Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study.

RATIONAL: Circulating tumor cells (CTCs) appear to be a promising tool for predicting the clinical outcome and monitoring the response to treatment in patients with solid tumors. The current study assessed the clinical relevance of monitoring CTCs in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel. PATIENTS AND METHODS: Patients with histologically confirmed mCRPC who were previously treated with a docetaxel-containing regimen and experienced disease progression were enrolled in this multicenter prospective study. CTC counts were enumerated using the CellSearch system at baseline (before cabazitaxel initiation), after one cabazitaxel cycle (post 1st cycle) and at disease progression (PD). Patients were stratified into predetermined CTC-positive and CTC-negative groups. The phenotypic characterization was performed using double immunofluorescence staining with anti-CKs and anti-Ki67, anti-M30 or anti-vimentin antibodies. RESULTS: The median PFS and OS were 4.0 (range, 1.0-17.9) and 14.5 (range, 1.2-33.9) months, respectively. At baseline, 48 out of 57 (84.2%) patients had ≥1 CTCs/7.5 mL of peripheral blood (PB) and 37 (64.9%) had ≥5 CTCs/7.5 mL of PB. After one treatment cycle, 30 (75%) out of the 40 patients with available measurements had ≥1 detectable CTC/7.5 mL of PB and 24 (60%) ≥ 5CTCs/7.5 mL of PB; 12.5% of the patients with detectable CTCs at the baseline sample had no detectable CTCs after one treatment cycle. The detection of ≥5CTCs/7.5 mL of PB at baseline and post-cycle 1 was associated with shorter PFS and OS (p = 0.002), whereas a positive CTC status post-cycle 1 strongly correlated with poorer OS irrespective of the CTC cut-off used. Multivariate analysis revealed that the detection of non-apoptotic (CK+/M30-) CTCs at baseline is an independent predictor of shorter OS (p = 0.005). CONCLUSIONS: In patients with mCRPC treated with cabazitaxel, CTC counts both at baseline and after the first cycle retain their prognostic significance, implying that liquid biopsy monitoring might serve as a valuable tool for predicting treatment efficacy and survival outcomes.

Front-Line Bevacizumab plus Chemotherapy with or without Maintenance Therapy for Metastatic Breast Cancer: An Observational Study by the Hellenic Oncology Research Group.

Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians' discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7-14.8) and 32.3 months (95% CI: 27.7-36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p < 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.

Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence?

Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.

Extended resections for the treatment of patients with T4 stage IIIA non-small cell lung cancer (NSCLC) (T4N0-1M0) with or without cardiopulmonary bypass: a 15-year two-center experience.

BACKGROUND: Stage IIIA non-small cell lung cancer (NSCLC) is a heterogeneous group of patients, often requiring variable and individualized approaches. The dilemma to operate or not frequently arises, since more than 75% of the cases of NSCLC are diagnosed in advanced stages (IIIA). The main objective of this study was to assess whether the benefits outweigh surgical risks for the T4N0-1M0 subgroup. METHODS: Data from 857 patients with locally advanced T4 NSCLC were retrospectively collected from two different institutions, between 2002 and 2017. Clinical data that were retrieved and analyzed, included demographics, comorbidities, surgical details, neoadjuvant or/and adjuvant therapy and postoperative complications. RESULTS: Twelve patients were in the cardiopulmonary bypass (CPB) group and thirty in the non-CPB. The most common types of lung cancer were squamous cell carcinoma (50.0%) and adenocarcinoma (35.7%). The most frequent invasion of the tumor was seen in main pulmonary artery and the superior vena cava. Significantly more patients of the CPB group underwent pneumonectomy as their primary lung resection (P=0.006). In all patients R0 resection was achieved according to histological reports. The overall 5-year survival was 60%, while the median overall survival was 22.5 months. Analysis revealed that patient age (P=0.027), preoperative chronic obstructive pulmonary disease (COPD) (P=0.001), tumor size (4.0 vs. 6.0 cm) (P=0.001), postoperative respiratory dysfunction (P=0.001) and postoperative atelectasis (P=0.036) are possible independent variables that are significantly correlated with patient outcome. CONCLUSIONS: We suggest that in patients with stage IIIA/T4 NSCLC, complete resection of the T4 tumor, although challenging, can be performed in highly selected patients. Such an approach seems to result in improved long-term survival. More specific studies on this area of NSCLC probably will further enlighten this field, and may result in even better outcomes, as advanced systemic perioperative approaches such as modern chemotherapy, immunotherapy and improvements in radiation therapy have been incorporated in daily practice.

Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials.

AIM: To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. METHODS: An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. RESULTS: Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes, bevacizumab and ixabepilone showed inadequate efficacy, while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising. CONCLUSION: At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.

Biosimilars: Hope and concern.

As patents of the first introduced biologic therapeutics in oncology have begun to expire, competing pharmaceutical companies are allowed to produce and market the same protein as the original agent. These products are called biosimilars. Upon patent expiration, biosimilars would hopefully be a cheaper alternative to the original agent and that is the main reason for their existence. Although the financial aspect is similar to generics, the complex nature of these products generates the need for a distinct regulatory environment. Biosimilars are produced by DNA technology in bacteria, plant cells, or animal cells, while generics are produced by chemical synthesis. Details in the process of synthesis, selection of the microorganism, protein extraction, purification and manufacturing, affect the precise nature of the end product. Monoclonal antibodies are large proteins with four polypeptide chains and interact variably with each other and with the environment. It is important for payors to realize that biosimilars are different from generics; therefore, they need to develop different set of rules for approving, registering, and dispensing biosimilars. Regulators ought to respect the physicians' request for non-interchangeability and facilitate in any possible way of traceability. Such regulations along with a rigorous pharmacovigilance program will satisfy the concerns for true equivalence in activity and long-term safety. This is the only way to accumulate over time reliable safety information for new biosimilars. In conclusion, the wish born by the medical community and the society for a more affordable health system triggers the emergence of biosimilars, which could meet that goal if properly regulated.

Ex situ reimplantation technique, in central lung tumors.

BACKGROUND: The parenchyma-sparing resection is most often performed in patients with impaired preoperative lung or cardiovascular function who would not be able to tolerate a pneumonectomy. METHODS: Our experience on the ex situ reimplantation procedure and the outcome of patients with lung malignancies, who underwent upper or upper-middle lobectomy, with reimplantation of the lower lobe was reported. RESULTS: We present 9 patients mean age 62.6+16.2 years (7 males/2 females) underwent ex situ reimplantation due to extensive lung tumor of upper lobes. The surgical technique precludes IV heparinization and then radical pneumonectomy. The entire lung was immersed in Ringer's solution (temperature 4 degrees centigrade) and bench surgery was performed. The involved upper (or upper-middle) lobes with involved lymph nodes were resected, thus leaving the healthy lower lobe of the lung. Pneumoplegia solution, named "Papworth pneumoplegia", was administered (1,473 mL) through catheterization of the pulmonary artery and vein stumps (ante grade and retrograde) along with 250 mL of prostaglandin E1. Re-implantation of the lower lobe was performed (I) on the right side, implantation involved the anastomosis of lower pulmonary vein in the site of the cuff of left atrium, followed by suturing the stump of the intermedius pulmonary artery to the right main pulmonary artery and finally the bronchial stumps-intermedius bronchus to the right main bronchus; (II) on the left side the pulmonary vein was anastomosed first, followed by the bronchial stumps and finally by the pulmonary artery. The graft ischemia time was 70.2+8.4 minutes ranged between 55 and 80 minutes. CONCLUSIONS: Re-implantation or auto-transplantation should be considered as a safe option for the appropriate patient with lung cancer. The ex situ separation of the cancerous lobes is technically feasible and allows extensive pulmonary resection while minimizing the loss of pulmonary reserve. Based on our work, the major factors that play a role for the survival of initially resected and then re-implanted lung graft, are: (I) the ischemia time of the re-implanted lobe; (II) the proper use of pneumoplegia solutions, along with prostaglandin E1 and heparin; (III) the occurrence of pulmonary vein thrombosis; and (IV) the bronchial anastomosis.

Feasibility of rapid infusion of the initial dose of bevacizumab in patients with cancer.

PURPOSE: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) widely used in clinical oncology. Bevacizumab is commonly co-adminis- tered with chemotherapy. It is recommended that the first infusion of the antibody last 90 min, the second 60 and all subsequent 30 min. Since there is no clear rationale for the proposed schedule of administration, our study assessed the feasibility of a 30 min initial infusion. METHODS: Cancer patients eligible for de novo bevacizumab treatment were enrolled. All patients received standard bevacizumab dose of 5, 7.5 or 10 mg/kg according to the indication, diluted in 250 ml normal saline, as a 30-min intravenous infusion. RESULTS: Thirty two patients were enrolled: male 18, female 14, median age 58 years, range 42-78. Oncologic diagnosis: lung cancer 16, colorectal 4, breast 3, ovarian 7, renal 2. All patients tolerated the infusion well. No hypersensitivity reactions were noted. Mean systolic and diastolic blood pressures were 122 and 73 mm/Hg respectively prior to the infusion and 125 and 75 mm/Hg 15 min after the infusion (p=0.3). During the observation period of 1 hour, blood pressure did not change. Transient grade 3 systolic hypertension was noted in 1 patient, with spontaneous regression in 45 min. CONCLUSION: Rapid administration of bevacizumab in 30 min, rather than the recommended in the package insert 90 min is feasible and safe. Such a practice limits the time of confinement in the treatment area to patients' satisfaction and would result in cost savings by reducing health resource utilization.

Operation for preservation of lung parenchyma in central lung cancer--in vivo and ex situ reimplantation techniques.

BACKGROUND/AIM: Lobar reimplantation techniques enable the safe resection of lung cancer when pneumonectomy is not desirable or not feasible. We report our experience with this procedure. PATIENTS AND METHODS: Patients with difficult to resect upper/middle lobe non-small cell lung cancer were included. In situ reimplantation technique requires the reanastomosis of the pulmonary vein of the healthy lower lobe to the upper lobe stump; bench surgery reimplantation involves the ex vivo surgical treatment of the whole excised lung and subsequent reimplantation of the healthy remnant. RESULTS: Nine patients with upper-middle lobe lung cancer underwent in situ reimplantation, mean age=70.7±4.2 years; 6 patients underwent ex situ resection, mean age=64.3±18.4 years. One obese patient succumbed due to thrombosis of the anastomosed pulmonary vein. One patient developed a stroke. CONCLUSION: The procedure was in general well-tolerated and enables for curative resection of otherwise unresectable lung cancer.

Efficacy and Safety of Sequential Use of Everolimus in Patients With Metastatic Renal Cell Carcinoma Previously Treated With Bevacizumab With or Without Interferon Therapy: Results From the European AVATOR Study.

BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1) trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients with mRCC. The sequence of everolimus second-line therapy after failure of bevacizumab ± interferon (IFN) first-line therapy has not yet been studied. METHODS: AVAstin(®) followed by afiniTOR(®) (AVATOR) was a noninterventional retrospective multicenter European observational study of 42 unselected patients with mRCC who were previously or currently treated with everolimus after failure of bevacizumab ± IFN. The primary end point was everolimus progression-free survival (PFS). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence and everolimus treatment and safety. RESULTS: Exploring the duration of second-line everolimus treatment, 63.8% of patients received at least 3 months of everolimus and 28.8% received at least 8 months of treatment. At the time of data analysis, 15 patients (36%) were still receiving everolimus, 40% had stopped because of progressive disease, and 24% had discontinued treatment for other reasons. Patients receiving everolimus after bevacizumab experienced a median PFS of 17 months (95% confidence interval [CI], 5 [not reached]). Median OS was not reached with everolimus second-line therapy. At 32 months after the start of first-line therapy, 53.3% of patients were still alive. All grades of common adverse events (AEs) were consistent with the known safety profile of everolimus. CONCLUSION: The AVATOR-studied sequence displayed a longer than expected median PFS. Further prospective exploratory studies need to be performed to confirm these encouraging results in a larger cohort of patients.

Active idiotypic vaccination versus control immunotherapy for follicular lymphoma.

PURPOSE: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. PATIENTS AND METHODS: Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n=287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. RESULTS: At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n=195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. CONCLUSION: This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.

Feasibility study of dose-dense biweekly administered pemetrexed in patients with non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: Pemetrexed is a multitargeted folate pathway inhibitor with documented activity in non-small cell lung cancer (NSCLC). The presumed maximum tolerated dose is 500 mg/m2 every 3 weeks, but pemetrexed-related toxicity is ameliorated when folate and B12 supplementation is provided and therefore a higher dose intensity may be tolerated. The current exploratory study assessed the feasibility of administration of pemetrexed at a fixed dose of 1000 mg every 2 weeks in patients with relapsed or refractory NSCLC. PATIENTS AND METHODS: The first cohort of 12 patients received pemetrexed monotherapy. No dose-limiting grade 4 toxicity was noted after 4 cycles, so the subsequent cohort of 14 patients received additional anticancer agents (bevacizumab, erlotinib, carboplatin, docetaxel, vinorelbine) given along with dose-dense pemetrexed. RESULTS: Toxicity overall was reversible and manageable. Among 19 patients who received pemetrexed either alone or with non-myelosuppressive targeted agents, there were only 2 instances of grade 4 neutropenia after prolonged treatment. Grade 3-4 hematologic toxicity was eventually noted in 11 of the 26 patients (42%; 95% confidence interval, 23% to 61%) after a median of 4 cycles (range, 2-14 cycles). There was no significant additional toxicity nor any treatment-related deaths. CONCLUSION: Our preliminary observations indicate that dose-dense pemetrexed every 2 weeks is feasible and this regimen can be used as monotherapy. These data may serve as a scaffold for combination studies.

Effect of type-specific human papillomavirus incidence on screening performance and cost.

BACKGROUND: Implementation of human papillomavirus (HPV) vaccination is expected to change the epidemiology of HPV infection. METHODS: Using age-dependent (inhomogeneous) Markov chains, we tested the effect of type-specific (ie, HPV-16/HPV-18 and other high-risk HPV types) HPV incidence on 3 screening strategies in a cohort of 100,000 women, starting screening at the age of 25 years and continuing until the age of 34 years. All the strategies started with an HPV test; if the result was positive, the next step was triage with cytology (strategy 1), cytology and colposcopy together (strategy 2), or colposcopy only (strategy 3). Published background data were used for the models. RESULTS: Strategy 2 had the highest sensitivity; the absolute number of missed cervical intraepithelial neoplasia (CIN)3+ cases was associated with HPV incidence in all the strategies, but their relative sensitivity remained unaffected. Strategy 2 was cheaper per diagnosed CIN3+ for very low HPV incidence rates, but this changed for higher incidence rates. For any given pair of HPV-16/HPV-18 and other high-risk-type incidence, the cost of the triage and the total cost of screening was highest in screening 2 and lowest in screening 1. For each screening strategy, the cost per diagnosed CIN3+ was mainly determined by the incidence of HPV-16/HPV-18, and the cost of the triage and the total screening cost by the incidence of other high-risk types. CONCLUSIONS: Type-specific HPV incidence affects the absolute number of missed CIN3+ cases and the cost of screening in a mathematically describable way and can be used for prediction of changes in these outcomes with changing HPV epidemiology.

Successful management of bulky osseous metastasis of renal cell carcinoma with selective arterial embolization and radiofrequency ablation: a case report.

The case of a 64-year-old male patient who presented with a bulky osseous tumor metastasis from renal cell carcinoma is reported. The metastatic lesion extended from the acetabulum of the left iliac bone into the iliosacral joint.Treatment plan included selective arterial embolization followed by transdermal radiofrequency ablation, followed by consolidation irradiation. This sequence resulted in considerable necrosis of the bulk of the tumor and creation of a large tissue deficit, which healed over the period of several months despite anti-angiogenetic systematic treatment. The patient remains in good state of health, 20 months after the procedure. This case illustrates the usefulness of the embolization-ablation sequence in controlling large osseus metastasis.

Prevalence and distribution of high-risk human papillomavirus in Greece.

As knowledge of regional human papillomavirus (HPV) type distribution is essential for the optimization of prevention strategies, this study was carried out to explore the prevalence and type distribution of high-risk HPV in a screening population across Greece. Cervical samples were collected by local physicians and nurses in hospitals and health centers across the country from 4139 women attending for cervical cancer screening. High-risk HPV-DNA was detected by using Hybrid Capture-2 (HC2) and positive samples with adequate cellular content were further typed by restriction fragment length polymorphism-polymerase chain reaction. Almost six percent (5.9%) of women tested positive in HC2. The most common type was HPV16 (1.4% in the whole sample and 32.4% of the typed samples), followed by HPV53 (0.6 and 14.0%, respectively), HPV31 (0.6 and 12.9%, respectively), HPV35 (0.5 and 12.3%, respectively), HPV51 (0.4 and 7.8%, respectively), HPV18 (0.3 and 7.3%, respectively) and 22 more types. Almost 15% of the typed samples showed a coinfection with two HPV types and 2.1% with three types. There was a bimodal distribution by age, with the highest peak in women 20-29 years old and a lower peak in women 50-59 years old. Apart from the types originally included in HC2 cocktail, PCR analysis identified 15 more types (HPV6, HPV11, HPV34, HPV37, HPV38, HPV42, HPV53, HPV54, HPV55, HPV61, HPV62, HPV66, HPV73, HPV82, HPV83). Eleven percent of HC2-positive results arose from single-type infections with HPV53 (10%) and HPV66 (1%), which are potentially high-risk types. In conclusion, HPV16 is the most common type in the largest Greek screening sample used to date and, together with its related types, accounts for more than half of high-risk HPV infections. Approximately 10% of positive HC2 results arise from HPV53, which is not normally detected by the test, but may be clinically significant.

Establishment of an animal model for Waldenström's macroglobulinemia.

OBJECTIVE: Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytoid lymphoma characterized by production of monoclonal immunoglobulin M (IgM). The present study was undertaken with the aim of developing a novel nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of WM. MATERIALS AND METHODS: Pairs of bone particles derived from adult humans were successfully implanted intramuscularly in NOD/SCID mice. Each mouse was implanted with a bone fragment taken from a neoplastic disease-free individual in the one hind limb and with a different biopsy taken from a WM patient in the other. RESULTS: All mice implanted with the bone marrow core biopsies had increased levels of serum IgM 1 month following the implantation onward. Histopathologic and immunohistochemical analysis showed that in approximately half of the mice WM cells metastasized from the WM bone implant to the distantly implanted non-WM bone. Serum IgM value records of all mice correlated with histopathological observations and immunohistochemical analysis for neoplastic cell density and metastatic growth. CONCLUSION: Results obtained in the present study suggest that IgM-producing WM cells not only retained viability in the bone marrow of the WM bone biopsy, but also metastasized to the normal bone marrow of the distant bone implant. The mouse model reported here improves on existing models of WM by recapitulating the adult human bone marrow microenvironment of abnormal WM neoplastic cells.

Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia.

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.

Review of Y-ibritumomab tiuxetan as first-line consolidation radio-immunotherapy for B-cell follicular non-Hodgkin's lymphoma.

Several studies have indicated that radioimmunotherapy is an effective and clinically relevant complementary therapeutic approach for patients with B-cell non-Hodgkin's lymphoma (NHL) and may convert partial to complete response when given as consolidation after induction chemotherapy. Yttrium-90((90)Y)-ibritumomab tiuxetan ((90)Y-IT, Zevalin(®), Y2B8) has documented efficacy for both indolent and aggressive NHL. Patients considered eligible for (90)Y-IT treatment should satisfy several screening criteria. A recently completed randomized study for patients with follicular lymphoma has demonstrated that (90)Y-ibritumomab consolidation also produced a marked prolongation of the median time to progression from 13.5 to 37 months, while partial responders seem to derive relatively more benefit. Other published and ongoing studies explore a similar use for patients with aggressive lymphoma. Studies are comparing the use of (90)Y-IT consolidation with the anti-CD20 antibody rituximab maintenance, which is also gaining acceptance. In conclusion, the documented benefit of radioimmunotherapy should be viewed in the context of the goals of treatment and the changing standards of care for lymphoma.

The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat.

Oxaliplatin is a novel chemotherapeutic agent which is effective against advanced colorectal cancer, but at the same time causes severe neuropathy in the peripheral nerve fibres, affecting mainly the voltage-gated sodium (Na(+)) channels (VGNaCs), according to literature. In this study the effects of oxaliplatin on the peripheral myelinated nerve fibres (PMNFs) were investigated in vitro using the isolated sciatic nerve of the adult rat. The advantage of this nerve-preparation was that stable in amplitude evoked compound action potentials (CAP) were recorded for over 1000min. Incubation of the sciatic nerve fibres in 25, 100 and 500microM oxaliplatin, for 300-700min caused dramatic distortion of the waveform of the CAP, namely broadening the repolarization phase, repetitive firing and afterhyperpolarization (AHP), related to the malfunction of voltage-gated potassium (K(+)) channels (VGKCs). At a concentration of 5microM, oxaliplatin caused broadening of the repolarization phase of the CAP only, while the no observed effect concentration was estimated to be 1microM. These findings are indicative of severe effects of oxaliplatin on the VGKCs. In contrast, the amplitude and the rise-time of the depolarization of the CAP did not change significantly, a clear indication that the VGNaCs of the particular nerve preparation were not affected by oxaliplatin. The effects of oxaliplatin on the PMNFs were similar to those of 4-aminopyridine (4-AP), a classical antagonist of VGKCs. These similarities in the pattern of action between oxaliplatin and 4-AP combined with the fact that the effects of oxaliplatin were more pronounced and developed at lower concentrations suggest that oxaliplatin acts as a potent VGKCs antagonist.

Durable complete responses from therapy with combined epratuzumab and rituximab: final results from an international multicenter, phase 2 study in recurrent, indolent, non-Hodgkin lymphoma.

BACKGROUND: In this international, multicenter trial, the authors evaluated rituximab (anti-CD20) plus epratuzumab (anti-CD22) in patients with postchemotherapy relapsed/refractory, indolent non-Hodgkin lymphoma (NHL), including long-term efficacy. METHODS: Forty-nine patients with follicular NHL (FL) (N = 41) or small lymphocytic lymphoma (SLL) (N = 7) received intravenous epratuzumab 360 mg/m2 and then intravenous rituximab 375 mg/m2 weekly x4. The regimen was tolerated well. RESULTS: Twenty-two of 41 patients with FL (54%) had an objective response (OR), including 10 (24%) complete responses (CR) (CR/unconfirmed CR [CRu]), whereas 4 of 7 patients with SLL (57%) had ORs, including 3 (43%) with CR/CRu. Rituximab-naive patients (N = 34) had an OR rate of 50% (26% CR/CRu rate), whereas patients who previously responded to rituximab (N = 14) had an OR rate of 64% (29% CR/CRu rate). An OR rate of 85% was observed in patients with FL who had Follicular Lymphoma International Prognostic Index (FLIPI) risk scores of 0 or 1 (N = 13), whereas 28 patients with intermediate or high-risk FLIPI scores (> or =2) had an OR rate of 39% (18% CR/CRu rate). In patients with FL, the median response duration was 13.4 months, and that duration increased to 29.1 months for 10 patients who had a CR/CRu, including 4 patients who had durable responses with remissions that continued for >4 years. In patients with SLL, the median response duration was 20 months, including 1 patient who had a response that continued for >3 years. CONCLUSIONS: The combination of epratuzumab and rituximab induced durable responses in patients with recurrent, indolent NHL.