Lenalidomide in Pretreated Patients with Diffuse Large B‐Cell Lymphoma: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice

2 months 3 weeks ago
AbstractBackground.Diffuse large B‐cell lymphoma (DLBCL) is the most common non‐Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency.Subjects, Materials, and Methods.An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice.Results.One hundred fifty‐three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow‐up of 36 months, median overall survival was reached at 12 months and median disease‐free survival was not reached at 62 months. At the latest available follow‐up, 29 patients are still in response out of therapy. Median progression‐free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation.Conclusion.Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real‐life context, especially for elderly patients.Implications for Practice.Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real‐life context, especially for elderly patients.
Alessandro Broccoli, Beatrice Casadei, Annalisa Chiappella, Carlo Visco, Monica Tani, Nicola Cascavilla, Annarita Conconi, Monica Balzarotti, Maria Christina Cox, Dario Marino, Maria Cecilia Goldaniga, Roberto Marasca, Cristina Tecchio, Caterina Patti,…

Twenty Years with Personalized Medicine: Past, Present, and Future of Individualized Pharmacotherapy

2 months 3 weeks ago
AbstractOn April 16, 1999, a short article appeared in The Wall Street Journal entitled “New Era of Personalized Medicine: Targeting Drugs for Each Unique Genetic Profile,” and here, the public was introduced to the term “personalized medicine” for the first time. A few months after publication of the article, it was reprinted in The Oncologist. The article describes the formation of the Single Nucleotide Polymorphisms Consortium, which was established as a collaboration between a number of major pharmaceutical companies and several academic research institutions, with support from the Wellcome Trust Foundation. Reading the article today, one will find that several of the important arguments for an individualized therapy are described in a similar way as we have known it from the past 20 years of discussion. The article mentioned the poor efficacy of the current pharmacotherapy, disease heterogeneity, and genetic variability, a showdown with the “one‐size‐fits‐all” approach, and the use of predictive safety and efficacy biomarkers. Today, personal medicine is in competition with other terms such as “precision medicine” and “stratified medicine” and is no longer the preferred term for describing the individualized health care approach. Even though personalized medicine arose from the idea of improving and individualizing pharmacotherapy, the concept has influenced most other areas of our health care system. No matter if we use the term precision medicine or personalized medicine, the ideas that originated 20 years ago have greatly impacted the way we develop and implement new initiatives in relation to diagnosis, prevention, and treatment today.Implications for Practice.Since the publication of the ideas behind personalized medicine in The Wall Street Journal and The Oncologist 20 year ago, they have permeated medical research and innovation. This review will provide an overview of the background, definitions, and terminology and will describe some of the achievements in relation to the treatment of malignant diseases.
Jan Trost Jorgensen

Genome‐Wide Analysis of Epstein‐Barr Virus Isolated from Extranodal NK/T‐Cell Lymphoma, Nasal Type

2 months 3 weeks ago
AbstractBackground.Extranodal natural killer (NK) cell/T‐cell lymphoma (NKTCL), a rare type of non‐Hodgkin's lymphoma, has strongly been associated with Epstein‐Barr virus (EBV) infection. However, there are no EBV genomes isolated from NKTCL, and the roles the variations of EBV strains play in the pathogenesis of NKTCL are still unclear.Materials and Methods.In this study, whole EBV genomes from eight primary NKTCL biopsy specimens were obtained using next‐generation sequencing, designated NKTCL‐EBV1 to NKTCL‐EBV8.Results.Compared with the six mostly referenced EBV strains, NKTCL‐EBVs closely resemble the GD1 strain but still harbor 2,072 variations, including 1,938 substitutions, 58 insertions, and 76 deletions. The majority of nonsynonymous mutations were located in latent and tegument genes. Moreover, the results from phylogenetic analysis of whole NKTCL genomes and specific genes demonstrated that all the NKTCL‐EBVs were related to Asian EBV strains. Based on the amino acid changes in certain residues of latent membrane protein 1 (LMP1) and EBV‐determined nuclear antigen 1 (EBNA1), all the NKTCL‐EBVs were sorted to China 1 and V‐val subtype, respectively. Furthermore, changes in CD4+ and CD8+ T‐cell epitopes of EBNA1 and LMP1 may affect the efficacy for a cytotoxic T lymphocyte (CTL)‐based therapy.Conclusion.This is the first large study to our knowledge to obtain EBV genomes isolated from NKTCL and show the diversity of EBV genomes in a whole genome level by phylogenetic analysis.Implications for Practice.In this study, the full‐length sequence of Epstein‐Barr virus (EBV) isolated from eight patients with nasal natural killer/T‐cell lymphoma (NKTCL) was determined and further compared with the sequences previously reported isolated from other malignancies. Phylogenetic analysis showed that NKTCL‐EBV strains are close to other Asian subtypes instead of non‐Asian ones, leading to the conclusion that EBV infections are more likely affected by different geographic regions rather than particular EBV‐associated malignancies. Therefore, these data have implications for the development of effective prophylactic and therapeutic vaccine approaches targeting the personalized or geographic‐specific EBV antigens in these aggressive diseases.
Ningjing Lin, Wenjing Ku, Yuqin Song, Jun Zhu, Zheming Lu

Hypomagnesemia and Survival in Patients with Ovarian Cancer Who Received Chemotherapy with Carboplatin

2 months 3 weeks ago
AbstractBackground.Hypomagnesemia is a known side effect of several antineoplastic agents, but its impact on outcomes of patients with cancer is not well understood. We examined whether magnesium abnormalities affect survival in patients with ovarian cancer who receive chemotherapy containing carboplatin.Materials and Methods.We included patients with advanced ovarian cancer who had undergone surgery and chemotherapy between January 1, 2004, and December 31, 2014, at our institution. Inclusion criteria were age 18 years or older, pathology of high‐grade serous carcinoma, first treatment (surgery or chemotherapy) within 60 days of diagnosis, and chemotherapy containing carboplatin. The final cohort consisted of 229 patients. Vital signs and laboratory tests were recorded at baseline and during the treatment course. The associations between magnesium abnormalities (and other clinical characteristics) and survival were analyzed.Results.The median patient age was 64 years. Higher baseline heart rate (beats per minute; hazard ratio [HR] = 1.02, p = .002) and greater frequency of hypomagnesemia during the treatment course (HR = 1.05, p = .002) were significantly associated with shorter survival independent of completeness of tumor reduction (HR = 1.60, p = .02), and International Federation of Gynecology and Obstetrics stage (HR = 1.63, p = .01).Conclusion.Baseline heart rate and the frequency of hypomagnesemia episodes during treatment are prognostic of survival for patients with advanced ovarian cancer receiving carboplatin‐containing chemotherapy and tumor reductive surgery. Future research is needed for strategies to detect and prevent hypomagnesemia in this patient population.Implications for Practice.Despite standard laboratory tests and intravenous magnesium replacement prior to each cycle of chemotherapy, hypomagnesemia remains a common side effect of platinum‐based chemotherapy. This study revealed that frequent occurrence of hypomagnesemia during the course of treatment including carboplatin‐containing chemotherapy and tumor reductive surgery was strongly predictive of shorter survival in patients with advanced ovarian cancer. Strategies to effectively mitigate hypomagnesemia, such as more frequent detection, dietary recommendations, and timely replacement, should be considered in the overall cancer treatment plan for these patients.
Wenli Liu, Aiham Qdaisat, Pamela T. Soliman, Lois Ramondetta, Gabriel Lopez, Santhosshi Narayanan, Shouhao Zhou, Lorenzo Cohen, Eduardo Bruera, Sai-Ching J. Yeung

The Impact of Cisplatin‐ or Non‐Cisplatin‐Containing Chemotherapy on Long‐Term and Conditional Survival of Patients with Advanced Urinary Tract Cancer

2 months 3 weeks ago
AbstractBackground.The impact of cisplatin use on long‐term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long‐term survival and the impact of treatment type in unselected patients with aUTC.Materials and Methods.A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional‐cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long‐term survival was defined as alive at 3 years following initiation of first‐line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first‐line chemotherapy.Results.Median follow‐up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long‐term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3‐year survival (95% confidence interval [CI]: 25.1–38.3), and 2‐year COS for patients surviving 3 years after initiation of cisplatin‐based chemotherapy was 83% (95% CI: 59.7–93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8–17.6) and 49.3% (95% CI: 28.2–67.4). Two‐year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation.Conclusion.Cisplatin‐based therapy was associated with the highest likelihood of long‐term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long‐term survival in cisplatin‐ineligible patients.Implications for Practice.Long‐term, disease‐free survival is possible in one in four eligible‐for‐cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin‐based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.
Aristotelis Bamias, Kimon Tzannis, Christina Bamia, Lauren C. Harshman, Simon Crabb, Elizabeth R. Plimack, Sumanta Pal, Ugo De Giorgi, Sylvain Ladoire, Christine Theodore, Neeraj Agarwal, Evan Y. Yu, Guenter Niegisch, Cora N. Sternberg, Sandy Srinivas,…

Computed Tomography‐Based Radiomics Signature: A Potential Indicator of Epidermal Growth Factor Receptor Mutation in Pulmonary Adenocarcinoma Appearing as a Subsolid Nodule

2 months 3 weeks ago
AbstractBackground.Lung adenocarcinoma (LADC) with epidermal growth factor receptor (EGFR) mutation is considered a subgroup of lung cancer sensitive to EGFR‐targeted tyrosine kinase inhibitors. We aimed to develop and validate a computed tomography (CT)‐based radiomics signature for prediction of EGFR mutation status in LADC appearing as a subsolid nodule.Materials and Methods.A total of 467 eligible patients were divided into training and validation cohorts (n = 306 and 161, respectively). Radiomics features were extracted from unenhanced CT images by using Pyradiomics. A CT‐based radiomics signature for distinguishing EGFR mutation status was constructed using the random forest (RF) method in the training cohort and then tested in the validation cohort. A combination of the radiomics signature with a clinical factors model was also constructed using the RF method. The performance of the model was evaluated using the area under the curve (AUC) of a receiver operating characteristic curve.Results.In this study, 64.2% (300/467) of the patients showed EGFR mutations. L858R mutation of exon 21 was the most common mutation type (185/301). We identified a CT‐based radiomics signature that successfully discriminated between EGFR positive and EGFR negative in the training cohort (AUC = 0.831) and the validation cohort (AUC = 0.789). The radiomics signature combined with the clinical factors model was not superior to the simple radiomics signature in the two cohorts (p > .05).Conclusion.As a noninvasive method, the CT‐based radiomics signature can be used to predict the EGFR mutation status of LADC appearing as a subsolid nodule.Implications for Practice.Lung adenocarcinoma (LADC) with epidermal growth factor receptor (EGFR) mutation is considered a subgroup of lung cancer that is sensitive to EGFR‐targeted tyrosine kinase inhibitors. However, some patients with inoperable subsolid LADC are unable to undergo tissue sampling by biopsy for molecular analysis in clinical practice. A computed tomography‐based radiomics signature may serve as a noninvasive biomarker to predict the EGFR mutation status of subsolid LADCs when mutational profiling is not available or possible.
Xinguan Yang, Xiao Dong, Jiao Wang, Weiwei Li, Zhuoran Gu, Dashan Gao, Nanshan Zhong, Yubao Guan

Accuracy and Prognostic Significance of Oncologists’ Estimates and Scenarios for Survival Time in Advanced Gastric Cancer

2 months 3 weeks ago
AbstractBackground.Worst‐case, typical, and best‐case scenarios for survival, based on simple multiples of an individual's expected survival time (EST), estimated by their oncologist, are a useful way of formulating and explaining prognosis. We aimed to determine the accuracy and prognostic significance of oncologists’ estimates of EST, and the accuracy of the resulting scenarios for survival time, in advanced gastric cancer.Materials and Methods.Sixty‐six oncologists estimated the EST at baseline for each of the 152 participants they enrolled in the INTEGRATE trial. We hypothesized that oncologists’ estimates of EST would be unbiased (∼50% would be longer or shorter than the observed survival time [OST]); imprecise (<33% within 0.67–1.33 times the OST); independently predictive of overall survival (OS); and accurate at deriving scenarios for survival time with approximately 10% of patients dying within a quarter of their EST (worst‐case scenario), 50% living within half to double their EST (typical scenario), and 10% living three or more times their EST (best‐case scenario).Results.Oncologists’ estimates of EST were unbiased (45% were shorter than the OST, 55% were longer); imprecise (29% were within 0.67–1.33 times observed); moderately discriminative (Harrell's C‐statistic 0.62, p = .001); and an independently significant predictor of OS (hazard ratio, 0.89; 95% confidence interval, 0.83–0.95; p = .001) in a Cox model including performance status, number of metastatic sites, neutrophil‐to‐lymphocyte ratio ≥3, treatment group, age, and health‐related quality of life (EORTC‐QLQC30 physical function score). Scenarios for survival time derived from oncologists’ estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 57% lived within half to double their EST, and 12% lived three times their EST or longer.Conclusion.Oncologists’ estimates of EST were unbiased, imprecise, moderately discriminative, and independently significant predictors of OS. Simple multiples of the EST accurately estimated worst‐case, typical, and best‐case scenarios for survival time in advanced gastric cancer.Implications for Practice.Results of this study demonstrate that oncologists’ estimates of expected survival time for their patients with advanced gastric cancer were unbiased, imprecise, moderately discriminative, and independently significant predictors of overall survival. Simple multiples of the expected survival time accurately estimated worst‐case, typical, and best‐case scenarios for survival time in advanced gastric cancer.
Anuradha Vasista, Martin Stockler, Andrew Martin, Nick Pavlakis, Katrin Sjoquist, David Goldstein, Sanjeev Gill, Vikram Jain, Geoffrey Liu, George Kannourakis, Yeul Hong Kim, Louise Nott, Stephanie Snow, Matthew Burge, Dean Harris, Derek Jonker, Yu Jo…

Severe Epididymo‐Orchitis and Encephalitis Complicating Anti‐PD‐1 Therapy

2 months 3 weeks ago
AbstractBackground.Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life‐threatening immune‐related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies.Case Presentation.We describe herein a patient with metastatic melanoma who developed epididymo‐orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo‐orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad‐spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next‐generation sequencing assay, was negative. He received high‐dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5‐week taper of oral steroids.Discussion.Here, we report a case of epididymo‐orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents.Key Points. Epididymo‐orchitis is a rare and potentially life‐threatening complication of anti‐programmed death protein 1 (anti‐PD‐1) therapy.For patients on anti‐PD‐1 therapy who develop either epididymo‐orchitis or epididymitis without clear infectious cause, immune‐related adverse events should be considered in the differential diagnosis.If severe, epididymo‐orchitis related to anti‐PD‐1 therapy may be treated with high‐dose corticosteroids.
Henry T. Quach, Charles J. Robbins, Justin M. Balko, Charles Y. Chiu, Steve Miller, Michael R. Wilson, George E. Nelson, Douglas B. Johnson

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

2 months 3 weeks ago
AbstractBackground.Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker‐stratified clinical trials; however, the clinical utility and U.S.‐centric financial sustainability of integrated next‐generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed.Materials and Methods.In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS‐based mutation and fusion detection, with MYB break‐apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement.Results.Among 181 consecutive ACC cases (2011–2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB‐NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1‐NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression‐free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.‐based) and international levels of reimbursementConclusion.Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program.Implications for Practice.Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.
Julia Thierauf, Nisha Ramamurthy, Vickie Y. Jo, Hayley Robinson, Ryan P. Frazier, Jonathan Gonzalez, Macie&#x0237; Pacula, Enrique Dominguez Meneses, Vania Nose, Valentina Nardi, Dora Dias-Santagata, Long P. Le, Derrick T. Lin, William C. Faquin, Lori J…

Attitudes and Barriers to Research Among Oncology Trainees in East Africa

2 months 3 weeks ago
AbstractBackground.East Africa is one of the fastest growing regions in the world and faces a rising burden of cancer; however, few people are equipped to effectively conduct research in this area.Materials and Methods.A 31‐item questionnaire was distributed to current trainees and recent graduates of the Master in Medicine in Clinical Oncology Program at Muhimbili University of Health and Allied Sciences in Tanzania. Areas that were assessed included (a) demographic information, (b) prior research training, (c) prior and current research activities, (d) attitudes toward the importance of research, and (e) supports and barriers to inclusion of research in an oncology career path.Results.A total of 30 individuals responded to the survey, of whom 53% (n = 16) were male and 70% (n = 21) identified as current trainees. Among the majority of respondents, attitudes toward research were strongly favorable. Although only 37% (n = 11) reported receiving any formal training in research methodology, 87% (n = 26) reported intentions to incorporate research into their careers. The absence of protected time for research and lack of access to research funding opportunities were identified by a majority of respondents as critical barriers.Conclusion.A majority of current or recent oncology trainees in Tanzania desire to incorporate research into their careers, but most also lack adequate training in research methodology and longitudinal mentorship. Our future collaboration will focus on creation of appropriate research training curriculums and fostering an environment that catalyzes interprofessional development and transforms and extends context‐specific cancer research in East Africa.Implications for Practice.Current and recent oncology trainees in East Africa expressed a high enthusiasm for research, driven by a sense of urgency related to the burden from cancer that the region faces. This highlights the need for cancer research training and mentorship in this setting. This work hypothesizes that African principal investigators can operate effectively if proper attention is given to selection and provision of high‐quality foundational didactic training to learn the theory and implementation of research as well as to the development of an environment conducive to mentoring.
Fidel Rubagumya, Sarah K. Nyagabona, Khadija H. Msami, Achille Manirakiza, Ahuka N. Longombe, Theoneste Maniragaba, Hilary Chan, Alan Paciorek, Li Zhang, Emmanuel Balandya, Leyna H. Germana, Elia J. Mmbaga, Nazima Dharsee, Katherine Van Loon

microRNA‐431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma

2 months 4 weeks ago
AbstractBackground.Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens.Materials and Methods.Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a “sensitive” and “resistant” cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed.Results.microRNA‐431 (miR‐431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR‐431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial‐mesenchymal transition underlies the action of miR‐431 with doxorubicin treatment, with Zinc Finger E‐Box Binding Homeobox 1 implicated as the molecular target of miR‐431 in ACC.Conclusion.This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well‐studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings.Implications for Practice.Adrenocortical carcinoma (ACC) is a rare endocrine cancer with outcomes not improving despite extensive research and new targeted therapies. Mitotane and etoposide/doxorubicin/cisplatin chemotherapy is trial validated for improved recurrence‐free survival. However, a minority of patients experience sustained benefit. Significant side effects exist for this regimen, with patients often unable to attain target drug doses shown to give survival benefit. This preclinical study examines the role of microRNAs in sensitizing ACC to doxorubicin or mitotane. This study offers an important bridge between new and existing cancer treatments, offering an imminently translatable approach to the treatment of adrenocortical carcinoma.
Grace T.Y. Kwok, Jing Ting Zhao, Anthony R. Glover, Anthony J. Gill, Roderick Clifton-Bligh, Bruce G. Robinson, Julian C.Y. Ip, Stan B. Sidhu

Clinical and Prognostic Characteristics of 53 Cases of Extracranial Malignant Rhabdoid Tumor in Children. A Single‐Institute Experience from 2007 to 2017

2 months 4 weeks ago
AbstractBackground.The aim of this study is to add to the current knowledge regarding extracranial malignant rhabdoid tumor (MRT), a rare and highly aggressive tumor that occurs most commonly in infants and young children.Patients and Methods.A retrospective medical record review was conducted on 53 patients with pathologically confirmed MRT in Beijing Children's Hospital between January 2007 and October 2017.Results.Fifty‐three patients were diagnosed with MRT at a median age of 16 months, including 32 cases of malignant rhabdoid tumor of the kidney (MRTK) and 21 cases of extrarenal extracranial rhabdoid tumor (EERT). Fourteen (14/32, 43.75%) patients with MRTK and five (5/21, 23.81%) patients with EERT had metastases at diagnosis, and quite a few number of cases occurred tumor rupture (26.42%). Among the 53 patients, 40 (75.47%) patients died, 10 (18.87%) patients survived, and 3 patients (5.66%) were lost to follow‐up. Among the 40 dead patients, 38 patients died from rapid progression of the disease or tumor recurrence, and 2 patients died of severe postoperative complications. Most of the recurrent or relapsed cases (94.11%) occurred within 8 months, with a median time of 76 days after diagnosis. The overall survival rates of 3 years and 5 years for the entire cohort were 23.71% and 18.44%, respectively. After survival analysis, it was clear that a younger age at diagnosis and distant stage patients had relatively poor outcomes. The effect of treatment was the most difficult to analyze because patients were not treated uniformly. Statistically significant differences in survival were noted among patients treated with standard chemotherapy, total resection, and radiotherapy.Conclusion.Extracranial MRT is still a highly aggressive tumor in children. Younger patients and those suffering from metastatic disease were most likely to have a poor outcome because of rapid progression or recurrence of the tumor.Implications for Practice.This is the largest single‐institutional report that investigates the clinical characteristics and outcomes of extracranial malignant rhabdoid tumor (MRT) in China. Our study showed that gross hematuria and tumor rupture were typical characteristics of malignant rhabdoid tumor of the kidney. After survival analysis, it was found that the advanced stage of the tumor and an age ≤12 months at diagnosis were significantly associated with poorer survival. Although extracranial MRT is still a highly aggressive tumor in children, multimodal treatment approach, including chemotherapy, surgery, and radiotherapy, should be employed for this disease.
Haiyan Cheng, Shen Yang, Siyu Cai, Xiaoli Ma, Hong Qin, Weiping Zhang, Libing Fu, Qi Zeng, Mingjie Wen, Xiaoxia Peng, Huanmin Wang

Role of Targeted Therapy and Immune Checkpoint Blockers in Advanced Non‐Small Cell Lung Cancer: A Review

2 months 4 weeks ago
AbstractAdvanced non‐small cell lung cancer (NSCLC) is a complex disease comprising molecularly distinct tumor types, each with a unique biology that is becoming increasingly better characterized. The aim of this review is to present an optimized treatment schema and the accompanying diagnostic testing approach for patients with advanced NSCLC. There are a number of therapies currently approved for patients with advanced NSCLC, including agents that target particular oncogenic drivers, as well as immune checkpoint blockers (ICBs) that elicit an antitumor response. Identification of genetic alterations (e.g., epidermal growth factor receptor, anaplastic lymphoma kinase, reactive oxygen species proto‐oncogene 1, B‐Raf proto‐oncogene) or programmed cell death ligand‐1 expression levels in NSCLC requires diligent molecular testing at initial diagnosis and, in some cases, at disease progression to ensure the most efficacious treatment is delivered. Accurate molecular diagnostic testing, along with the careful selection of currently approved targeted agents, ICBs, or systemic chemotherapy, provides therapy that is personalized according to patients’ needs to achieve the best possible outcome. Enrollment in clinical trials that further the development of tailored therapies is highly recommended at all stages of treatment.Implications for Practice.Targeted therapies and immune checkpoint blockers provide effective and tailored options for patients with non‐small cell lung cancer. Careful molecular analysis of tumor samples is necessary to identify the genetic alterations that are present, to ensure that each patient receives the most efficacious treatment for their specific tumor type. Personalized therapy provides each patient with the best probability for prolonged survival. Enrolling patients in clinical trials should be the first consideration before making each treatment decision.
Nagla Abdel Karim, Karen Kelly

FDA Approval Summary: Brentuximab Vedotin in First‐Line Treatment of Peripheral T‐Cell Lymphoma

2 months 4 weeks ago
AbstractIn November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma or other CD30‐expressing peripheral T‐cell lymphomas (PTCL), including angioimmunoblastic T‐cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval was based on ECHELON‐2, a randomized, double‐blind, actively controlled trial that compared BV+CHP with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 452 patients with newly diagnosed, CD30‐expressing PTCL. Efficacy was based on independent review facility‐assessed progression‐free survival (PFS). The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71 (95% confidence interval [CI]: 0.54–0.93). The trial also demonstrated improvement in overall survival (HR 0.66; 95% CI: 0.46–0.95), complete response rate (68% vs. 56%), and overall response rate (83% vs. 72%) with BV+CHP. The most common adverse reactions (incidence ≥20%) observed ≥2% more with BV+CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy rates were similar (52% with BV+CHP, 55% with CHOP). Through the Real‐Time Oncology Review pilot program, which allows FDA early access to key data, FDA granted this approval less than 2 weeks after official submission of the application.Implications for Practice.This is the first U.S. Food and Drug Administration approval for treatment of patients with newly diagnosed peripheral T‐cell lymphomas (PTCL). Improvement in progression‐free and overall survival over cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, which has been the standard of care for decades, is unprecedented. The new regimen represents a major advance for the frontline treatment of patients with CD30‐expressing PTCL.
Nicholas C. Richardson, Yvette L. Kasamon, Haiyan Chen, R. Angelo de Claro, Jingjing Ye, Gideon M. Blumenthal, Ann T. Farrell, Richard Pazdur

Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients’ Outcome in Neuroendocrine Tumors (NET)—The GREPONET Study

3 months ago
AbstractIntroduction.Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications.Materials and Methods.Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow‐up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow‐up (TGRfirst), and 3(±1) months of study entry (TGR3m).Results.Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression‐free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5–32.4 vs. 9.3 m; 95% CI, 6.1–22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21–6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97–6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15–4.31; p = .018) was also an independent factor related to shorter PFS.Conclusion.TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow‐up.Implications for Practice.Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression‐free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow‐up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.
Angela Lamarca, Joakim Crona, Maxime Ronot, Marta Opalinska, Carlos Lopez Lopez, Daniela Pezzutti, Pavan Najran, Luciana Carvhalo, Regis Otaviano Franca Bezerra, Philip Borg, Naik Vietti Violi, Hector Vidal Trueba, Louis de Mestier, Niklaus Schaefer,…

Clinical Characteristics and Prognostic Factors of Patients with Intrahepatic Cholangiocarcinoma with Fever: A Propensity Score Matching Analysis

3 months ago
AbstractBackground.Patients with intrahepatic cholangiocarcinoma (ICC) rarely present fever as the initial symptom. We aimed to identify clinical characteristics and prognostic factors for these feverish patients.Subjects, Materials, and Methods.This study retrospectively reviewed 31 patients with ICC with fever (≥38.0°C) treated at our hospital between January 2002 and December 2014. A propensity score was used to match patients with and without fever at a ratio of 1:2.Results.Patients with ICC with fever had higher serum γ‐glutamyl transferase and carcinoembryonic antigen levels, larger tumors, poorer tumor differentiation, and worse prognosis (all p < .05) than those without fever. This was supported by propensity score matching (PSM) analysis. Univariate and multivariate analyses indicated that microvascular invasion, hilar lymph node metastasis, and temperature ≥ 38.6°C were related to prognosis. Patients with ICC with fever had higher levels of leucocytes, neutrophils, neutrophil‐to‐lymphocyte ratio (NLR), and platelet‐to‐lymphocyte ratio (PLR) in peripheral blood before and after PSM analysis. Body temperature positively correlated with leucocytes (r = 0.599, p < .001), neutrophils (r = 0.644, p < .001), NLR (r = 0.681, p < .001), and PLR (r = 0.457, p = .010).Conclusion.Patients with ICC with fever ≥38.0°C and ≥38.6°C had poor and extremely poor prognosis, respectively. Radical surgical treatment may improve the prognosis of patients with ICC with fever <38.6°C. However, systemic therapy (e.g., anti‐inflammatory and immune therapy) may be preferable to surgery for these patients with fever ≥38.6°C.Implications for Practice.Patients with intrahepatic cholangiocarcinoma (ICC) with fever (≥38.0°C) as the initial symptom are extremely rare. Because their symptoms are similar to those of liver abscess, diagnosis is challenging, and most of these patients are already at an advanced stage at the time of diagnosis. Patients with ICC with fever had different clinical characteristics and worse prognosis than those without fever. The prognosis of those with temperature <38.6°C would be improved by timely surgical intervention. Those with fever ≥38.6°C had an extremely dismal outcome, although they all received radical surgical treatment. New therapeutic strategies are needed to improve survival for patients with ICC with temperature ≥38.6°C.
Zi-Jun Gong, Jian-Wen Cheng, Pin-Ting Gao, Ao Huang, Yun-Fan Sun, Kai-Qian Zhou, Bo Hu, Shuang-Jian Qiu, Jian Zhou, Jia Fan, Xin-Rong Yang
1 hour 58 minutes ago
The Oncologist RSS feed -- Early Online Editions of Accepted Articles
Subscribe to Early View from The Oncologist feed