Dynamics and Control of a Magnetic Transducer Array Using Multi-Physics Models and Artificial Neural Networks.

A linear mechanical oscillator is non-linearly coupled with an electromagnet and its driving circuit through a magnetic field. The resulting non-linear dynamics are investigated using magnetic circuit approximations without major loss of accuracy and in the interest of brevity. Different computational approaches to simulate the setup in terms of dynamical system response and design parameters optimization are pursued. A current source operating in baseband without modulation directly feeds the electromagnet, which consists commonly of a solenoid and a horseshoe-shaped core. The electromagnet is then magnetically coupled to a mass made of soft magnetic material and attached to a spring with damping. The non-linear system is described by a linearized steady-space representation while is examined for controllability and observability. A controller using a pole placement approach is built to stabilize the element. Drawing upon the fact that coupling works both ways, enabling estimation of the mass position and velocity (state variables) by processing the induced voltage across the electromagnet, a state observer is constructed. Accurate and fast tracking of the state variables, along with the possibility of driving more than one module from the same source using modulation, proves the applicability of the electro-magneto-mechanical transducer for sensor applications. Next, a three-layer feed-forward artificial neural network (ANN) system equivalent was trained using the non-linear plant-linear controller-linear observer configuration. Simulations to investigate the robustness of the system with respect to different equilibrium points and input currents were carried out. The ANN proved robust with respect to position accuracy.

Let-7, mir-98 and mir-183 as biomarkers for cancer and schizophrenia [corrected].

Recent evidence supports a role of microRNAs in cancer and psychiatric disorders such as schizophrenia and bipolar disorder, through their regulatory role on the expression of multiple genes. The rather rare co-morbidity of cancer and schizophrenia is an old hypothesis which needs further research on microRNAs as molecules that might exert their oncosuppressive or oncogenic activity in the context of their role in psychiatric disorders. The expression pattern of a variety of different microRNAs was investigated in patients (N = 6) suffering from schizophrenia termed control, patients with a solid tumor (N = 10) and patients with both schizophrenia and tumor (N = 8). miRNA profiling was performed on whole blood samples using the miRCURY LNA microRNA Array technology (6th & 7th generation). A subset of 3 microRNAs showed a statistically significant differential expression between the control and the study groups. Specifically, significant down-regulation of the let-7p-5p, miR-98-5p and of miR-183-5p in the study groups (tumor alone and tumorand schizophrenia) was observed (p<0.05). The results of the present study showed that let-7, miR-98 and miR-183 may play an important oncosuppressive role through their regulatory impact in gene expression irrespective of the presence of schizophrenia, although a larger sample size is required to validate these results. Nevertheless, further studies are warranted in order to highlight a possible role of these and other micro-RNAs in the molecular pathways of schizophrenia.

The effect of metronomic versus standard chemotherapy on the regulatory to effector T-cell equilibrium in cancer patients.

BACKGROUND: The host's immune system is crucially involved in cancer development and progression. The ratio of regulatory to effector T-cells, as well as the interplay of T-cells with therapeutic agents, impact on cancer prognosis. The current study aimed to comparatively investigate the effect of metronomic and standard chemotherapy on the number and functionality of peripheral regulatory and effector T-cells in cancer patients. METHODS: CD4+CD25+ regulatory and CD4+CD25- effector T-cells were purified from the peripheral blood of 36 cancer patients and co-cultured in the presence of a polyclonal stimulus. The proliferative capacity and frequency of CD4+CD25+/CD4+CD25- T-cells were analysed before and during various chemotherapeutic regimes, by ELISA and flow cytometry, respectively. RESULTS: Chemotherapy shifted immune responses in favour of regulatory T-cells. The relative ratio of regulatory to effector T-cells increased, and the T-cell-mediated suppressive activity of regulatory on effector T-cells was augmented. This effect was more profound in metronomic than in standard chemotherapeutic approaches. Moreover, an association between the chemotherapy strategy followed and the mode of action of specific drugs (anti-mitotic, anti-DNA) was revealed. CONCLUSIONS: In comparison to standard chemotherapeutic strategies, metronomic approaches, though more patient-friendly, result in a significantly more prominent expansion of regulatory T-cells that aggravate the regulatory to effector T-cell imbalance. Our findings impact on the modulation of chemotherapy-treated patients' anti-tumor immunity and, thus, may be proven useful for selecting the most advantageous drug-delivery strategy, particularly when immunotherapeutics are eventually to be applied.

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab.

BACKGROUND: The vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death. RESULTS: Among the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald's p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald's p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death. CONCLUSIONS: TOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials.

Hepatoid pancoast tumor. A case report and review of the literature.

A 48-year-old male patient presented with a Pancoast tumor of the right lung and a serum alpha-fetoprotein (αFP) at 39,000 ng/ml. Alpha-fetoprotein is a tumor marker found elevated in patients with hepatocellular carcinoma (HCC), germ cell or stromal tumors of the ovary and nonseminomatous testicular cancer. Occasionally, this tumor marker may rise in non-neoplastic conditions such as cirrhosis and hepatitis and only exceptionally in rare cancers with hepatoid differentiation. We present our case report and review the English literature for αFP-producing lung carcinomas. To the best of our knowledge this is the first report in the literature of an αFP producing Pancoast tumor.

A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study.

BACKGROUND: Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer. METHODS: The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (i.v.), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 i.v. bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years. RESULTS: The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms. CONCLUSIONS: Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12610000148077.

Irinotecan/fluorouracil/leucovorin or the same regimen followed by oxaliplatin/fluorouracil/leucovorin in metastatic colorectal cancer.

BACKGROUND: This study reports the long-term follow-up of patients with metastatic colorectal cancer (CRC) participating in a randomised phase II study that compared the efficacy and toxicity of the combination of irinotecan (IRI), fluorouracil (FU) with leucovorin (LV) (arm A) versus sequential chemotherapy with IRI plus FU/LV followed by oxaliplatin (OXA) plus FU/LV (arm B) as first line therapy. MATERIALS AND METHODS: Intent-to-treat analysis was performed on 417 patients (211 in arm A and 206 in arm B). Treatment schedules of weekly IRI 80 mg/m(2) or OXA 45 mg/m(2) plus LV 200 mg/m(2) immediately followed by intravenous bolus FU 450 mg/m(2) for 6 weeks were followed by a 2-week rest period. Treatment continued for 4 cycles. Patients in arm A were treated with IRI/FU/LV for 4 cycles, while patients in arm B were initially treated with IRI/FU/LV for 2 cycles followed by sequential administration of 2 cycles of OXA/FU/LV. RESULTS: No significant difference emerged in overall response rate or overall survival. There was a difference in progression-free survival (median, 7.3 versus 8.2 months, p=0.040) in favour of arm B. Toxicity profiles were similar in both arms. CONCLUSION: IRI/FU/LV and IRI/FU/LV followed by OXA/FU/LV showed comparable activity with a manageable toxicity profile.

Methotrexate, paclitaxel, ifosfamide, and cisplatin in poor-risk nonseminomatous germ cell tumors.

OBJECTIVE: The efficacy and tolerability of M-TIP was evaluated as first-line treatment for patients with poor-risk germ cell tumors (GCT), according to International Germ Cell Cancer Collaborative Group (IGCCCG) criteria. PATIENTS AND METHODS: Thirty patients with poor-risk GCT were treated with M-TIP (methotrexate 250 mg/m(2) given as a 4-hour infusion with folinic acid rescue on day 1, paclitaxel 175 mg/m(2) given as a 3-hour infusion on day 1, followed by ifosfamide 1.2 g/m(2) given as a 2-hour infusion and cisplatin 20 mg/m(2) given as a 2-hour infusion on days 2 to 6) regimen for four cycles. RESULTS: Five (16.6%, 95% confidence interval [CI]: 2%-31%) patients achieved clinical complete response (cCR) with chemotherapy only, 15 (50%, 95% CI: 31-69%) patients pathologic complete response (pCR) (11 had necrosis/fibrosis and 4 had mature teratoma) and 3 (10%) patients surgical complete response (sCR) for an overall favorable response of 76.6%. Twenty-one patients are continuously disease-free at a median follow-up of 5.3 years (range 0.9-8.4+ years), resulting in a 5-year progression-free survival (PFS) rate of 66.6% (95% CI = 49%-85%) and a 5-year survival rate of 70% (95% CI = 53%-87%). Toxicity was generally mild except for myelotoxicity. Patients with febrile neutropenia were successfully treated with broad spectrum antibiotics and G-CSF support. Hematologic toxicity in this trial was ameliorated with the use of G-CSF. Neurotoxicity and nephrotoxicity were not a problem, since only 6.6% and 3.3% of patients developed sensory neuropathy and renal toxicity, respectively. CONCLUSION: M-TIP is a highly effective (high proportion of patients achieved long-term disease-free status, lack of relapses) and well tolerated regimen for first-line treatment of poor-risk GCT patients. These results have to be compared with the standard BEP chemotherapy or more intensive regimens in multicentre randomized trials.

Panhypopituitarism due to metastases to the hypothalamus and the pituitary resulting from primary breast cancer: a case report and review of the literature.

Pituitary metastasis occurs rarely in cancer patients and often remains undiagnosed. However, early detection and appropriate treatment can improve the patient's quality of life and possibly prolong survival. Herein, we describe the case of a 52-year-old woman with panhypopituitarism caused by metastases to the hypothalamus and pituitary from primary breast cancer. She had a 5-year history of breast cancer with metastases to the bones 1.5 years after initial diagnosis and mastectomy. She presented with severe headaches, generalized fatigue, dizziness, hypotension, difficulties with balance and coordination, polyuria, and polydipsia. Laboratory work-up revealed panhypopituitarism (central diabetes insipidus; hypothyroidism; and low prolactin, gonadotrophin, and adrenocorticotropic hormone levels), and magnetic resonance imaging confirmed the pituitary and hypothalamic involvement. She received hormone replacement therapy, radiation therapy of the sella turcica and suprasellar lesion, and chemotherapy, with significant improvement of her clinical status, but she died 15 months later.

Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy.

BACKGROUND: Thymidylate synthase (TS) and Topoisomerase I (Topo I) are significant biomarkers in colorectal cancer (CRC). We aimed to study the expression of TS and Topo I in patients with resected CRC who received adjuvant chemotherapy and correlated it with clinical outcome. METHODS: All patients diagnosed with CRC between 1989 and 2007 and treated with adjuvant chemotherapy within Hellenic Cooperative Oncology Group's (HeCOG) protocols, were identified. Archival paraffin-embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I. The results were correlated with survival (OS) and disease free survival (DFS). RESULTS: A cohort of 498 patients with a median age of 61 years and Dukes' stage B (49%) and C (51%) fulfilled the criteria of the study. All patients received adjuvant 5-FU-based chemotherapy, 38% irinotecan-containing. Positive TS and Topo I expression was found in 43% and 48% of cases, respectively. Five-year OS was 74% and DFS was 68%. In univariate analysis no association of TS and Topo I expression with OS and DFS was identified. In multivariate analysis however, Topo I expression was associated with a reduced risk of death (HR = 0.61, 95% CI 0.42-0.88, p = 0.009). In the irinotecan-treated subgroup, those patients who expressed Topo I had a better OS (HR = 0.47, 95% CI 0.23-0.94, p = 0.033). CONCLUSION: Patients with resected CRC expressing Topo I seem to benefit from irinotecan-containing adjuvant chemotherapy. However randomised prospective trials are needed to confirm these results.

Combination chemotherapy with docetaxel, vinorelbine and estramustine phosphate in metastatic androgen-resistant prostate cancer: a single institution experience.

UNLABELLED: The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC). PATIENTS AND METHODS: Fifty-two eligible patients were treated with docetaxel at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) every 3 weeks for 12 cycles. Patients with osseous metastases received zoledronic acid of 4 mg every 3 weeks. Low molecular weight heparin was administered on a prophylaxis basis to all patients. RESULTS: A prostate-specific antigen (PSA) response > or = 50% from baseline was obtained in 29 (56%; 95% confidence interval [CI], 42-70%) patients. Objective responses among the 25 patients with measurable disease were observed in 48% (95% CI, 27-69%), including 1 patient with complete response (CR) and 11 patients with partial response (PR). Patients with extraosseous only, skeletal only, and extraosseous and skeletal metastases showed different PSA responses (87% vs. 44% vs. 59%, respectively, p = 0.094). Furthermore, patients with soft tissue disease only showed insignificantly better PSA response than those with skeletal metastases (response rate: 87% vs. 50%, p = 0.064). The median progression-free survival was 7.6 months (95% CI, 6.7-8.4 months) and the median overall survival was 18.2 months (95% CI, 15.5-20.8 months). The only parameters which were found to have an impact on survival were the extent of disease and the baseline levels of PSA. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 33% of patients and 6% experienced febrile neutropenia. Anemia and thrombocytopenia grade 3 or 4 were not a problem. Three patients (6%) developed grade 3 sensory neuropathy and 2 patients (4%) developed grade 3 fatigue. Edema grade 3 occurred in 1 (2%) patient and thromboembolism grade 3 occurred in 2 (4%) patients. CONCLUSION: The combination of docetaxel, vinorelbine and oral estramustine is a well-tolerated regimen with high biochemical and objective response rates in patients with ARPC.

Biliogastric diversion for the management of high-output duodenal fistula: report of two cases and literature review.

High-output duodenal fistula occurs as a result of a duodenal wall defect caused by gastroduodenal surgery, endoscopic sphincterotomy, duodenal injury, and tumors with high morbidity and mortality rate. A new technique for its management is reported along with literature review. This procedure consists of transection of the duodenum 2 cm distally to the pylorus, transection of the common bile duct, and end duodenostomy with or without suturing the duodenal wall defect. The continuity of the alimentary tract is reinstated by an end-to-end duodenojejunostomy, end-to-side choledochojejunostomy, and end-to-side Roux-en-Y jejunojejunostomy, obtaining biliogastric diversion from the duodenum and closure of the fistula. This technique was performed in two patients with excellent results.

Myelotoxicity as a prognostic factor in patients with advanced breast cancer treated with chemotherapy: a pooled analysis of two randomised trials conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: A number of studies have shown that absence of myelotoxicity during chemotherapy is associated with worse outcome for various types of cancer, including carcinoma of the breast. The aim of this study was to determine whether myelosuppression in patients being treated with chemotherapy for advanced breast cancer has an impact on their prognosis. PATIENTS AND METHODS: A retrospective review was conducted of a series of 475 patients with advanced breast cancer enrolled in two randomised trials, who received first-line chemotherapy. The impact of severe (grade 3 or 4) hematological toxicity on survival and time to disease progression was assessed. RESULTS: When severe myelotoxicity was evaluated as a whole, a significant negative association for time to disease progression and a trend for a worse survival were demonstrated. In multivariate analysis, hematological toxicity retained its significance as an independent negative prognostic factor for time to disease progression. CONCLUSION: Our findings do not confirm the results of previous studies which have demonstrated a better outcome for patients experiencing hematological toxicity during treatment.

Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation.

The combination of gemcitabine and gefitinib was evaluated in advanced pancreatic cancer. Totally, 53 patients were treated with a 7 week cycle of gemcitabine (1,000 mg/m(2) given weekly) followed by six 4 week cycles of gemcitabine given on days 1, 8 and 15. Gefitinib 250 mg was administered daily. Responses were seen in 6, and stabilization of the disease in 12 patients. The main toxicity was myelotoxicity (92%). The 6-month progression-free survival (PFS) was 30%. Median PFS was 4.1 months and median survival 7.3 months with a 1 year survival rate of 27%. The above combination demonstrated promising activity in advanced pancreatic cancer.

Combination chemotherapy with carboplatin, paclitaxel and pegylated liposomal doxorubicin for advanced or recurrent carcinosarcoma of the uterus: clinical experience of a single institution.

OBJECTIVES: The purpose of this study was to evaluate the activity and toxicity of carboplatin, paclitaxel and pegylated liposomal doxorubicin combination in advanced or recurrent of the uterine carcinosarcoma. METHODS: Twenty-nine eligible patients with measurable disease were treated with carboplatin [area under the curve (AUC) 5], paclitaxel 175 mg/m(2) and pegylated liposomal doxorubicin 25 mg/m(2) every 3 weeks for 6-8 cycles. RESULTS: There were 10 complete responses (CRs) (34%) and 8 partial responses (PRs) (28%) for an overall response rate (RR) of 62% (95% confidence interval [CI], 43-81%). The median progression-free survival (PFS) was 8.2 months (95% CI, 4.1-12.2 months) and the median overall survival (OS) was 16.4 months (95% CI, 14.7-18.0 months). There was no statistically significant difference between histology and response to therapy. Patients with PS of 0 or 1 had a higher RR than those with worst PS. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 52% of patients and 10% experienced febrile neutropenia. Anemia grade 3 or 4 developed in 27% of patients and thrombocytopenia grade 3 or 4 in 31% of patients. Three patients (10%) developed grade 3 sensory neuropathy and only 2 patients (8%) grade 3 palmar-plantar erythrodysesthesias. No treatment-related deaths were recorded in our series. CONCLUSION: The combination of carboplatin, paclitaxel and pegylated liposomal doxorubicin appears to have activity in advanced, persistent or recurrent endometrial carcinosarcoma with an acceptable toxicity profile.

Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: a multicentre Hellenic Cooperative Oncology Group phase II study.

INTRODUCTION: Taxane/platinum combinations exhibit synergistic cytotoxicity and activity against a broad range of solid tumours. We sought to optimise the regimen as a suitable outpatient palliative treatment for cancer of unknown primary (CUP). PATIENTS AND METHODS: Eligible CUP patients with adenocarcinoma or poorly differentiated carcinoma, performance status of 0-2, adequate organ function and assessable disease were treated with docetaxel 75 mg/m(2) and carboplatin at an area under the concentration time-curve (AUC) of 5, both as 30-minute intravenous infusions, every three weeks. Patients with isolated axillary adenopathy, squamous cell cervical or inguinal adenopathy and PSA or germ-cell serum tumour markers were excluded. RESULTS: Forty-seven patients entered the trial, 24 with predominantly nodal disease or non-mucinous peritoneal carcinomatosis (favourable risk) and 23 with visceral metastases (unfavourable risk). A median of 6 cycles of chemotherapy were administered, with relative dose intensities of both drugs >90%. Response rates were 32% (46% in favourable risk, 17% in unfavourable), comparable to the activity of paclitaxel/platinum regimes, though complete remissions were seen only in favourable risk patients. Granulocyte-colony stimulating factor support was used in a third of treatment cycles. Toxicity was mild and manageable, with grade 3-4 neutropenia in 26% of patients, febrile neutropenia in 7% and severe non-hematologic side-effects in less than 8% of patients. No toxic deaths or severe neurotoxicity were seen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 16.2 months respectively. Survival was driven mainly by favourable-risk patients (22.6 months), as those with visceral metastases had a poor median survival of only 5.3 months. Good performance status and low-volume disease predicted for superior outcome, while docetaxel relative dose-intensity was a positive prognosticator only in favourable-risk patients. CONCLUSIONS: One-hour docetaxel/carboplatin is a convenient, safe and effective outpatient palliative treatment for CUP patients, providing meaningful survival prolongation only in favourable-risk patients. Insights in the molecular biology of CUP are needed for the development of targeted therapeutic manipulations of malignant resistance and progression.

Phase II study of low-grade non-Hodgkin lymphomas with fludarabine and mitoxantrone followed by rituximab consolidation: promising results in marginal zone lymphoma.

The majority of patients with indolent lymphomas relapse due to minimal residual disease (MRD). In the present study, we sought to determine whether by using rituximab consolidation, for eradication of MRD, following induction chemotherapy with fludarabine and mitoxantrone (FN) combination could improve the outcome of indolent lymphomas. Patients with indolent lymphoma received fludarabine 25 mg/m2 Day 1-3 and mitoxantrone 10 mg/m2 on Day 1 every 28 days. Patients who attained a response (complete response, CR or partial response, PR) received four weekly doses of Rituximab 375 mg/m2 1 month and 3 months after completion of treatment. Forty-five patients were entered into this Phase II trial. The median follow-up time was 39 months. The median number of delivered cycles was 6. Fifty-three percent of patients attained a CR and 38% a PR for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 39 months, 32 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included leucopenia (37%), neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). Grade V toxicities included septic death in one patient and death due to hepatitis B reactivation 6 months after the last Rituximab dose in another patient. FN followed by R consolidation is a well-tolerated and active regimen in the treatment of patients with indolent lymphomas. Further follow-up is required to determine if these remissions are maintained.

Her-2 protein expression, cellular localization, and gene amplification in colorectal carcinoma.

This study was sought to evaluate the relationship between Her-2 protein expression, cellular localization, gene amplification, and other clinicopathologic parameters in colorectal carcinomas. Her-2 protein expression and gene amplification were assessed in paraffin sections from 106 primary colorectal adenocarcinoma cases using immunohistochemistry and fluorescence in situ hybridization. Both membranous and cytoplasmic immunostaining was evaluated. The results were correlated with each other and with tumor grade, stage, and overall survival. Membranous and cytoplasmic protein expression was identified in 6 (5.6%) and 13 (12.26%) cases, respectively. Gene amplification was detected in 4 (3.7%) cases. There was a high concordance between membranous protein expression and gene amplification (kappa=0.791). No apparent association with any of the clinicopathologic parameters was identified. Membranous Her-2 protein expression and gene amplification are encountered in a small subset of colorectal carcinomas and are highly concordant events. Cytoplasmic protein expression might be either artifactual or it might represent a cross-reacting protein or a precursor form of the mature protein.

A clinicopathological study of B-cell differentiation markers and transcription factors in classical Hodgkin's lymphoma: a potential prognostic role of MUM1/IRF4.

BACKGROUND AND OBJECTIVES: Although most patients with classical Hodgkin's lymphoma (CHL) are cured, a significant minority are refractory to treatment. The investigation of biological markers could improve the predictive capacity of clinical staging systems. The aim of our study was to detect B-cell differentiation markers and transcription factors in CHL in order to define subgroups with different histogeneses and prognoses. DESIGN AND METHODS: We evaluated 107 cases of CHL for BCL6, CD79a, MUM1/IRF4 and B-cell transcription factors BOB.1, OCT.2 expression by immunohistochemistry. Statistical analysis was performed using Fisher's exact test, the Mann-Whitney test, the Kaplan-Meier method and the log rank test. Univariate and multivariate regression analyses were performed to identify variables with a significant effect on survival. RESULTS: CD79a was expressed in 5.8%, BCL6 in 14.7%, MUM1/IRF4 in 92.3%, BOB.1 in 53.4% and OCT.2 in 12.6% of cases. There was no significant association between CD79a or BCL6 expression and clinical characteristics. Univariate analysis showed that age of 45 or more, stage III and IV disease and MUM/IRF4 negative status were associated with significantly shorter time to progression (TTP) and overall survival (OS). On multivariate analysis the lack of MUM/IRF4 expression was associated with significantly shorter TTP while age of 45 or more and the presence of extralymphatic sites of disease were associated with significantly shorter OS. INTERPRETATION AND CONCLUSIONS: Our study has confirmed that MUM1/IRF4 is expressed in most cases of CHL and shows that lack of this expression in a minority of cases may be a potential adverse prognostic factor.