Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Cross-validation study of class III beta-tubulin as a predictive marker for benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of four randomized trials.

BACKGROUND: The IALT, JBR.10, ANITA and Cancer and Leukemia Group B 9633 trials compared adjuvant chemotherapy with observation for patients with resected non-small-cell lung cancer (R-NSCLC). Data from the metastatic setting suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to tubulin-targeting agents (e.g. vinorelbine, paclitaxel). In 265 patients from JBR.10 (vinorelbine-cisplatin versus observation), high TUBB3 was an adverse prognostic factor and was associated (nonsignificantly) with 'greater' survival benefit from chemotherapy. We explored this further in additional patients from JBR.10 and the other three trials. PATIENTS AND METHODS: TUBB3 immunohistochemical staining was scored for 1149 patients on the four trials. The original JBR.10 cut-off scores were used to classify tumors as TUBB3 high or low. The prognostic and predictive value of TUBB3 on disease-free survival (DFS) and overall survival (OS) was assessed by Cox models stratified by trial and adjusted for clinical factors. RESULTS: High TUBB3 expression was prognostic for OS [hazard ratio (HR)=1.27 (1.07-1.51), P=0.008) and DFS [HR=1.30 (1.11-1.53), P=0.001). TUBB3 was not predictive of a differential treatment effect [interaction P=0.20 (OS), P=0.23 (DFS)]. Subset analysis (n=420) on vinorelbine-cisplatin gave similar results. CONCLUSIONS: The prognostic effect of high TUBB3 expression in patients with R-NSCLC has been validated. We were unable to confirm a predictive effect for TUBB3.

Genetic polymorphisms associated with outcome in multiple myeloma patients receiving high-dose melphalan.

High-dose melphalan (HDM) is an essential component in the treatment of patients with multiple myeloma (MM). Few data are available regarding genetic polymorphisms associated with patient outcome or toxicity in this setting. To identify such polymorphisms, we performed a retrospective analysis, genotyping single nucleotide polymorphisms (SNPs) with the arrayed primer extension (APEX) technology in 169 patients having received HDM for MM. We analyzed 209 SNPs in 95 genes involved in drug metabolism, DNA repair, cell cycle and apoptosis. SNPs in ABCB1, CYP3A4 and TP53BP2 were associated with response to VAD induction therapy (P<0.01). SNPs in ALDH2, GSTT2 and BRCA1 were associated with response to HDM (P<0.01). Polymorphisms in CYP1A1, RAD51 and PARP were associated with disease progression whereas polymorphisms in ALDH2 and CYP1A1 were correlated with OS. Polymorphisms in BRCA1, CDKN1A and XRCC1 were associated with the occurrence of severe mucositis after HDM. These results suggest that SNPs of genes involved in drug metabolism or DNA repair could be used to distinguish MM patient subgroups with different toxicity/efficacy profiles.

International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation.

In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.

Exercise preferences among a population-based sample of non-Hodgkin's lymphoma survivors.

In the present study, we examined the exercise preferences of a population-based sample of non-Hodgkin's lymphoma (NHL) survivors. A secondary purpose was to explore the association between various demographic, medical, and exercise behaviour variables and elicited exercise preferences. Using a retrospective survey design, 431 NHL survivors residing in Alberta, Canada completed a mailed questionnaire designed to assess exercise preferences, past exercise behaviour, and various demographic variables. Overall, 77% of participants preferred or maybe preferred to receive exercise counselling at some point after their NHL diagnosis. An overwhelming majority indicated that they would possibly be interested (81%) and able (85%) to participate in an exercise programme designed for NHL survivors. The majority of participants (55%) listed walking as their preferred choice of exercise. Logistic regression analyses indicated that NHL survivors' exercise preferences were influenced by body mass index (BMI), exercise behaviour, and gender. Eliciting exercise preferences from the population in question yields important information for cancer care professionals designing exercise programmes for NHL survivors. Furthermore, tailoring exercise programmes to the preferences of NHL survivors may be one method to potentially enhance exercise adherence in this population both inside and outside of clinical trials.

Persistent preswitch clonotypic myeloma cells correlate with decreased survival: evidence for isotype switching within the myeloma clone.

Multiple myeloma (MM) is identified by unique immunoglobulin heavy chain (IgH) variable diversity joining region gene rearrangements, termed clonotypic, and an M protein termed the "clinical" isotype. Transcripts encoding clonotypic pre and postswitch IgH isotypes were identified in MM peripheral blood mononuclear cells (PBMCs), bone marrow (BM), and mobilized blood. For 29 patients, 38 BM, 17 mobilized blood, and 334 sequential PBMC samples were analyzed at diagnosis, before and after transplantation for 2 to 107 months. The clinical clonotypic isotype was readily detectable and persisted throughout treatment. Eighty-two percent of BM and 38% of PBMC samples also expressed nonclinical clonotypic isotypes. Clonotypic immunoglobulin M (IgM) was detectable in 68% of BM and 25% of PBMC samples. Nonclinical clonotypic isotypes were detected in 41% of mobilized blood samples, but clonotypic IgM was detected in only 12%. Patients with persistent clonotypic IgM expression had adverse prognostic features at diagnosis (lower hemoglobin, higher beta(2)-microglobulin) and higher numbers of BM plasma cells compared with patients with infrequent/absent clonotypic IgM. Patients with persistent clonotypic IgM expression had significantly poorer survival than patients with infrequent IgM expression (P <.0001). In a multivariate analysis, persistent clonotypic IgM expression in the blood correlated independently with poor survival (P =.01). In nonobese diabetic severe combined immunodeficiency mice, xenografted MM cells expressed clinical and nonclinical postswitch clonotypic isotypes. MM expressing clonotypic IgM engrafted both primary and secondary mice, indicating their persistence within the murine BM. This study demonstrates that MM clonotypic cells expressing preswitch transcripts are tied to disease burden and outcomes. Because MM pathology involves postswitch plasma cells, this raises the possibility that IgH isotype switching in MM may accompany worsening disease.

Upper gastrointestinal bleeding as a metastatic manifestation of breast cancer: a case report and review of the literature.

CASE PRESENTATION: A 64-year-old woman with known metastatic lobular breast cancer presented with fever, epigastric pain, hematemesis, and melena. A bleeding, ulcerated gastric metastasis was found and was treated with endoscopic therapy, omeprazole, and hormonal therapy. The patient was alive and well 13 months later. The bleeding was probably precipitated by necrosis of the lesion during chemotherapy. DISCUSSION: Gastrointestinal tract metastases from primary breast carcinoma are present in 14% to 35% of cases in autopsy series, with gastric involvement in 6% to 18% of cases. Recognized much less commonly during life than in autopsy studies, they can occur anywhere in the gut and can mimic virtually any gastrointestinal disorder. Endoscopy and barium studies facilitate diagnosis. Gastric lesions that have been noted include "linitis plastica", nodules, polyps, and ulcers. They are usually due to lobular breast carcinoma and resemble primary gastric carcinoma on microscopy. Reported cases of bleeding gastric metastases have been treated successfully with various local and systemic modalities. The median survival time of reviewed cases was four months from presentation (with a range of zero to 24 months). CONCLUSIONS: Gastrointestinal metastasis is an underdiagnosed complication of breast cancer. Gastrointestinal bleeding from metastatic breast cancer is an uncommon presentation that is readily diagnosed and that can be treated successfully by endoscopic hemostatic therapy.

Concurrent weekly carboplatin and radiotherapy for nasopharyngeal carcinoma: report of a joint phase II study.

We report a phase I/II study of weekly concurrent carboplatin and radiotherapy in patients with nasopharyngeal carcinoma (M0 stage). Of 47 patients registered, 45 completed the treatment course. Twenty-six (55%) (95% CI, 41-69%) patients experienced > or =grade 3 acute toxicity (RTOG). Five (11%) (95% CI, 2-20%) patients experienced > or =grade 3 chronic toxicity. This regimen appears to have acceptable toxicity compared to the experimental arm of Phase III Intergroup Study 0099, but progression-free and overall survival are probably inferior. At present, there is no data to suggest that carboplatin can replace cisplatin for concurrent chemoradiation for NPC.

Clinical MR imaging with a Helmholtz-type surface coil.

Limited-field-of-view radio-frequency receiver antennas provide improved near-field sensitivity for magnetic resonance imaging by decreasing the antenna volume. The Helmholtz-type surface coil, consisting of two flat rings, is an organ-encompassing antenna that takes advantage of this principle to yield an improved signal-to-noise ratio (S/N). The coil was tested in a group of 50 patients and 16 healthy volunteers. Images obtained with the Helmholtz coil demonstrated quantitatively superior S/N of 2.2-fold or greater than that of comparison body coil images, as well as qualitatively superior anatomic resolution.

Suprapancreatic biliary obstruction: CT evaluation.

In a 5-year period, 92 patients with biliary obstruction proximal to the pancreatic segment were evaluated with computed tomography (CT). Seventy-three were judged to have technically optimal studies. Observations of the level of obstruction were compared with data from 50 percutaneous transhepatic cholangiograms; CT data enabled the level of obstruction to be correctly predicted in 46. CT enabled correct prediction of the distribution of obstructing lesions in all 18 patients with intrahepatic obstruction. Forty-four of the 73 patients had pathologic examination of the porta hepatitis. CT findings of obstructing mass and lesser omental nodes resulted in correct prediction of malignancy in 25 (92%) of 27 patients; the absence of such findings enabled correct prediction of benign disease in 13 (77%) of 17 individuals. CT is most valuable as a noninvasive means of planning surgical or radiologic drainage procedures in patients with biliary obstruction.

Wilms tumor in children: abdominal CT and US evaluation.

Computed tomographic (CT) scans and sonograms of 13 children with Wilms tumor were reviewed to determine the ability of each imaging test to characterize the tumor and determine its extent. The findings of this review were correlated with diagnoses based on surgical and pathologic evidence. Tumor necrosis and a pseudocapsule were detected more often using CT scans than sonograms. CT scanning also was more sensitive in assessing perinephric extension, lymph node involvement, and bilateral tumors. Overall, CT scans allowed better determination of the extent of a suspected tumor, enabling correct diagnosis in 77% of patients, while US study was correct in only 23%.