Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease.

Light chain deposition disease (LCDD) is characterized by monotypic immunoglobulin depositions which will eventually lead to loss of organ function if left untreated. While the kidney is almost always affected, the presence and degree of LCDD in other organs vary. Ten to thirty percent of LCDD patients have underlying Multiple Myeloma (MM), yet outcome and prognostic markers in this particular patient group are still lacking. Here, we analyzed 69 patients with MM and biopsy proven LCDD and report on renal and extra-renal involvement and its impact on prognosis as well as renal response depending on hematologic response. Coexisting light chain diseases such as AL amyloid and cast nephropathy were found in 30% of patients; those with LCDD and concurrent amyloid tended to have shorter survival. Cardiac involvement by LCDD was seen in one-third of our patients and was associated with shorter overall survival; such patients also had a significantly higher risk of treatment-related mortality (TRM) after stem cell transplant (SCT) compared to LCDD patients without cardiac involvement. This study highlights that MM patients with LCDD present with different clinical features compared to previously reported LCDD cohorts. Rapid initiation of treatment is necessary to prevent progressive renal disease and worse outcome. Coexisting light chain diseases and cardiac involvement are more common than previously reported and confer worse clinical outcome, emphasizing the need for careful patient careful patient evaluation and treatment selection.

Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants.

Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.Experimental Design: A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50 mg/m2/d for 4 days.Results: Grade ≥3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (P = 0.2; TT4-S, 59%; TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (P = 0.05; TT4-S, 87%; TT4-L, 81% at 2 years). With a median follow-up of 4.5 years, there was no difference in overall survival (OS) and progression-free survival (PFS). Whereas metaphase cytogenetic abnormalities (CAs) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q < 0.0001), seven of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such a difference was not observed in TT4-L.Conclusions: We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-multiple myeloma effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial. Clin Cancer Res; 23(11); 2665-72. ©2016 AACR.

Patterns of central nervous system involvement in relapsed and refractory multiple myeloma.

BACKGROUND: Invasion of CNS in MM is an extremely rare occurrence that is associated with advanced disease with poor prognosis. PATIENTS AND METHODS: Our MM database identified 35 CNS MM cases presenting between January 1996 and March 2012. Descriptive analyses were performed on available data on patient characteristics, disease course, and outcomes. RESULTS: The mean age at diagnosis was 55.4 years; 23.5% (n = 8) patients had elevated levels of beta-2-microglobulin > 5.5 mg/L; 68.6% (n = 24) of patients had elevated lactate dehydrogenase (LDH) levels (≥ 2 times upper limit of normal); and 14% (n = 5) of patients had secondary plasma cell leukemia. Magnetic resonance imaging (MRI), which was performed in 34 patients, showed diffuse or localized leptomeningeal disease in 20 patients (58.8%). Monoclonal malignant plasma cells were found by CSF analysis in all 35 patients. In total, 31 patients received chemotherapy, including intrathecal chemotherapy as a part of their treatment, with a median survival of 4 months after CNS MM diagnosis. DISCUSSION: In our experience, CNS MM is an aggressive terminal disease feature associated with high beta-2-microglobulin level, high LDH level, and secondary plasma cell leukemia. This study highlights an unmet need in this subset of patients with high-risk, relapsed or refractory MM. CONCLUSION: Achieving adequate CSF penetration while limiting the off-target effects needs to be considered in MM-specific novel drug development.

Baseline platelet count and creatinine clearance rate predict the outcome of neutropenia-related invasive aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) is a life-threatening infection for immunocompromised patients. Improvement in IA outcome has been hampered by lack of early prognostic factors, namely, those available before starting chemotherapy (baseline) or early in the course of IA (nonbaseline). We hypothesized that prognostic factors can be identified before chemotherapy, ≤7 days from the first positive serum Aspergillus galactomannan index (s-GMI). METHODS: We analyzed 98 patients with multiple myeloma who developed neutropenia-related IA and had a positive s-GMI. Three response criteria were used: kinetics of s-GMI, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definitions, and 6-week survival. Baseline and nonbaseline variables were analyzed separately. RESULTS: Independent response predictors at baseline were a platelet count ≥65,000 platelets/mm(3) (odds ratio [OR], 1.009; 95% confidence interval [CI], 1.001-1.017; P = .03) by s-GMI kinetics, and a platelet count ≥65,000 platelets/mm(3) (OR, 1.009; 95% CI, 1.002-1.017; P = .01) and a creatinine clearance rate ≥53 mL/min (OR, 1.024; 95% CI, 1.006-1.042; P = .009) by EORTC/MSG criteria, with response rates of 83% and 28% when both variables were above or below these cutoffs, respectively (P < .001). Only baseline creatinine clearance rate ≥53 mL/min predicted 6-week survival (P = .003). Normalization of the s-GMI ≤7 days after the first positive s-GMI and neutrophil recovery were the nonbaseline factors associated with positive outcomes. CONCLUSIONS: Two simple, inexpensive to measure, widely available, and routinely collected prechemotherapy values, platelet count and creatinine clearance rate, predict IA outcome and stratify patients into low-, intermediate-, and high-risk categories, while early evaluation of s-GMI allows timely treatment modification. These findings may improve patient outcomes by optimizing management strategies for this serious infection and may prove valuable in designing clinical trials of interventions to improve IA outcomes.

Earlier response assessment in invasive aspergillosis based on the kinetics of serum Aspergillus galactomannan: proposal for a new definition.

BACKGROUND: Current criteria for assessing treatment response of invasive aspergillosis (IA) rely on nonspecific subjective parameters. We hypothesized that an Aspergillus-specific response definition based on the kinetics of serum Aspergillus galactomannan index (GMI) would provide earlier and more objective response assessment. METHODS: We compared the 6-week European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) response criteria with GMI-based response among 115 cancer patients with IA. Success according to GMI required survival with repeatedly negative GMI for ≥2 weeks. Time to response and agreement between the 2 definitions were the study endpoints. RESULTS: Success according to EORTC/MSG and GMI criteria was observed in 73 patients (63%) and 83 patients (72%), respectively. The GMI-based response was determined at a median of 21 days after treatment initiation (range, 15-41 days), 3 weeks before the EORTC/MSG time point, in 72 (87%) of 83 responders. Agreement between definitions was shown in all 32 nonresponders and in 73 of the 83 responders (91% overall), with an excellent κ correlation coefficient of 0.819. Among 10 patients with discordant response (EORTC/MSG failure, GMI success), 1 is alive without IA 3 years after diagnosis; for the other, aspergillosis could not be detected at autopsy. The presence of other life-threatening complications in the remaining 8 patients indicates that IA had resolved. CONCLUSIONS: The Aspergillus-specific GMI-based criteria compare favorably to current response definitions for IA and significantly shorten time to response assessment. These criteria rely on a simple, reproducible, objective, and Aspergillus-specific test and should serve as the primary endpoint in trials of IA.

Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients: clinical and research implications.

BACKGROUND: Lower alimentary tract mucositis is a serious complication of chemotherapy. The aim of the study was to determine the incidence, risk factors, and mortality of lower alimentary tract mucositis in a homogeneous population of patients with newly diagnosed myeloma receiving similar antineoplastic therapy and standardized supportive care. METHODS: Lower alimentary tract mucositis was evaluated among 303 consecutive patients with myeloma (2004-2007) enrolled in a clinical trial consisting of induction chemotherapy, tandem melphalan-based autologous stem cell transplantation (ASCT), and consolidation. Lower alimentary tract mucositis was defined as neutropenia-associated grade II-IV enteritis/colitis. Pretreatment risk factors were examined including body surface area (BSA), serum albumin (albumin), and estimated creatinine clearance (CrCl). Multiple logistic regression model was used to compute adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Forty-seven (15.5%) patients developed lower alimentary tract mucositis during 1529 courses of chemotherapy (including 536 melphalan-based ASCT). Pre-enrollment BSA <2 m² (OR, 2.768; 95% CI, 1.200-6.381; P = .0169) increased the risk for lower alimentary tract mucositis, whereas higher albumin was protective (OR, 0.698; 95% CI, 0.519-0.940; P = .0177). Pretransplant variables associated with lower alimentary tract mucositis were BSA <2 m² (OR, 4.451; 95% CI, 1.459-13.58, P = .0087) and estimated CrCl <60 mL/min (OR, 3.493; 95% CI, 1.173-10.40; P = .0246). Higher albumin level conferred protection (OR, 0.500; 95% CI, 0.304-0.820; P = .0061). No lower alimentary tract mucositis-related death was observed. CONCLUSIONS: Lower alimentary tract mucositis is not uncommon among a homogenous population of oncology patients undergoing sequential courses of chemotherapy including melphalan-based ASCT but does not contribute to mortality. Lower BSA, renal function, and albumin are associated with increased risk for lower alimentary tract mucositis.

Probable invasive aspergillosis without prespecified radiologic findings: proposal for inclusion of a new category of aspergillosis and implications for studying novel therapies.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) and the Mycosis Study Group (MSG) definition of invasive aspergillosis used in clinical trials lacks sensitivity. We hypothesize that giving lower weight to the prespecified radiologic findings in patients with a positive serum galactomannan index test result will improve the definition's diagnostic sensitivity. METHODS: The medical records of 121 patients with 125 cases of invasive aspergillosis treated at a referral cancer institute from January 2003 through December 2009 were reviewed. Aspergillosis was diagnosed as EORTC-MSG proven or probable (controls, 83) or probable invasive aspergillosis without prespecified radiologic criteria (cases, 42). The latter differed from the former by the inclusion of patients whose pulmonary infiltrates, although well described in invasive aspergillosis, do not fulfill EORTC-MSG invasive aspergillosis requirements. The host, clinical, and mycologic characteristics and survival of cases and controls served as end points. RESULTS: A total of 114 (91%) of 125 patients had multiple myeloma. Patients had a median age was 65 years (range, 26-81 years), and 74 were male. All had received antineoplastic therapy, including stem cell transplantation (58 [46%]). Aspergillosis involved lungs (88 patients), sinuses (9 patients), or both (28 patients). Except for higher median baseline platelet count and shorter duration of neutropenia among cases, there were no statistically significant differences between groups on all predefined end points, including 4-, 6-, and 12-week survival. Eleven of 26 cases were reclassified as controls on the basis of subsequent imaging. CONCLUSIONS: Except for less well-circumscribed consolidations, the host, clinical, radiologic, and mycologic characteristics and outcome of patients with probable invasive aspergillosis but without prespecified radiologic criteria are similar to those with EORTC-MSG invasive aspergillosis. Enrolling such patients in clinical trials of novel therapies will increase the pool of eligible study participants and improve trial speed and efficiency.

Strong correlation between serum aspergillus galactomannan index and outcome of aspergillosis in patients with hematological cancer: clinical and research implications.

BACKGROUND: Galactomannan is an Aspergillus-specific polysaccharide released during aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test. Preclinical and preliminary clinical reports have suggested a good correlation between GMI and aspergillosis outcome. METHODS: We reviewed the literature to assess the strength of correlation between GMI and aspergillosis outcome using the kappa correlation coefficient. We included 27 studies that enrolled patients with hematological cancer and proven or probable aspergillosis and that used sequential GMI testing. We examined the 3 following outcomes: survival (survival vs. death), global outcome (survival vs. death [including autopsy findings]), and autopsy outcome (autopsy findings only). RESULTS: Overall, 257 patients fulfilled criteria for proven or probable aspergillosis and were eligible for outcome evaluation. Correlation between GMI (within

Serum Aspergillus galactomannan antigen values strongly correlate with outcome of invasive aspergillosis: a study of 56 patients with hematologic cancer.

BACKGROUND: Determining the outcome of patients with aspergillosis can be particularly difficult because patients with aspergillosis are at risk for other conditions that mimic this infection. Galactomannan is an Aspergillus-specific antigen released during invasive aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test. METHODS: Using a kappa correlation coefficient test (KCC), the strength of correlation was determined between GMI and survival outcome of aspergillosis among 56 adults with hematologic cancer (90% had myeloma) who underwent serial GMI monitoring until hospital discharge or death. RESULTS: All 56 patients received antineoplastic therapy (myeloablative followed by stem cell transplantation [autologous in 21 patients and allogeneic in 3 patients] or nonmyeloablative therapy [32 patients]). The overall correlation between survival outcome and GMI was excellent (KCC = 0.8609; 95% confidence interval [95% CI], 0.7093-1.000 [P < .0001]) and was comparable among neutropenic and nonneutropenic patients (KCC = 0.8271; 95% CI, 0.6407-1.000 [P < .0001] and KCC = 1.0; 95% CI, 1-1 [P = .0083], respectively). CONCLUSIONS: The survival outcome of patients with aspergillosis strongly correlated with serum GMI. These findings have important implications for patient care and clinical trials of mold-active antifungal agents.

Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications.

BACKGROUND: Assessing the outcome of patients with invasive pulmonary aspergillosis by using conventional criteria is difficult, particularly when clinical and radiologic worsening coincides with neutrophil recovery. Usually, it is assumed that this deterioration is related to progressive aspergillosis, prompting changes in patient management. However, its temporal relation with neutrophil recovery suggests that it may be caused by an immune reconstitution syndrome (IRIS). Galactomannan is an Aspergillus-specific polysaccharide that is released during aspergillosis and is detected by the serum galactomannan test, which has been approved by the United States Food and Drug Administration for the diagnosis of invasive aspergillosis. In this study, the authors used sequential galactomannan testing to distinguish IRIS responses from progressive aspergillosis. METHODS: From April 2001 to December 2006, patients with hematologic malignancies underwent galactomannan screening during periods when they were at risk. The clinical and laboratory findings from patients who had >or=2 consecutive positive galactomannan assays (optical density, >or=0.5) were reviewed. RESULTS: Nineteen neutropenic patients with aspergillosis developed clinical and radiologic pulmonary deterioration during neutrophil recovery. Deterioration coincided with microbiologic response, as documented by rapid normalization of serum galactomannan, and, in 16 patients, was followed by complete clinical response and survival at 3 months, although there were no changes in antifungal therapy. The 3 patients who died during the first month had no evidence of aspergillosis at autopsy examination. CONCLUSIONS: The authors propose that IRIS was responsible for the current findings and provide a definition for the syndrome. They also recommend serial galactomannan testing to guide aspergillosis management. Declining galactomannan values imply IRIS with an aspergillus response and obviate the need for invasive procedures and alternative antifungal therapies, whereas persistent galactomannan elevation indicates progressive aspergillosis and requires prompt treatment modification.

Testing standard and genetic parameters in 220 patients with multiple myeloma with complete data sets: superiority of molecular genetics.

Prognostic models for multiple myeloma have been fraught with tremendous heterogeneity in outcome among subgroups. In the context of Total Therapy 2, a tandem transplant trial for newly diagnosed myeloma, comprehensive information was available in 220 patients on standard prognostic factors (SPF), magnetic resonance imaging (MRI)-defined focal lesions, cytogenetic abnormalities (CA), fluorescence-in-situ-hybridisation (FISH)-derived amplification of chromosome 1q21 (amp1q21) and deletion of 13q14, as well as gene expression profiling (GEP). Five multivariate analysis-based survival models were derived, utilising SPF only (model 1), with progressive addition of CA (model 2), MRI (model 3), FISH (model 4) and GEP (model 5). The R(2) value, a measure of accounting for clinical outcome variability, increased progressively from 18% in model 1 to 38% in model 5. The hazard ratio for overall survival was highest for GEP (3.07, P < 0.001) followed by amp1q21 (1.71, P = 0.05). According to the presence of none (49%), one (35%) or both of these two risk features (16%), 3-year survival decreased progressively from 92% to 78% to 43% (P < 0.0001). Thus, the dominance over other prognostic parameters of molecular genetics justifies the generation of quantitative reverse transcription polymerase chain reaction methodology ('MM genetic kit') for the optimal risk stratification of patients participating in therapeutic trials.

Stenotrophomonas maltophilia infections.

Stenotrophomonas maltophilia is a ubiquitous, gram-negative organism that causes hospital-acquired infections. Persons often come in contact with S. maltophilia through environmental water sources, including hospital tap water or faucets, and it has been associated with nosocomial outbreaks of infection. S. maltophilia often infects debilitated persons and those with underlying medical conditions, including immunosuppression. Manifestations of infection include pneumonia, often in mechanically ventilated patients, bacteremia, skin and soft tissue infection, urinary tract infection, and endocarditis. Treatment of S. maltophilia infection is difficult because the organism is resistant to a number of agents typically used for hospital-acquired infections. In vitro and clinical data indicate that trimethoprim-sulfamethoxazole is the agent of choice. Beta-lactamase inhibitors such as clavulanate are also active, and combination therapy may be indicated for certain serious infections due to S. maltophilia.

Tuberculosis ulcerosa perianal / Ulcerative perianal tuberculosis

Se presenta un paciente de 48 años de edad, oriundo de Corrientes, que consulta por ulceración dolorosa, en región anal y perianal, de 6 cm de diametro aproximadamente, de 7 meses de evolución, acompañada de tos seca de no más de un mes de evolución. La biopsia de las lesiones cutáneas y los exámenes complementarios confirman el diagnóstico de tuberculosis cutáneo-pulmonar, la que responde satisfactoriamente al tratamiento específico. El propósito de este trabajo es el de insistir una vez más en pensar y descartar siempre la etiología bacilar en este tipo de lesiones cutáneas crónicas, dado que la tuberculosis no es una enfermedad erradicada aún de nuestro medio

Tuberculosis ulcerosa perianal / Ulcerative perianal tuberculosis

Se presenta un paciente de 48 años de edad, oriundo de Corrientes, que consulta por ulceración dolorosa, en región anal y perianal, de 6 cm de diametro aproximadamente, de 7 meses de evolución, acompañada de tos seca de no más de un mes de evolución. La biopsia de las lesiones cutáneas y los exámenes complementarios confirman el diagnóstico de tuberculosis cutáneo-pulmonar, la que responde satisfactoriamente al tratamiento específico. El propósito de este trabajo es el de insistir una vez más en pensar y descartar siempre la etiología bacilar en este tipo de lesiones cutáneas crónicas, dado que la tuberculosis no es una enfermedad erradicada aún de nuestro medio (AU)