Reconfigurable systems for sequence alignment and for general dynamic programming

Reconfigurable systolic arrays can be adapted to efficiently resolve a wide spectrum of computational problems; parallelism is naturally explored in systolic arrays and reconfigurability allows for redefinition of the interconnections and operations even during run time (dynamically). We present a reconfigurable systolic architecture that can be applied for the efficient treatment of several dynamic programming methods for resolving well-known problems, such as global and local sequence alignment, approximate string matching and longest common subsequence. The dynamicity of the reconfigurability was found to be useful for practical applications in the construction of sequence alignments. A VHDL (VHSIC hardware description language) version of this new architecture was implemented on an APEX FPGA (Field programmable gate array). It would be several magnitudes faster than the software algorithm alternatives.

Monoclonal gammopathy after low-grade MALT lymphoma: evidence for a second neoplasm.

We report the case of a patient with lymphoma of the salivary gland, at first diagnosed as lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but later found to infiltrate the bone marrow. At diagnosis, the patient had a polyclonal increase of gamma-globulins. Five years after initial diagnosis, the patient presented with monoclonal gammopathy and infiltration of the bone marrow with neoplastic cells. Initially, the patient had received chemotherapy with different protocols (including etoposide, cyclophosphamide, fludarabin, methotrexate, and vincristine), none of which induced a lasting response. Therapy with rituximab (chimeric anti-CD20 monoclonal antibody) finally led to partial remission. Eighteen months after rituximab, progressive lymphoma in the abdomen and a monoclonal gammopathy developed. The bone marrow showed infiltration by lymphoplasmacytoid cells (monoclonal expression of the light-chain type lambda, positive for CD20, heterogeneous expression of CD45). The patient achieved another short clinical response with 4 cycles of the CHOP-protocol, but soon the lymphoma progressed again. Five years and 8 months after the initial diagnosis, the patient died from septicemia and progressive lymphoma. By polymerase chain reaction (PCR) for the IgH gene it was shown that lymphoma cells were initially oligoclonal in the salivary gland and, later, biclonal in the bone marrow. Sequencing of two bands of apparently same length showed that these manifestations of lymphoma were not identical. Taken together, our data show that the initial low-grade oligoclonal MALT lymphoma was no longer present and a more aggressive biclonal lymphoma with plasmacytoid differentiation had developed. The new lymphoma was clonally distinct and produced high amounts of monoclonal IgG lambda by immunoelectrophoresis. The relationship of the second lymphoma to the initial MALT lymphoma is discussed.

Advanced head and neck cancer: long-term results of chemo-radiotherapy, complications and induction of second malignancies.

BACKGROUND: Chemo-radiotherapy is superior to radiotherapy alone in the treatment of advanced, inoperable head and neck cancer. The long-term treatment results, the induction of second malignant tumors, and other long-term toxicities are not well defined. PATIENTS AND METHODS: 100 consecutive patients with advanced head and neck cancer who were treated at our center were studied. Treatment results, survival, the occurrence of late complications, and second malignant tumors (SMT) were investigated. 78 patients were treated with a protocol combining cisplatinum, 5-fluorouracil, folinic acid and hyperfractionated irradiation. 22 patients were treated with other chemo-radiotherapy protocols. The relative risk of developing an SMT was compared with that within the normal population. RESULTS: The cumulative total probability of survival was 51.1% at 2 years and 38.7% at 4 years. The probability of relapse-free survival was 39.9% at 2 years and 36.7% at 4 years. A total of 7 patients developed SMT (4 cases of lung cancer, 2 colon cancers, 1 skin cancer). After 6 years, a cumulative risk of SMT of 8.7% was observed. The relative risk of developing an SMT was significantly increased (4.45-fold in males) compared with a normal population. 13 of 38 evaluable patients (34.2%) had severe late complications like fibrosis of soft tissues, nerve lesions, or were dependent on tracheal cannulas. CONCLUSIONS: The treatment results and long-term prognoses in our population of unselected high-risk patients are unsatisfactory, but comparable to those from multicenter studies. About 35% of patients become long-term (> 4 years) survivors. SMT generally occur early, have a poor prognosis and, most likely, are not treatment-related. Approximately 30% of long-term survivors have severe, often incapacitating late effects. The treatment and - if possible - prevention of these late effects is important for the quality of life of patients who survived advanced head and neck cancer.

Acute myelogenous leukaemia and myelomonocytic blast crisis following polycythemia vera in HIV positive patients: report of cases and review of the literature.

BACKGROUND: Acute myelogenous leukaemia (AML) and myeloproliferative diseases are rare in HIV-infected individuals and optimal treatment has not been defined. PATIENTS AND METHODS: We report on the cases of two HIV-infected men, one with AML and one with myeloid blast crisis after polycythaemia vera (PV). A comprehensive review of the available literature will be presented. RESULTS: Patient 1, a 57-year-old bisexual man known to be HIV seropositive for more than four years (CDC-category A1), presented with a pulmonary infiltrate. On admission WBC showed leukocytes 5.6 x 10(9)/l and the differential revealed 80% blasts. A diagnosis of AML FAB M0 was made. Pneumonia resolved under antibiotic treatment and the patient received induction chemotherapy. However, he once more developed multiple pulmonary infiltrates and died of respiratory failure despite broad spectrum antibiotic and antimycotic therapy. Autopsy revealed pulmonary aspergillosis. Patient 2 was a 63-year old HIV-positive hemophiliac (CDC A3) with a 10-year history of PV. On admission his white cell count showed leukocytes 256.6 x 10(9)/l with 82% blasts. Cytochemistry revealed myelomonocytic differentiation. The patient died of tumor lysis syndrome with renal and cardio-pulmonary failure two days later. CONCLUSIONS: This is the first report of an HIV-infected individual with AML M0. The literature describes the cases of 39 HIV+ patients with AML and only one further case with PV. The association of both, myeloproliferative disease and AML with HIV infection is coincidental. However, the proportion of FAB type M4/5 appears to be higher than in the general population. Despite a high risk of treatment associated mortality durable remissions can be achieved in a small proportion of HIV-infected patients with AML.

Oncology and Palliative Care.

Oncology developed as a discipline over the last decades. Treatment is concentrated on cure or palliation of the illness with the help of chemotherapy, radiotherapy or surgery. Palliative care has its origin in the hospice movement that started around 1960 in the UK. Centre of care is the patient and his family. Focus of care has moved from quantity to quality of life. Symptom control, communication, rehabilitation and care for the dying are main areas of palliative care. Palliative care and palliative medicine have only developed over the last 10 years in Germany. It is still seen as care for the dying after completion of oncological treatment. The integration of palliative care in earlier stages of the disease is essential to offer a continuity of care for the patient and his family. Principles of palliative care need also be part of medical and post-graduate training. Copyright 2000 S. Karger GmbH, Freiburg

Spontaneous Bleeding in a Patient with Malignant Lymphoma: A Case of Acquired Hemophilia.

BACKGROUND: Acquired hemophilia is a rare condition which can be associated with lymphoproliferative disease. CASE REPORT: Eleven years after the diagnosis of immunocytoma had been made, a 72-year-old man developed a high-titer factor VIII inhibitor. At this time, the lymphoma was without significant progress and there was no paraprotein in the serum. Partial thromboplastin time (PTT) was 83s, factor-VIII clotting activity was <1%, and inhibitor level was 50.4 Bethesda units. The patient presented with spontaneous hematomas in the skin and musculature of the extremities. Following combination chemotherapy with cyclophosphamide, vincristine and prednisolone (COP), there was a prompt disappearance of the inhibitor and normalization of coagulation; however, the patient developed serious infectious complications. When the inhibitor recurred he was treated with low-dose cyclophosphamide and prednisolone. This time there was a more delayed response, but the inhibitor disappeared again completely. Two months after cessation of therapy, there was again relapse. CONCLUSION: Causal relationship between lymphoma and acquired hemophilia remains speculative. At least in some cases of factor VIII inhibitors associated with malignant disease, immunosuppressive therapy may be sufficient to suppress the inhibitor. Copyright 2000 S. Karger GmbH, Freiburg

Advances in the management of metastatic non-seminomatous germ cell tumours during the cisplatin era: a single-institution experience.

Long-term outcome was reviewed in 266 consecutive patients with metastatic non-seminomatous germ cell tumours treated at a single institution. The overall 3 year survival was 77%, and 3 year progression-free survival was 71%. Multivariate analysis identified the following clinical features as independent prognostic factors: the presence of liver, bone or brain metastasis, serum human chorionic gonadotropin > or = 10000 U l-1 and/or alpha-fetoprotein > or = 1000 ng ml-1, a mediastinal mass > 5 cm and the presence of 20 or more lung metastases. Age was not of prognostic significance. Patients without any of the above poor-risk factors had a 3 year survival of 91% regardless of etoposide- or vinblastine-containing chemotherapy compared with 61% for the remaining patients. However, etoposide-containing protocols led to significantly improved survival in patients with at least one poor risk factor. After 612 patient-years of observation no case of secondary leukaemia was observed among 119 surviving patients who had received etoposide as part of their treatment. With a median follow-up of 93 months, five patients developed a second germ cell tumour, two patients nongerm cell malignancies. Fourteen patients relapsed after a disease-free interval of more than 2 years, and nine patients died more than 5 years after commencement of treatment underscoring the need to report long-term results. There is some evidence that cumulative experience translates into improved survival and cure rates for patients with poor-risk metastatic disease.

Does serum tumor marker half-life complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors?

The goal of this study was to determine whether the serum tumor marker half-life (MHL) of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) during initial chemotherapy can complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors. One hundred forty-seven patients were assessable for MHL during the first two cycles of platinum-based chemotherapy. MHL calculation was based on two consecutive values using Kohn's apparent half-life formula (MHL =ln 1/2/G, where G was the gradient of the marker slope) or on three (or more) values using simple linear regression. MHL was regarded as prolonged if it was more than 3.5 days for HCG or more than 7 days for AFP. The median MHL for HCG was 2.8 days (range, 0.7-16.7) and for AFP was 6.2 days (range, 2. 6-65.4). Thirty-five of 108 patients (32%) had a prolonged MHL for HCG, 41 of 114 (36%) had a prolonged MHL for AFP, and in 59 of 147 patients (40%), either or both MHLs were prolonged. If patients with both MHLs normal were compared against patients with either or both MHLs prolonged, highly significant differences in progression-free survival (P < 0.0001) and overall survival (P = 0.0005) were demonstrated. The test accuracy was 70% for both progression-free and overall survival, and it was slightly greater than the overall predictive value of the Medical Research Council prognostic classification. A combination of Medical Research Council criteria and MHL analysis allowed us to refine prognostic assessment. Because MHL analysis is able to complement pretreatment risk stratification and can support selection of patients for early-dose intensified chemotherapy, it should be included in prospective clinical trials for patients with poor-prognosis disease.

Testicular germ cell tumors in patients with human immunodeficiency virus infection.

BACKGROUND: There has been evidence of a higher incidence of testicular germ cell tumors (GCT) in human immunodeficiency virus (HIV)-seropositive men than in the non HIV-infected male population. Most authors recommend standard therapy for HIV-positive patients with GCT but the immumosuppressive effects of chemotherapy and/or radiotherapy must be considered. METHODS: The records of all patients in whom testicular cancer was diagnosed and/or treated at a single institution between January 1986 and July 1995 were reviewed with regard to HIV seropositivity. Tumor histology, initial staging, treatment, and the patients' outcomes were analyzed in connection with a review of the literature. RESULTS: Six patients with GCT and documented HIV seropositivity at the time of tumor diagnosis (four homosexuals, one bisexual, and one heterosexual former intravenous drug abuser) of 192 documented cases of testicular cancer are reported. In addition, 1 patient proved to be HIV seropositive 34 months after completing chemotherapy (vinblastine, ifosfamide, and cisplatin) for Stage IIB (minimal disease) seminoma. Intensified platinum-based chemotherapy was administered to two patients with clinical Stage IIIC (advanced disease) nonseminomatous germ cell tumors (NSGCT). Both patients achieved a transient partial response but suffered from progressive HIV disease and died 24 and 7 months, respectively, after orchiectomy. One patient with Stage IIIA (moderate disease) seminoma received four courses of chemotherapy (etoposide, ifosfamide, and cisplatin) and has remained in complete remission for 40 months. One patient with bilateral Stage I seminoma underwent adjuvant radiotherapy but was lost to follow-up. One patient with clinical Stage IIA (minimal disease) NSGCT refused any further treatment after hemiorchiectomy, but four courses of chemotherapy (cisplatin, etoposide and bleomycin) had to be given 32 months later because of symptomatic abdominal disease. A partial remission was obtained and there was no evidence of active tumor 16 months after the completion of chemotherapy. A retroperitoneal lymph node dissection was performed in 1 patient with Stage I NSGCT who was free of disease 111 months after diagnosis. The Centers for Disease Control classification for HIV infection and acquired immune deficiency syndrome (AIDS) did not change after therapy in two patients, whereas three patients suffered from progressive HIV disease. CONCLUSIONS: HIV infection should be considered in patients with testicular cancer who belong to an urban population. Oncologic therapy based on a patient's individual situation is recommended.

Prognosis after salvage treatment for unselected male patients with germ cell tumours.

Long-term outcome of salvage treatment was reviewed in 67 unselected male patients relapsing during or after their primary cisplatin-based chemotherapy for metastatic germ cell tumours. Seven patients underwent only surgery and/or radiotherapy as curatively intended salvage treatment. Thirty-five patients (52%) had a complete or partial response to salvage treatment, 20 (57%) of whom relapsed again. With a median follow-up of 90 months (range 3-143 months) 20 patients (30%) are alive with no evidence of disease, 15 continuously disease-free and five currently disease-free. The 5 year survival from start of salvage treatment is 37% for the group as a whole. Multivariate analysis identified age < or = 35 years, complete response to primary treatment and a relapse-free interval > 3 months as independent predictors of favourable outcome of salvage treatment. A group of patients with these good-risk factors (42%) had a 5 year survival of 72% compared with the remaining patients (58%) with a 5 year survival of only 11%. Whereas patients with good-risk features may be adequately managed by conventional salvage treatment, the remaining patients carry a very poor prognosis and require innovative and more aggressive approaches.

Adult Wilms' tumor. Report of two cases and review of the literature.

BACKGROUND: Wilms' tumor is rare in adults. The recommended treatments for patients with Stage II adult Wilms' tumor with favorable histology (FH) nephroblastomas are conflicting. METHODS: Two patients with Stage II, favorable histology, adult nephroblastomas are described. Current treatment modalities are discussed and the literature is reviewed. RESULTS: The first patient, a 52-year-old woman, probably had a late local relapse of a Wilms' tumor 21 years after nephrectomy because of a renal tumor originally diagnosed as reticular sarcoma. In this case, a recurring or an extrarenal Wilms' tumor should have been considered. After the tumor was removed, the patient received adjuvant chemotherapy with dactinomycin and vincristine and was disease free 44 months after diagnosis. The Wilms' tumor in the second patient, a 33-year-old woman, was discovered accidentally and classified as Stage II/FH based on preoperative biopsy. She was treated with radical nephrectomy and adjuvant chemotherapy with dactinomycin and vincristine. This patient was disease free 24 months after surgery. CONCLUSIONS: Surgery and two-drug chemotherapy with dactinomycin and vincristine is suggested for patients with Stage II adult Wilms' tumor with FH nephroblastomas.

Etoposide, cisplatin, bleomycin, and cyclophosphamide (ECBC) as first-line chemotherapy for poor-risk non-seminomatous germ cell tumors.

Sixty-one patients with advanced metastatic non-seminomatous germ cell tumors were treated with etoposide 120 mg/m2, cisplatin 30 mg/m2, bleomycin 12 mg/m2, and cyclophosphamide 300 mg/m2 daily for four days; and additional bleomycin bolus injection of 15 mg was given on day 1. Fifty patients (82%) were treated with four to six courses at 3-week intervals. Forty patients (66%) attained complete remission, and further 7 patients (11%) achieved a marker-negative partial remission accounting for a favorable response rate of 77%. Hematologic toxicity was considerable and there were two treatment-related deaths. After a median observation time of 47 months (range 12 to 108 months), 43 patients were alive, of which 38 had continuous complete remission, one a second complete remission, two marker-negative stable disease and two progressive disease. Our results are similar to those reported by other investigators for poor-risk metastatic non-seminomatous germ cell tumors treated with dose-intensified regimens.

[Cardiac function and the skin microcirculation in acromegaly]. / Kardiale Funktion und kutane Mikrozirkulation bei Akromegalie.

The microcirculation was measured by nail-fold capillary video microscopy in 21 patients (12 men, 9 women; mean age 54.7 [29-74] years) with acromegaly. Levels of growth hormone (12.0-71.7 microU/ml) and of somatomedin C (2.4-10.5 IU/ml) were elevated in 10 patients, despite preceding treatment. Eleven patients had an increase in myocardial thickness and nine had impairment of left ventricular function, although only slight in most. Left ventricular hypertrophy was demonstrable even in the absence of hypertension. No patient had evidence of coronary heart disease. Nail-fold capillary video microscopy (capillary density, torque index, reactive hyperaemia, epidermal blood flow) failed to distinguish between successfully treated patients and those with persistently elevated growth hormone concentrations or disease duration of over 5 years. There was no evidence of inadequate capillary blood flow as a cause of abnormal function in hypertrophied organs.

Prevention of chemotherapy-induced nausea and emesis in patients responding poorly to previous antiemetic therapy. Comparing tropisetron with optimised standard antiemetic therapy.

In a multicentre trial, 78 patients with a variety of malignancies, who had experienced insufficient control of emesis (greater than or equal to 3 episodes within 24 hours) while receiving standard antiemetics during previous chemotherapy, were randomly assigned to receive tropisetron 5mg once daily for 5 days or conventional antiemetic drugs. No attempt was made to standardise the conventional antiemetic treatment, which was given according to the usual practice of the participating institutions. Emesis was evaluated by counting emetic episodes and nausea by asking the patients to record on a diary chart the duration and severity of the nausea. Emesis was much better controlled with tropisetron than with standard drugs, complete control during the first 24 hours being achieved in 42% and 8% of patients, respectively, (p less than 0.001). Nausea was of significantly shorter duration (6.9 vs 10.3 hours; p less than 0.01) and was less severe (p less than 0.005) in the tropisetron group. The patients' overall assessment of treatment outcome was markedly better for tropisetron than for the standard antiemetic therapy. The superior efficacy of tropisetron was especially marked during the first 24 hours. For delayed nausea, no significant difference between treatments was seen. No serious adverse effects were observed.

[Treatment of stage I-IIB nonseminomatous testicular tumors]. / Behandlung nicht-seminomatöser Hodentumoren im Stadium I-IIB.

Data on 90 patients (median age 26 years, range 15-65) with nonseminomatous testicular tumour (NTT) were analysed retrospectively to evaluate the effectiveness of adjuvant chemotherapy: 55 patients had received postoperatively (semicastration, retroperitoneal lymphadenectomy) adjuvant chemotherapy. They have now lived tumour-free for a median period of 67 (range 8-107) months. These results were compared with a group of 35 patients with recurrence of NTT who, after the primary operation, had been merely followed-up but, on diagnosis of recurrence, had received intensive chemotherapy with removal of the recurring tumour, if indicated. Nonetheless, only 24 of these 35 patients (69%) went into a lasting remission. A favourable factor was regular follow-up examinations with early diagnosis of any recurrence. Thus in a quarter of the patients a possible curative chance was missed despite an initially low tumour stage. The results suggest that omission of operative or chemotherapeutic measures is justified only if careful followup is assured.

Chemotherapy of invasive thymoma. A retrospective study of 22 cases.

The authors report on combination chemotherapy in 22 patients (seven men, 15 women; age 20-67, median 38.5 years) with incompletely resected invasive thymoma. Twelve of 22 patients have had prior radiotherapy of the tumor (four of 12 local failure, eight of 12 remote metastases). By subsequent chemotherapy five of 12 obtained complete remission (CR). One of them died by relapsed tumor, another by an intercurrent infection. At 5 years after diagnosis the survival rate of the 12/22 patients was 33% (Kaplan-Meier). Ten of 22 patients received chemotherapy as primary treatment of incompletely resected thymoma. Four of 10 obtained CR. One of them was lost during follow-up, the others received adjuvant irradiation of the mediastinum and are free of disease. Two of ten obtained partial remission (PR), but relapsed within 6 months after chemotherapy. At 3 years after diagnosis the survival rate of the 10/22 patients was 34%. Thirteen of 22 patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP/bleomycin as first chemotherapeutic regimen. Five of them achieved CR. Cyclophosphamide, vincristine, and prednisone (COP) or COP plus procarbazine (COPP) was administered to six of 22. Three of them obtained a CR and one a PR. In an alternating manner COPP and Einhorn regimens were given to two of 22, one of which had a CR. In one of 22 the doxorubicin, bleomycin, cisplatin, prednisone (BAPP) regimen was followed by a PR. The authors conclude that combination chemotherapy is effective in the first-line postsurgical treatment of incompletely resected thymoma and also in the treatment of local or metastatic relapses after radiotherapy.