Papers by Bernardo Rapoport
International Journal of Molecular Sciences
Aside from their key protective roles in hemostasis and innate immunity, platelets are now recogn... more Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs i...
Frontiers in Oncology
Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cance... more Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all ...
Regular and Young Investigator Award Abstracts, Nov 1, 2022
Regular and Young Investigator Award Abstracts
Table 1 Difference in median plasma concentrations of soluble systemic immune checkpoint molecule... more Table 1 Difference in median plasma concentrations of soluble systemic immune checkpoint molecules in newly diagnosed breast cancer patients and healthy controls.
Cancers
Background: Tumor-infiltrating lymphocytes are associated with a better prognosis in early triple... more Background: Tumor-infiltrating lymphocytes are associated with a better prognosis in early triple-negative breast cancer (TNBC). These cells can be enumerated in situ by the “Immunoscore Clinical Research” (ISCR). The original Immunoscore® is a prognostic tool that categorizes the densities of CD3+ and CD8+ cells in both the invasive margin (IM) and center of the tumor (CT) in localized colon cancer, yielding a five-tiered classification (0–4). We evaluated the prognostic potential of ISCR and pathological complete response (pCR) following neoadjuvant chemotherapy (NACT). Methods: The cohort included 53 TNBC, 32 luminal BC, and 18 HER2-positive BC patients undergoing NACT. Pre-treatment tumor biopsies were immune-stained for CD3+ and CD8+ T-cell markers. Quantitative analysis of these cells in different tumor locations was performed using computer-assisted image analysis. Results: The pCR rate was 44%. Univariate analysis showed that primary tumor size, estrogen-receptor negative, p...
Cancer Research
Background: In the phase III MONARCH plus study (NCT02763566) the cyclin-dependent kinase (CDK) 4... more Background: In the phase III MONARCH plus study (NCT02763566) the cyclin-dependent kinase (CDK) 4&6 inhibitor abemaciclib in combination with non-steroidal aromatase inhibitors (NSAI) or with fulvestrant compared with placebo demonstrated its efficacy and acceptable safety profile at interim analysis in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locoregionally recurrent or metastatic breast cancer. One of the most common treatment-emergent adverse event (TEAE) was diarrhea, typically low grade and of early onset. We will further characterize abemaciclib-associated diarrhea and describe its management in MONARCH plus trial. Methods: MONARCH plus study included two cohorts of patients. Cohort A enrolled patients with initial treatment of endocrine therapy, received abemaciclib or placebo plus NSAI (anastrozole or letrozole); Cohort B enrolled patients who progressed on prior endocrine therapy, receiving abemacicli...
Frontiers in Immunology
Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to... more Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to evade anti-tumor immune responses. To explore the possible involvement of this mechanism in promoting systemic immunosuppression, the pre-treatment levels of soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed breast cancer patients and compared with those of 45 healthy controls using multiplex bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2, whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those of the growth factors, M-CSF, FGF-21 and GDF-15 were significan...
Current Opinion in Oncology, 2021
Purpose of review The past decade has witnessed unprecedented delivery to the clinical arena of a... more Purpose of review The past decade has witnessed unprecedented delivery to the clinical arena of a range of novel, innovative, and effective targeted anticancer therapies. These include immunotherapies, most prominently immune checkpoint inhibitors, as well as agents that target growth factors and cancer-related mutations. Many of these new cancer therapies are, however, associated with an array of toxicities, necessitating insight and vigilance on the part of attending physicians to achieve high-quality supportive care alongside toxicity management. In this review, we consider some of the key supportive care issues in toxicity management. Recent findings Although both supportive care and targeted therapies have brought significant benefits to cancer care, the management of novel cancer therapy toxicities is nevertheless often complex. This is due in large part to the fact that target organs differ widely, particularly in the case of checkpoint inhibitors, with minor dermatological disorders being most common, while others, such as pneumonitis, are more severe and potentially life threatening. Accordingly, efficient management of these immune-related adverse events requires collaboration between multiple medical specialists. Summary Supportive care is a key component in the management of new cancer therapy toxicities and needs to be incorporated into treatment pathways.
Journal of The National Comprehensive Cancer Network, 2021
Supportive Care in Cancer, 2020
Despite the success and ongoing promise of monoclonal antibody–targeted immune checkpoint inhibit... more Despite the success and ongoing promise of monoclonal antibody–targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint–targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.
Journal of Clinical Oncology, 2017
90 Background: Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibito... more 90 Background: Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity in NSCLC patients. Methods: A retrospective review of data from 20 patient records were used to describe the response of patients with NSCLC receiving treatment with Nivolumab after failing chemotherapy. Two patients were too early to evaluate. Results: A total of 18 patients (pts) (10 males and 8 females) were included in the analysis. The median age was 66 years (range 46-85). Adenocarcinoma was documented in 15 pts and squamous cell carcinoma in 3 pts. A Ros-1 positive mutation was documented in 1 pt, 3 EGFR positive mutations were recorded and no pts tested positive for ALK. All pts failed frontline treatment: 14 pts failed platinum based chemotherapy and 4 pts failed TKI-inhibitors (3 on erlotinib and 1 on crizotinib). Pts received a median of 4 cycles of nivolumab (range 1-16). The performance status ra...
Oncology Nursing Forum, 2020
PURPOSE Hot flashes are a common and troublesome side effect of surgery or endocrine therapy. The... more PURPOSE Hot flashes are a common and troublesome side effect of surgery or endocrine therapy. They may lead to physical and psychological distress and negatively affect quality of life. This clinical practice guideline presents evidence-based recommendations for pharmacologic, behavioral, and natural health product interventions for treatment-related hot flashes in patients with breast or prostate cancer. METHODOLOGIC APPROACH An interprofessional panel of healthcare professionals with patient representation prioritized clinical questions and patient outcomes for the management of hot flashes. Systematic reviews of the literature were conducted. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess the evidence and make recommendations. FINDINGS The panel agreed on 14 pharmacologic, behavioral, and natural health recommendations. IMPLICATIONS FOR NURSING Conditional recommendations include the use of antidepressants rather than no treatment, physical activity rather than no treatment, and the avoidance of gabapentin and dietary supplements in the treatment of hot flashes. SUPPLEMENTARY MATERIAL CAN BE FOUND AT&NBSP;HTTPS //onf.ons.org/ons-guidelines-hot-flashes-supplementary-material.
Supportive Care in Cancer, 2016
Supportive Care in Cancer, 2016
Purpose Addition of rolapitant to standard antiemetic therapy improved protection against chemoth... more Purpose Addition of rolapitant to standard antiemetic therapy improved protection against chemotherapy-induced nausea and vomiting (CINV) in phase 3 trials of patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Here, we assessed the impact of CINV on the daily lives of patients receiving HEC or MEC using the Functional Living Index-Emesis (FLIE). Methods In three double-blind phase 3 studies, patients receiving HEC or MEC were randomized 1:1 to receive oral rolapitant 180 mg or placebo prior to chemotherapy plus 5hydroxytryptamine type 3 receptor antagonist and dexamethasone therapy. Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included FLIE total score, nausea and vomiting domain scores, and the proportion of patients with no impact on daily life (total score >108 [range 18-126]). We performed a prespecified analysis of the MEC/ anthracycline-cyclophosphamide (AC) study and a post hoc analysis of two pooled cisplatin-based HEC studies. Results In the pooled HEC studies, rolapitant significantly improved the FLIE total score (114.5 vs 109.3, p < 0.001), nausea score (55.3 vs 53.5, p < 0.05), and vomiting score (59.2 vs 55.8, p < 0.001) versus control; similar results were observed in the MEC/AC study for FLIE total score (112.7 vs 108.6, p < 0.001), nausea score (54.1 vs 52.3, p < 0.05), and vomiting score (58.6 vs 56.3, p < 0.001). A higher proportion of patients reported no impact on daily life with rolapitant than with control in the MEC/AC study (73.2 vs 67.4, p = 0.027). Conclusions Compared with control, rolapitant improved quality of life in patients receiving HEC or MEC.
Current Opinion in Supportive & Palliative Care, 2016
Purpose of review Anaemia is a common problem in patients with solid tumors and haematological ma... more Purpose of review Anaemia is a common problem in patients with solid tumors and haematological malignancies. Certain cancer therapies also contribute to anaemia. This article reviews the pathophysiology of cancer-related anaemia, investigation of a cancer patient with anaemia as well as how anaemia impacts patients in terms of quality of life, disease-related outcomes and treatment choices. Recent findings Different treatments for anaemia include transfusions, erythropoiesis-stimulating agents (ESA) and iron therapy. Within this context, we review the advantages and disadvantages concerning anaemia management in cancer patients as well as the risk-benefit ratio of different treatment choices, particularly the increased risk of thromboembolic events of ESAs and concern around mortality and effect on tumor growth. Summary This review is aimed at guiding treating physicians to make the best evidence-based treatment choices according to the product label and according to current guidelines for patients with cancer-related anaemia.
Oncology & Hematology Review (US), 2014
Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogene... more Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumors, both clinically and pathologically. These cancers are characterized by the lack of expression of the hormone receptors estrogen receptor (ER) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2(HER2)gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant, and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combina...
International Journal of Dermatology, 2011
The last decade in oncology has been highlighted by the emergence of novel, highly specific anti-... more The last decade in oncology has been highlighted by the emergence of novel, highly specific anti-cancer agents, targeting a variety of molecular structures and able to inhibit aberrantly activated oncogenic pathways. Epidermal growth factor receptor inhibitors (EGFRIs) represent one type of such ''targeted'' agents. Their use made treatment more tolerable and resulted in significant reduction of systemic adverse effects. However, EGFRIs are associated with toxicities affecting the skin and adnexal structures, and mucosal surfaces that affect the majority of treated patients. Significant dermatologic toxicities have changed the role and involvement of dermatologists in their care. It is essential to be familiar with these adverse effects, potential complications, long-term sequelae, and available effective treatment strategies in order to appropriately manage these patients. This review will describe the clinical presentation, histopathology, underlying mechanisms, and management options, emphasizing evidence-based approaches.
Breast Cancer Research, 2011
Breast cancer consists of multiple diff erent molecular subtypes and diff erent biological proces... more Breast cancer consists of multiple diff erent molecular subtypes and diff erent biological processes, and consequently diff erent molecular markers are associated with prognosis and chemotherapy sensitivity in the distinct disease subsets [1]. A large number of biological processes including cell cycle regulation, DNA replication, mitotic spindle checkpoint, and p53 function are strongly prognostic in ER + cancers but not among ERcancers [2,3]. Interestingly, the number of biological pathways, and therefore genes, that are associated with prognosis or treatment sensitivity are substantially larger and more consistent in ER + cancers than among ERtumors [1,4]. This implies that it is easier to discover prognostic and predictive markers for ER + than for ERcancers. In ERcancers, the single most consistent, but still modestly accurate, good prognostic predictor is the presence of immune cell infi ltration [5]. Immune cell signatures are also associated with more favorable prognosis in highly proliferative ER + cancers but not in ER + cancers with low proliferation [6]. It is also increasingly clear that the same molecular marker can be associated with several diff erent outcome endpoints in various and often opposing manners. For example, high Ki67 expression is predictive of worse prognosis in the absence of any systemic therapy in ER + cancers, but at the same time it is also predictive of higher sensitivity to chemotherapy. Similar opposing bidirectional associations with treatment response and prognosis exist for many other markers including histologic grade, Tau protein expression and almost all prognostic gene signatures [7]. It is important to be aware of these complex multi-directional interactions between molecular markers and various clinical endpoints that may also vary from breast cancer subtype to subtype. Ignoring these potential marker-disease subset-outcome interactions can lead to contradictory and confusing results across studies (due to diff erences in patient composition and heterogeneity of therapy between studies) and may also lead to the discovery of biomarkers that are clinically less useful (because of unrecognized subtype-restricted performance) [8,9]. References 1. Iwamoto T, Bianchini G, Booser D, et al.: Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.
Annals of Hematology, 2011
The soluble Triggering Receptor Expressed on Myeloid cells 1 (sTREM-1) is a useful marker of infe... more The soluble Triggering Receptor Expressed on Myeloid cells 1 (sTREM-1) is a useful marker of infection in patients with sepsis, but has not been adequately evaluated in patients with chemotherapy-associated febrile neutropenia (FN). The value of sTREM-1 in this setting has been tested in a retrospective, pilot study using stored serum from 48 cancer patients with documented FN. On presentation, patients were categorized according to the Talcott risk-index clinical score. Circulating soluble sTREM-1 was measured using an ELISA procedure, while procalcitonin (PCT) or interleukins 6 (IL-6) and 8 (IL-8), included for comparison, were measured using an immunoluminescence-based assay and Bio-Plex suspension bead array system, respectively. Circulating concentrations of both sTREM-1 and PCT were significantly (P < 0.05) elevated in patients at high risk for complications or death, as predicted by the Talcott score and were significantly lower in patients who responded to empiric antimicrobial agents. Neither IL-6 nor IL-8 accurately predicted serious complications in patients with FN. These observations, albeit from a pilot study, demonstrate that sTREM-1 is indeed elevated in high-risk patients with FN and is potentially useful to predict their clinical course, either together with, or as an alternative to PCT.
Journal of Clinical Oncology, 2005
ABSTRACT Background: The majority of cancer patients who present with febrile neutropenia experie... more ABSTRACT Background: The majority of cancer patients who present with febrile neutropenia experience uncomplicated and speedy recovery. Nevertheless, the frequency of complications remains unacceptably high, with a reported mortality rate by all major cooperative groups of approximately 10%. Infections are the major cause of morbidity/mortality in cancer patients undergoing chemotherapy. In this setting, there is a critical requirement for the development of strategies, such as the MASCC risk- index, which enables early identification of patients at high risk for serious infective complications, who would benefit from hospitalization and prompt, aggressive antimicrobial therapy. Methods: The objective was to determine the value of combining PCT, a selective, systemic marker of severe bacterial infection, measured in cancer patients on presentation with chemotherapy-induced febrile neutropenia, with the MASCC score, as a strategy to distinguish between patients with serious infection and those with less serious infection, or non-infective causes of pyrexia. Patients, who experienced 78 febrile neutropenic episodes were classified, into groups with low (&lt;0.5 ng/ml) or high (≥0.5 ng/ml) initial circulating levels of PCT and these groups were compared with MASCC scores, neutrophil and monocyte counts Results: Sixty four % of patients (all survived), presented with low-risk MASCC scores and low PCT values. 19.2%, presenting with high-risk MASCC scores and high PCT values, (46.7% of whom died, p &lt;0.0001), was considered to be at extremely high risk. The remaining patients (16.8%) were classified either as low-risk MASCC score/high PCT (all survived) or high-risk MASCC/low PCT (1 died). By using the MASCC score in conjunction with measurement of PCT, it was possible to categorize around 83% of patients into those at low risk and those at extremely high risk for severe infection and death. Conclusions: PCT values measured on presentation with febrile neutropenia, combined with the MASCC score, distinguish patients with severe infection, who are at high risk of death, from those with less severe infection and non-infective causes of pyrexia.
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Papers by Bernardo Rapoport