Bruno Bockorny

Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature

Richter transformation in chronic lymphocytic leukaemia (CLL) represents an entity of considerable genetic, molecular, immunological and clinical heterogeneity. A rare occurrence, Hodgkin variant of Richter syndrome, has not been comprehensively characterized or systematized to date. We conducted a retrospective analysis of the existing cases of Hodgkin lymphoma as Richter syndrome reported in the medical literature in the previous three and a half decades. Our search identified 86 such patients; this entity affects predominantly older men and the most common histological subtype is mixed cellularity. Interval between the diagnosis of CLL and subsequent development of Hodgkin lymphoma is circa 4·3 years. The overall survival of patients was approximately 1·7 years in our analysed cohort. However, our pooled data showed that patients in whom CLL had been treated with fludarabine had a shorter survival after transformation compared to the ones not treated with this agent. The role of immunosuppression and Epstein–Barr virus infection in the aetiopathogenesis of this entity remains to be clarified.

Severe Heart Failure after Bortezomib Treatment in a Patient with Multiple Myeloma: A Case Report and Review of the Literature

Background: Bortezomib is a novel, first-in-class peptide which reversibly inhibits the proteasome and is Food and Drug Administration approved for the treatment of multiple myeloma, non-Hodgkin lymphoma, Waldenström’s macroglobulinemia, and systemic light chain amyloidosis, among others. Case Report: Very few cases of bortezomib-induced cardiotoxicity have been reported in the literature, and most of them have been confounded by the previous use of anthracyclins. We reviewed the case of a 56-year-old woman with a medical history of well-controlled hypertension who was newly diagnosed with International Staging System stage I multiple myeloma. She presented with new symptoms of exertional dyspnea, paroxysmal nocturnal dyspnea, and orthopnea after a 4th cycle of a bortezomib/dexamethasone-based chemotherapy. Clinical examination was consistent with heart failure. 2-D echocardiogram showed an left ventricular ejection fraction of 25%, abnormal wall motion, severe eccentric mitral regurgitation, and moderate pericardial effusion. Coronary angiogram showed normal coronaries, and cardiac magnetic resonance did not show delayed gadolinium enhancement. Conclusion: We reviewed the possible mechanisms involved in cardiotoxicity caused by bortezomib, and the diagnostic methods and importance of early identification of this adverse event. Differential diagnoses such as cardiac amyloidosis and viral myocarditis are also discussed. To our knowledge, this is the first case where pericardial effusion and mitral regurgitation were described after bortezomib treatment.

Autoimmune Manifestations in Large Granular Lymphocyte Leukemia

Large granular lymphocyte (LGL) leukemia features a group of indolent lymphoproliferative diseases that display a strong association with various autoimmune conditions. Notwithstanding, these autoimmune conditions have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. The authors offer a comprehensive review of the existing literature on various autoimmune conditions documented in the course of T-cell LGL (T-LGL) leukemia. Though some of them are thought be secondary to the LGL leukemia, others could be primary and might even play a role in its pathogenesis. A considerable clinico-laboratory overlap between T-LGL leukemia associated with rheumatoid arthritis and Feltys syndrome suggests that they are just different eponyms for the same clinical entity.

Derivation and Multicenter Validation of the Drug Resistance in Pneumonia Clinical Prediction Score.

ABSTRACT The health care-associated pneumonia (HCAP) criteria have a limited ability to predict pneumonia caused by drug-resistant bacteria and favor the overutilization of broad-spectrum antibiotics. We aimed to derive and validate a clinical prediction score with an improved ability to predict the risk of pneumonia due to drug-resistant pathogens compared to that of HCAP criteria. A derivation cohort of 200 microbiologically confirmed pneumonia cases in 2011 and 2012 was identified retrospectively. Risk factors for pneumonia due to drug-resistant pathogens were evaluated by logistic regression, and a novel prediction score (the drug resistance in pneumonia [DRIP] score) was derived. The score was then validated in a prospective, observational cohort of 200 microbiologically confirmed cases of pneumonia at four U.S. centers in 2013 and 2014. The DRIP score (area under the receiver operator curve [AUROC], 0.88 [95% confidence interval {CI}, 0.82 to 0.93]) performed significantly better (P = 0.02) than the HCAP criteria (AUROC, 0.72 [95% CI, 0.64 to 0.79]). At a threshold of ≥4 points, the DRIP score demonstrated a sensitivity of 0.82 (95% CI, 0.67 to 0.88), a specificity of 0.81 (95% CI, 0.73 to 0.87), a positive predictive value (PPV) of 0.68 (95% CI, 0.56 to 0.78), and a negative predictive value (NPV) of 0.90 (95% CI, 0.81 to 0.93). By comparison, the performance of HCAP criteria was less favorable: sensitivity was 0.79 (95% CI, 0.67 to 0.88), specificity was 0.65 (95% CI, 0.56 to 0.73), PPV was 0.53 (95% CI, 0.42 to 0.63), and NPV was 0.86 (95% CI, 0.77 to 0.92). The overall accuracy of the HCAP criteria was 69.5% (95% CI, 62.5 to 75.7%), whereas that of the DRIP score was 81.5% (95% CI, 74.2 to 85.6%) (P = 0.005). Unnecessary extended-spectrum antibiotics were recommended 46% less frequently by applying the DRIP score (25/200, 12.5%) than by use of HCAP criteria (47/200, 23.5%) (P = 0.004), without increasing the rate at which inadequate treatment recommendations were made. The DRIP score was more predictive of the risk of pneumonia due to drug-resistant pathogens than HCAP criteria and may have the potential to decrease antibiotic overutilization in patients with pneumonia. Validation in larger cohorts of patients with pneumonia due to all causes is necessary.

Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59-73. ©2017 AACR.See related commentary by Carugo and Draetta, p. 17This article is highlighted in the In This Issue feature, p. 1.

Recurrent pseudocellulitis due to gemcitabine: Underrecognized and underreported?

Pseudocellulitis has been previously described with the use of chemotherapy agent gemcitabine. This condition is thought to occur due to vascular toxicity and increased localized permeability of the skin capillaries. We report herein a case of recurrent pseudocellulitis due to gemcitabine in a patient with metastatic pancreatic cancer. We believe this condition is underreported and underrecognized. Furthermore, it may be misdiagnosed as cellulitis and inappropriately treated with systemic antibiotics. As the diagnosis is clinical and the condition is self-limited, referral to other specialists is usually not required. Awareness of gemcitabine-induced pseudocellulitis is important in order to reassure the patients, their families, and non-oncology providers and to avoid unnecessary (and often costly) diagnostic work-up.

HMG-CoA reductase inhibitors as adjuvant treatment for hematologic malignancies: what is the current evidence?

Statins have been shown to possess properties that go beyond their lipid-lowering effects. These agents act on the mevalonate pathway and inhibit synthesis of cholesterol, geranylgeranyl pyrophosphate, and farnesyl pyrophosphate, which are necessary for posttranslational modification of the Rho, Rac, and Ras superfamily of proteins. Early phase studies have demonstrated that this modulation of cellular signaling can ultimately exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, and might even restore chemosensitivity in several hematologic cancers. Nonetheless, these promising preclinical results have not yet migrated from the bench to the bedside as their effectiveness as adjuvant agents in hematologic malignancies is currently uncertain. In the present review, we summarize the existing evidence stemming from preclinical and clinical studies pertaining to the use of statins as adjuvant therapies in hematologic malignancies, and discuss the new insights gained from the ongoing translational research.

The emerging role of immunotherapy in gastric and esophageal adenocarcinoma

Gastric and esophageal adenocarcinomas are aggressive malignancies. Systemic therapy for these tumors relies primarily on cytotoxic chemotherapy but outcomes remain poor. In recent years, immunotherapy has emerged as a new, promising therapeutic approach for a variety of solid tumors. Characterization of gastroesophageal cancers has revealed genomic and immune features of these tumors that may predict response to immunotherapy. Indeed, preliminary results from the initial trials of immune checkpoint inhibitors have been encouraging, with objective response rates of 20% in heavily pretreated patient populations. Based on these results, additional trials of single-agent checkpoint inhibitors as well as combinations with chemotherapy and targeted therapies are currently ongoing. Further work to identify predictive biomarkers will be crucial for the successful implementation of immunotherapy.

Pyoderma gangrenosum due to lenalidomide use for multiple myeloma

Pyoderma gangrenosum has been described in association with multiple myeloma and usually affects patients with active/untreated disease. This dermatologic condition was shown to resolve after successful anti-myeloma therapy. We report herein occurrence of pyoderma gangrenosum involving bilateral knees in a patient with multiple myeloma responding to lenalidomide therapy. Previous papers claimed usefulness of thalidomide and its newer derivatives for the therapy of this neutrophilic dermatosis. Occurrence of pyoderma gangrenosum in a myeloma patient responding to lenalidomide would argue against its effectiveness in treating this skin condition. Moreover, the clinical setting suggested that lenalidomide either induced or contributed to the occurrence of pyoderma gangrenosum in our patient. If our hypothesis is correct, we expect more reports of pyoderma gangrenosum with the use of this class of pharmaceuticals.

Pulmonary Hemorrhage With Capillaritis Secondary to Mycophenolate Mofetil in a Heart-Transplant Patient

Immunosuppressive drugs are an integral part of therapy in organ transplantation. However, they are not without side effects, and although rare, these agents should be considered in the differential diagnosis of pulmonary complications in patients receiving transplants. We present a case of a patient who developed acute respiratory failure 7 days after orthotopic heart transplantation and who had been on both mycophenolate mofetil (MMF) and tacrolimus agents. Lung biopsy revealed features of pulmonary hemorrhage with capillaritis. Considered as a possible etiology, MMF was withdrawn. There was immediate improvement of the patients symptoms. The temporal relationship between MMF exposure and onset of pulmonary symptoms in the absence of other possible etiologies strongly suggests a causal relationship. Previously published reports of pulmonary toxicity from MMF included interstitial fibrosis. To the best of our knowledge, this is the first reported case of pulmonary hemorrhage with capillaritis because of administration of MMF.