Clinical outcomes of curative-intent multimodal management of chemorefractory nonmetastatic inflammatory breast cancer.

INTRODUCTION: Chemorefractory nonmetastatic inflammatory breast cancer (IBC) which progresses under neoadjuvant chemotherapy poses specific therapeutic challenges: either pursuing a curative-intent treatment with a salvage combination of radiotherapy and surgery or switching to second-line systemic treatments despite the absence of metastasis. Due to the rarity of this situation, no specific management guidelines exist and the outcomes of these patients remain uncertain. In this retrospective observational study, we aimed to report the clinical outcomes of patients treated in a curative intent for chemorefractory nonmetastatic IBC, with a multimodal salvage treatment combining radiotherapy and surgery. MATERIALS AND METHODS: This single-center retrospective observational study included all chemorefractory nonmetastatic IBC treated at the Institut Curie (Paris, France). Overall survival (OS), disease-free survival (DFS), and locoregional relapse-free survival (LRRFS) were calculated from the time of diagnosis and from the time of neoadjuvant chemotherapy interruption. RESULTS: Between January 2010 and January 2018, 7 patients presented with chemorefractory nonmetastatic IBC with a progressive disease during neoadjuvant chemotherapy. Overall, chemorefractory IBC patients were young (median age of 50 years), had a good performance status, and usually presented with node-positive tumors characterized by a combination of adverse histological factors such as triple-negative breast cancer (TNBC), grade III, and high proliferation index. From the date of pathological diagnosis, 1­year OS, DFS, and LRRFS were 64.3%, 53.6%, and 71.4%, respectively. From the date of neoadjuvant chemotherapy interruption, 1­year OS, DFS, and LRRFS were 47.6%, 19.0%, and 45.7%, respectively, and median OS, DFS, and LRRFS were 8.3, 5.0, and 5.0 months, respectively. CONCLUSION: The prognosis of chemorefractory nonmetastatic IBC treated with a multimodal approach combining surgery and radiotherapy is particularly reserved, despite the curative intent of the salvage treatment and the lack of distant metastasis at the time of treatment. Optimal treatment modalities are still to be defined in this rare but critical presentation of IBC.

An update on: molecular genetics of high-risk chronic lymphocytic leukemia.

Introduction: During the past few years, new genomic approaches have elucidated the molecular genetics of chronic lymphocytic leukemia (CLL) to a large extent. As a consequence, specific high-risk genetic features of the disease, e.g. TP53 disruption, have become the backbone of the treatment algorithm for CLL and serve as robust biomarkers for a precision medicine approach to this leukemia.Areas covered: This review covers the genetics of CLL and highlights the translational implications of molecular biomarkers that characterize patients with a high risk of disease progression. Knowledge of the genetic landscape of CLL has allowed the identification of the main molecular features associated with chemo-refractoriness, as well as resistance to BCR inhibitors and BCL2 inhibitors. The molecular basis of Richter transformation has also been characterized.Expert opinion: The term 'high risk CLL' has been changing over time, and might be subject to further changes in the future. With the advent of new therapeutic strategies targeting pathogenetic pathways of the disease, the definition is shifting from the historical view of refractoriness to chemo-immunotherapy, to refractoriness to BCR inhibitors and/or to BCL2 inhibitors. Patients failing these novel medicines are those for whom new therapeutic approaches are still highly needed.

Aldehyde dehydrogenase 1A1 (ALDH1A1) expression by immunohistochemistry is associated with chemo-refractoriness in patients with high-grade ovarian serous carcinoma.

Aldehyde dehydrogenase-1A1 (ALDH1A1), CD133, CD44, and CD24 have been reported as cancer stem cell markers in ovarian cancers. The goal of our study was to assess the prognostic significance of these markers in patients with advanced serous ovarian cancer. Formalin-fixed, paraffin-embedded tissues from 347 ovarian cancers were used to construct a microarray. Immunohistochemical studies for ALDH1A1, CD133, CD44, and CD24 were performed and scored semiquantitatively by 2 pathologists based on intensity and percent of positive immunoreactive cells. Immunohistochemistry was compared to clinical parameters and survival. Of the 347 cases, early stage disease, nonserous tumors, cases with incomplete therapy, and cores with no tumor were excluded. Immunohistochemistry was interpretable in 124 of the 136 stage III and IV ovarian serous carcinoma. ALDH1A1, CD24, and CD44 were variably detected in both tumor and stromal cells, and immunoreactivity in tumor was stronger than in stromal cells. CD133 immunoreactivity was not quantified due to nonspecific staining in tumor and stroma. Statistical analyses using χ2 and Student t test revealed that ALDH1A1-positive (n=53) carcinoma were 3 times more likely to demonstrate platinum refractoriness than ALDH1A1-negative (n=71) tumors (17% vs. 6%, respectively; p=.04); however, neither progression free nor overall survival was influenced by ALDH1A1 status in this cohort. The expression of CD44 and CD24 had no clinicopathological associations in the present study. Our study supports that ALDH1A1 expression is associated with poor response to platinum-based therapy in patients with high-grade ovarian serous carcinoma. Further study of this relationship is needed to understand how this could impact clinical care.

Salvage therapy for acute chemorefractory leukemia by allogeneic stem cell transplantation: the Korean experience.

Little is known about the characteristics that make patients with acute leukemia suitable for undergoing salvage therapy by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we analyzed the clinical outcomes of 223 patients with acute leukemia who underwent allo-HSCT while not in complete remission (CR). The primary end points were overall survival (OS) and CR rate. CR was achieved in 79.8% of patients after allo-HSCT. Acute graft-versus-host disease (GVHD) was significantly associated with CR (P = 0.045). During a median follow-up of 30.1 months, the median OS was 6.1 months. OS was significantly longer in patients with good or standard risk cytogenetic characteristics than in those with poor risk cytogenetic characteristics (P = 0.029, P = 0.030, respectively). Patients who received allo-HSCT from a matched sibling donor had better survival than those with unrelated donors (P = 0.015). Primary chemorefractoriness was not associated with poor survival (P = 0.071). The number of chemotherapies before allo-HSCT was significantly correlated with outcome (P = 0.006). Chronic GVHD was a strong predictor of a longer OS (P = 0.025). In conclusion, survival of patients with primary chemorefractory acute leukemia is not lower when treated upfront with allo-HSCT. Hence, allo-HSCT should be actively considered in such patients. Acute and chronic GVHD is associated with better outcomes patients with acute leukemia who have undergone allo-HSCT and not achieved CR.

Vascular endothelial growth factor expression correlates with serum CA125 and represents a useful tool in prediction of refractoriness to platinum-based chemotherapy and ascites formation in epithelial ovarian cancer.

There is an increasing need for the identification of novel biological markers and potential therapeutic targets in epithelial ovarian cancer (EOC). Given the critical role of growth factors in the biology of EOC, we aimed in the present study to evaluate the intratumoral expressions of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) proteins and their clinical relevance in a cohort of 100 patients with EOC. All patients received platinum-based chemotherapy after surgery. A comparative immunohistochemical study of normal ovarian and EOC tissues showed that both growth factors were expressed at higher levels in tumor samples. In our statistical analysis, while no association existed between the FGF expression status and the clinicopathological characteristics of patients, intratumoral VEGF was identified as a potential biomarker for the prediction of ascites formation. In addition, the expression status of VEGF appeared to independently predict overall survival and response to chemotherapy. Furthermore, a direct association was demonstrated between the pre-treatment VEGF expression and serum CA125 after three cycles of chemotherapy. In sum, we report for the first time to our knowledge the correlation between intratumoral VEGF and serum CA125 in EOC. Our data also shows the prognostic value of VEGF expression in EOC. These results suggest the potential value of intratumoral VEGF in patient stratification. Dual inhibition of VEGF and CA125 might bring about a better outcome for patients with EOC.

Primary refractory and early-relapsed Hodgkin's lymphoma: strategies for therapeutic targeting based on the tumour microenvironment.

Classical Hodgkin's lymphoma (cHL), a distinct disease entity with characteristic clinical and pathological features, accounts for approximately 10% of all malignant lymphomas. cHL can be considered a prototype model for how the tumour microenvironment influences cancer pathogenesis. Cellular components of the cHL microenvironment express molecules involved in cancer cell growth and survival, such as CD30L or CD40L. Moreover, several signal transduction pathways that are critical for the proliferation and survival of neoplastic Hodgkin Reed-Sternberg (HRS) cells, including NF-κB, JAK-STAT, PI3K-AkT and ERK, are deregulated in cHL. Although most patients can be cured with modern treatment strategies, approximately a quarter experience either primary or secondary chemorefractoriness or disease relapse, thus requiring novel treatments. Preclinical and clinical evidence has elucidated a complex crosstalk between malignant HRS cells and the reactive cells of the microenvironment, which suggests that novel therapeutic approaches capable of targeting HRS cells along with reactive cells might overcome chemorefractoriness. In the near future, these novel therapies will also be tested in chemosensitive patients, to reduce the long-term toxicity of chemo-radiotherapy.