mutations in this gene. Mutations in exon 3 of beta-catenin were found in 2 of 92 CRCs and in the colorectal cancer cell line HCT 116. Both tumors with beta-catenin mutations exhibited widespread microsatellite instability, which is indicative of a replication error phenotype, a phenotype known to be present in HCT 116. This suggests that mutations in beta-catenin are infrequent in CRC and miscellaneous cancer cell lines and may occur in association with a replication error phenotype.

Immunoglobulin/Myc recombinations in murine Peyer's patch follicles.

Immunoglobulin heavy chain (Igh)/Myc recombinations are a hallmark of pristane-induced mouse plasmacytomas but are also frequently found in non-tumorous tissues. Here we describe for the first time a PCR-based technique for detecting fusions between Igh mu or Igh alpha and Myc in situ. Igh/Myc recombinations were found in transplanted and primary plasmacytomas. In addition, the gut-associated lymphoid tissues of plasmacytoma-free BALB/c mice were investigated for the presence of Igh/Myc fusions. Igh/Myc rearrangements were detected in Peyer's patch follicles and in the intestinal lamina propria both in normal mice and in mice shortly after pristane treatment. The sequence analysis showed that i) three to five different Igh/Myc hybrid sequences were present in individual follicles, ii) Igh/Myc recombinations can be subjected to additional switch recombinations as shown by related sequences in neighboring cells, and iii) cells harboring these rearrangements migrate into the adjacent lamina propria. The results indicate that Peyer's patches are a hyper-recombinogenic tissue. Myc recombination-positive cells are present in at least 100-fold more frequently than expected if recombinations were random, which suggests that this kind of trans-chromosomal rearrangement may be targeted.

Characterization of C57BL/6 plasmacytomas lacking a c-myc translocation.

BALB/c peritoneal plasmacytomas induced by a variety of agents are invariably associated with a c-myc translocation. In contrast, naturally arising bone marrow plasma cell tumors in C57BL/KaLwRij mice lack this translocation. This difference has led to the suggestion that these are 2 fundamentally different plasma cell diseases. Herein, we have analyzed 2 rare C57BL/6 peritoneal plasmacytomas in terms of characteristics associated with the bone marrow-derived lines. Like the bone marrow lines, these peritoneal plasmacytomas do not exhibit c-myc translocations, indicating that c-myc translocation is not an obligatory event in the development of all murine extramedullary plasmacytomas. However, myc is dysregulated at the mRNA level, indicating that myc overexpression may be fundamental to most plasma cell diseases but that dysregulation can occur by alternative mechanisms possibly reflecting different genetic backgrounds.

[Use of flow cytometry in the diagnosis of acute leukemias in childhood]. / Vyuzití prutokové cytometrie v diagnostice akutních leukémií detského veku.

The authors examined, using the method of flow cytometry, 56 children with acute lymphoblastic leukaemia. Leukaemic cells of the bone marrow aspirate and peripheral blood were examined on a FACS 440 apparatus for establishment of the diagnosis before treatment was initiated. Individual immunological subtypes were differentiated by means of a panel of monoclonal antibodies. 80.5% of acute lymphoblastic leukaemias originated from different developmental stages of B cells, 12.5% were formed by leukaemias from T cells and 7% were non-differentiated leukaemias. The mean follow-up period in the group was 33 months. According to the therapeutic results children with leukaemia ensuing from precursors of B cells had a more favourable prognosis than children with T leukaemia and children with non-differentiated leukaemia. Quantitative examination of nuclear DNA of leukaemic cells revealed in 55% of the patients of the group aneuploidy with clear predominance of hyperdiploidy, 45% of the patients suffered from diploidy. The least number of relapses was recorded in the investigation period in children with hyperploid acute lymphoblastic leukaemia. The proliferating activity of leukaemic blasts was expressed by the number of cells in the S + G2M stage of the cellular cycle and was higher in the bone marrow than in peripheral blood but did not differ in individual immunological subtypes or in diploid leukaemias. The authors were not able to prove its prognostic importance. Flow cytometry is a rapid and sensitive diagnostic method which makes it possible to characterize more satisfactorily the heterogeneous group of acute lymphoblastic leukaemias.

[DNA flow cytometry: perspective prognostic parameters in carcinoma of the uterine cervix]. / DNA flow cytometrie: perspektivní prognostický parametr karcinomu delozního cípku.

We studied the relation between the 5-year disease free interval and the flow cytometric DNA content in a group of 55 patients treated by radiation for squamous cell carcinoma of the uterine cervix, stages Ib-IIIb (FIGO). The diploid DNA content was associated with a better prognosis, while prognostically unfavourable tumours tended to be aneuploid. The relation was statistically significant in the whole group (p = 0.016), in stage II disease (p = 0.003) and in the subgroup formed by the combination of stages I and II (p = 0.000). In stage III we did not prove the relation. Analysis of the survival function revealed also a better prognosis of diploid tumours (p = 0.041) in the whole group. The division into clearly diploid and non-diploid tumours seems to be more suitable for evaluation (p = 0.012). The difference between the prognostically favourable and unfavourable groups is expressed more clearly. We consider the flow cytometric DNA content a perspective prognostic parameter in squamous cell carcinoma of the uterine cervix. Its significance is apparent especially in patients treated by radiotherapy, because the size of the tumour cannot be assessed reliably in these cases.

[Cervico-acetabular impingement after femoral neck fracture]. / Zervikoazetabuläres Impingement nach Schenkelhalsfraktur.

Six cases of femoral neck-acetabular impingement following fracture of the femoral neck are reported. To our knowledge, this complication has not previously been described in the literature. A bony prominence at the level of the former fracture site following primary or secondary valgus position of the femoral head showed a conflict with the acetabular rim causing pain and limited motion. In four patients this impingement was posterior, between the femoral neck and the acetabulum in extension with external rotation, and in two patients it was anterior in flexion with internal rotation. A detailed description of the symptoms, diagnostic procedures and treatment options is presented.

[T-lymphocyte subpopulations in chronic active hepatitis]. / Subpopulace lymfocytu T u chronické aktivní hepatitidy.

In 33 patients with chronic active hepatitis quantitative changes were found in the ratio of different sub-populations of T lymphocytes in the peripheral blood stream which were either associated with treatment or with the presence of HbsAg in serum. A reduction of CD 3 positive lymphocytes was found in patients not treated by immunosuppression. In HbsAg positive patients an increase of CD 4 positive lymphocytes was found, as compared with HBsAg negative patients. Signs of activity of the hepatic process correlated with the presence of sign CD 8.

[Advances in the treatment of acute lymphoblastic leukemia in childhood: experience with intensive protocol treatments]. / Pokrok v lécbe detské akutní lymfoblastické leukémie: zkusenosti s lécbou pomocí intenzívních protokolu.

The authors analyzed a group of 64 children with acute lymphoblastic leukaemia (ALL) treated according to three protocols of different intensity. The best therapeutic results were obtained in children treated according to the most intensive protocol of the West German Multicentre Investigation BFM 83 which is graded as to its intensity with regard to the degree of risk of an adverse course. Successful remission in the entire group of patients was 93%, one third of the children developed during the investigation period a relapse of the basic disease. 12% of the children died during remission from complications of treatment. The surprising agreement of therapeutic results of different protocols after three years' complete remission is apparent from the fact that early relapses during the first two years of treatment, implying resistance to administered therapy, are at present the greatest problem of effective treatment which is not resolved even by the ever increasing intensity of treatment. In the conclusion the authors define the group of patients with a high risk of early relapse for whom new therapeutic procedures must be sought.

[Factors affecting the prognosis of acute lymphoblastic leukemia in childhood]. / Faktory ovlivnující prognózu akutní lymfoblastické leukémie v detském veku.

The authors tried to test the value of some clinical and laboratory characteristics for the prognosis of acute lymphoblastic leukaemia (ALL) in a group of 69 children treated according to three different protocols. The results were evaluated by methods of one-dimensional and multidimensional analysis. The absolute number of blasts in the peripheral blood stream and initial leucocytosis during establishment of the diagnosis proved to be the most important risk factors influencing the prognosis of the patients. Other adverse signs for the prognosis of ALL in the group were a mediastinal tumour, L2 type of leukaemic blasts according to the morphological FAB classification and age above 10 years when the diagnosis was established. The patient's sex, immunophenotype of the leukaemic blasts, chromosomal abnormality of the karyotype in the leukaemic cells, marked hepatosplenomegaly, thrombocytopenia, haemoglobin values and PAS reaction in the blasts, did not affect the therapeutic results in the author's group of patients.

[Immunologic profile in patients with acute anterior uveitis]. / Imunologický profil nemocných akutní prední uveitidou.

The authors investigated 52 patients (22 men and 30 women) with acute anterior uveitis where they ruled out systemic autoimmune disease, metabolic disease and focal or chronic infection. At the time of the infection the patients had not been treated for several months by any immunosuppressive treatment. The authors investigated in these patients serum concentrations of immunoglobulins G, A and M, the concentration of the C3 component of complement and the concentration of circulating immune complexes. Before the onset of therapy they investigated the response to antigens of the Immunoskin test. They assessed also the ratio of transplantation antigens class I by the microlymphocytotoxic test. They compared furthermore immunological indicators in subjects with a first attack and relapse of the disease and in groups, classified by the severity of the inflammatory symptoms. The authors detected significantly more frequently (p = 0.0005) the incidence of HLA-B27 antigen. Those where it was present were more frequently affected with a severe inflammation, as compared with subjects who did not have this phenotype (p less than 0.04). The relapse of the disease was more frequent in women (p = 0.1). The immunological laboratory findings did not differ in the first attacks and relapses of the disease, differences were, however, found in groups which differed as to the severity of inflammatory symptoms. In these groups the response rate to tests of skin sensitivity differed also. Based on these findings the authors assume that the ratio of immune processes in the development of acute idiopathic anterior uveitis cannot be ruled out.

Common variable immunodeficiency and malignancy: a report of two cases and possible explanation for the association.

Two patients with common variable immunodeficiency (CVID) and malignant tumours are reported. The first patient developed myelogenous leukaemia soon after the myelodysplastic syndrome has been diagnosed. The undifferentiated gastric lymphoma found in the second patient suggests that an increased risk of gastrointestinal malignancies in CVID could partly be due to lymphomas. We hypothesize that the tissue- or site-specific risk of lymphomas and gastrointestinal cancer can be explained by an increased chromosomal or genomic instability with a higher mutation rate and genomic disorganization, and that this instability could be related to viral carcinogenesis. The primary immunodeficiency per se may not be responsible for the cancer susceptibility in CVID patients.

Amplification of N-myc oncogene in human melanoma cells.

Tissue specimens from two melanoma patients and two patients with laryngeal carcinoma were studied for the expression of c-myc, N-myc and v-src oncogenes. Out of three different probes, only the N-myc probe one signalled amplification. While the two patients with laryngeal carcinoma showed only single copy of the N-myc gene in tumor cells, amplification of this gene was found in both two melanoma patients. The patients with 1 extra copy of the N-myc gene and its protein product had an early recurrence but is still alive, while the other melanoma patient with 4 extra copies of the gene, relapsed very early and died of melanoma within 7 months after diagnosis. Thus a higher amplification (4 extra copies) seems to correlate with very poor outcome of the disease.