An emerging role for cytopathology in precision oncology

Precision medicine is an emerging field in medicine for disease prevention and treatment that takes into account the individual variability in genes, environment, and lifestyle for each individual patient. The authors have developed a special program as part of the Englander Institute for Precision Medicine to grow patient‐derived, 3‐dimensional tumor organoids for tumor‐specific drug testing, tailoring treatment strategies, and as models for studying drug resistance. Routine cytology preparations represent a cost‐effective and powerful tool to aid in performing molecular testing in the age of personalized medicine. In this commentary, the platforms used for the characterization and validation of patient‐derived, 3‐dimensional tumor organoids are outlined and discussed, and the role of cytology as a cost‐effective and powerful quality‐control measure is illustrated. Cancer Cytopathol 2016;124:167–173. © 2015 American Cancer Society.     

Molecular predictive testing in precision oncology: The Italian experience

In this review, we describe molecular pathology testing to predict response to targeted treatment of solid tumors, focusing on Italian routine clinical practice. The combination of the universal health care system organized at national, regional, and local levels has led a decentralized model, with a large number of local laboratories performing in-house molecular testing following guidelines issued and external quality assessment organized by the Italian Society of Pathology and Cytopathology–Italian Division of the International Academy of Pathology. In this framework, in the early days of predictive testing, sponsored informatics platforms support to set up national programs that aimed to integrate the activity of oncologists and pathologists to test cancer patients for druggable alterations. More recently, reimbursement for molecular testing is being covered completely by the Italian National Health Service. In the near future, considering the development of complex technologies, we expect that outsourcing samples to next-generation sequencing referral laboratories will take place.     

肿瘤精准医学时代下精准检测技术的发展现状与临床应用

精准检测技术推动了精准医学时代个体化肿瘤诊治的发展,同时,临床精准诊治的需求进一步驱动精准检测技术的 改良与应用。近年来,精准医学检测实现了从基因低通量测序到高通量测序、组织活检到液体活检及多细胞混杂检测到单细胞 精准检测的变革,推动了肿瘤精准医学时代新技术、新靶点、新药物的产生与发展。未来,多维度联合检测有助于提高精准医学 的精准度,ctDNA甲基化检测分析则有助于拓宽精准医学研究领域,临床试验设计的变革也有助于推动精准医学深入发展。     

An overview of precision oncology basket and umbrella trials for clinicians

With advancements in biomarkers and momentum in precision medicine, biomarker-guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine—to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.     

The application of current classification systems in pediatric cytopathology: Perspectives from the pediatric cytopathology symposium at the 20th International Congress of Cytology 2019

A pediatric cytopathology symposium was held at the recent 20th International Congress of Cytology, which convened in Sydney, Australia, in May 2019. This educational event brought together cytopathologists from different countries and different institutions to discuss some of the practical considerations when applying current diagnostic classification systems to cytopathology specimens from young (pediatric and adolescent) patients. Within the past decade, various classification systems have been developed to create more standardized terminology for cytopathology specimen reporting among institutions, which can lead to improved management guidelines based on evidence-based medicine. It is well known that a majority of the peer-reviewed publications in cytopathology discussing the usefulness of these classification schemes predominantly contain case cohorts of adult patients. Although pediatric cases are not excluded from following these diagnostic guidelines, there is less of an emphasis on this age group with respect to unique findings and management differences. Thus, discussing the role of these guidelines and their applications in pediatric cases at an international educational gathering can not only be beneficial in educating the cytopathology community about the value of applying these classification systems to pediatric populations, but also can raise awareness of unique entities in cytologic specimens obtained from young patients.     

精准肿瘤医学之实践：靶向肿瘤免疫微环境

近年来,肿瘤免疫治疗技术的发展为拓宽精准肿瘤医学领域做出了巨大贡献。免疫微环境是影响免疫治疗效果的重 要因素,其在肿瘤进展和动员抗肿瘤免疫方面都有不可忽视的作用。针对肿瘤免疫微环境的免疫性放疗、免疫检查点抑制剂、肿 瘤疫苗和免疫细胞治疗等手段已在临床研究中取得了很多成果,但其临床疗效仍有待提高。本文在介绍肿瘤免疫微环境的组成 和特征的基础上,从临床应用的角度阐述针对目前靶向肿瘤免疫微环境的治疗手段可行的优化策略。     

Chronological improvement in precision oncology implementation in Japan

In Japan, comprehensive genomic profiling (CGP) tests for refractory cancer patients have been approved since June 2019, under the requirement that all cases undergoing CGP tests are annotated by the molecular tumor board (MTB) at each government‐designated hospital. To investigate improvement in precision oncology, we evaluated and compared the proportion of cases receiving matched treatments according to CGP results and those recommended to receive genetic counseling at all core hospitals between the first period (11 hospitals, June 2019 to January 2020) and second period (12 hospitals, February 2020 to January 2021). A total of 754 and 2294 cases underwent CGP tests at core hospitals in the first and second periods, respectively; 28 (3.7%) and 176 (7.7%) patients received matched treatments (p < 0.001). Additionally, 25 (3.3%) and 237 (10.3%) cases were recommended to receive genetic counseling in the first and second periods, respectively (p < 0.001). The proportion was associated with the type of CGP test: tumor‐only (N = 2391) vs. tumor‐normal paired (N = 657) analysis (10.0% vs. 3.5%). These results suggest that recommendations regarding available clinical trials in networked MTBs might contribute to increasing the numbers of matched treatments, and that tumor‐normal paired rather than tumor‐only tests can increase the efficiency of patient referrals for genetic counseling.     

Harnessing the potential of reverse-phase protein array technology: Advancing precision oncology strategies

The last few decades have seen remarkable strides in the field of cancer therapy. Precision oncology coupled with comprehensive genomic profiling has become routine clinical practice for solid tumors, the advent of immune checkpoint inhibitors has transformed the landscape of oncology treatment, and the number of cancer drug approvals has continued to increase. Nevertheless, the application of genomics-driven precision oncology has thus far benefited only 10%–20% of cancer patients, leaving the majority without matched treatment options. This limitation underscores the need to explore alternative avenues with regard to selecting patients for targeted therapies. In contrast with genomics-based approaches, proteomics-based strategies offer a more precise understanding of the intricate biological processes driving cancer pathogenesis. This perspective underscores the importance of integrating complementary proteomic analyses into the next phase of precision oncology to establish robust biomarker-drug associations and surmount challenges related to drug resistance. One promising technology in this regard is the reverse-phase protein array (RPPA), which excels in quantitatively detecting protein modifications, even with limited amounts of sample. Its cost–effectiveness and rapid turnaround time further bolster its appeal for application in clinical settings. Here, we review the current status of genomics-driven precision oncology, as well as its limitations, with an emphasis on drug resistance. Subsequently, we explore the application of RPPA technology as a catalyst for advancing precision oncology. Through illustrative examples drawn from clinical trials, we demonstrate its utility for unraveling the molecular mechanisms underlying drug responses and resistance.     

The microbiome in pediatric oncology

The human microbiome comprises a diverse set of microorganisms, which play a mostly cooperative role in processes such as metabolism and host defense. Next-generation genomic sequencing of bacterial nucleic acids now can contribute a much broader understanding of the diverse organisms composing the microbiome. Emerging evidence has suggested several roles of the microbiome in pediatric hematology/oncology, including susceptibility to infectious diseases, immune response to neoplasia, and contributions to the tumor microenvironment as well as changes to the microbiome from chemotherapy and antibiotics with unclear consequences. In this review, the authors have examined the evidence of the role of the microbiome in pediatric hematology/oncology, discussed how the microbiome may be modulated, and suggested key questions in need of further exploration.     

SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN: Path to the realization of biomarker-guided precision oncology in advanced solid tumors

Comprehensive genomic profiling enables the detection of genomic biomarkers in advanced solid tumors. However, efficient patient screening for the success of precision oncology remains challenging due to substantial barriers, such as genotyping costs and accessibility to matched therapies. To address these challenges, we launched GI-SCREEN, a nationwide gastrointestinal cancer genomic screening project within the SCRUM-Japan network in 2015 with the specific purpose of matching patients with a diverse portfolio of affiliated interventional targeted therapy trials. Subsequently, we initiated the molecular profiling projects GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2, which incorporate tissue and plasma multiomics approaches to accurately identify patients with advanced solid tumors who would benefit from matched therapies. These projects have led to a significant increase in patient participation in targeted clinical trials and the approval of several therapeutics and companion diagnostics. Additionally, clinicogenomic analyses utilizing the SCRUM-Japan database have provided new insights into the molecular mechanisms of advanced solid tumors. In this review, we describe the path to the realization of cancer precision medicine for patients with advanced solid tumors based on the SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN platforms.     

Characteristics of pediatric chemotherapy medication errors in a national error reporting database

BACKGROUND: Little is known regarding chemotherapy medication errors in pediatrics despite studies suggesting high rates of overall pediatric medication errors. In this study, the authors examined patterns in pediatric chemotherapy errors. METHODS: The authors queried the United States Pharmacopeia MEDMARX database, a national, voluntary, Internet-accessible error reporting system, for all error reports from 1999 through 2004 that involved chemotherapy medications and patients aged <18 years. RESULTS: Of the 310 pediatric chemotherapy error reports, 85% reached the patient, and 15.6% required additional patient monitoring or therapeutic intervention. Forty-eight percent of errors originated in the administering phase of medication delivery, and 30% originated in the drug-dispensing phase. Of the 387 medications cited, 39.5% were antimetabolites, 14.0% were alkylating agents, 9.3% were anthracyclines, and 9.3% were topoisomerase inhibitors. The most commonly involved chemotherapeutic agents were methotrexate (15.3%), cytarabine (12.1%), and etoposide (8.3%). The most common error types were improper dose/quantity (22.9% of 327 cited error types), wrong time (22.6%), omission error (14.1%), and wrong administration technique/wrong route (12.2%). The most common error causes were performance deficit (41.3% of 547 cited error causes), equipment and medication delivery devices (12.4%), communication (8.8%), knowledge deficit (6.8%), and written order errors (5.5%). Four of the 5 most serious errors occurred at community hospitals. CONCLUSIONS: Pediatric chemotherapy errors often reached the patient, potentially were harmful, and differed in quality between outpatient and inpatient areas. This study indicated which chemotherapeutic agents most often were involved in errors and that administering errors were common. Investigation is needed regarding targeted medication administration safeguards for these high-risk medications.     

Characteristics and outcome of pediatric patients enrolled in phase I oncology trials

PURPOSE: To describe the characteristics of pediatric subjects who enroll in phase I trials, to determine the associations between pre-enrollment characteristics and the risk for toxicity, and to analyze response and survival outcomes. EXPERIMENTAL DESIGN: Pre-enrollment characteristics and study outcomes were retrospectively analyzed for children with refractory solid tumors treated in one of 16 phase I trials with similar eligibility criteria at the National Cancer Institute between 1992 and 2005. RESULTS: The 262 subjects analyzed had received a median of two (range, 0-9) prior chemotherapy regimens, and were on one (range, 0-12) concomitant medication. The Eastern Cooperative Oncology Group performance status scores for subjects were 0 (29%), 1 (48%), and 2 (19%); 19% had received a prior stem cell transplantation and 73% had received prior radiation. Approximately 90% of subjects were evaluable for the primary trial endpoints (toxicity and pharmacokinetics). Seventeen percent of subjects experienced a dose-limiting toxicity (DLT), 5% discontinued the study drug because of toxicity, and a drug-related death occurred in one subject (0.4%). Variables associated with a higher risk for developing a DLT, by multiple logistic regression analysis, were drug dose and prior radiation, for myelosuppressive agents, and drug dose and performance status, for nonmyelosuppressive agents. The complete and partial response rate was 4%; however, 17% of subjects had stable disease (received three or more cycles). The median overall survival time from the time of enrollment was five months. CONCLUSIONS: Primary trial objectives are achieved in approximately 90% of subjects with the standard phase I trial design and eligibility criteria despite the intensification of frontline and salvage therapies in pediatric subjects with cancer.     

Social adjustment and repressive adaptive style in survivors of pediatric cancer

Purpose: The aim of the study was to explore the relationship between repressive adaptive style and self-reports of social adjustment in survivors of pediatric cancer compared to their siblings. We hypothesized that there would be a greater proportion of repressors among survivors of pediatric cancer compared to siblings, and that repressive adaptive style would be significantly associated with more positive self-reports of social adjustment. Methods: We utilized a cross-sectional approach. Seventy-seven families participated. Survivors of pediatric cancer (n = 77, 48% male; 8–18 years of age) and one sibling (n = 50, 48% male; 8–18 years of age) completed measures assessing repressive adaptive style and social adjustment. As well, one parent from each family completed a socio-demographic questionnaire. Questionnaire packages were mailed to eligible families who agreed to participate, and were mailed back to investigators in a pre-addressed, pre-stamped envelope. Results: Chi-square analyses revealed there was no significant difference in the proportion of repressors among survivors and siblings. Social adjustment scores were subjected to a two (group: survivor, sibling) by two (repressor, nonrepressor) ANCOVA with gender and age as covariates. There was a significant main effect of repressive adaptive style (F = 5.69, p < .05, η² = 0.05) with a modest effect. Survivors and siblings with a repressive style reported significantly higher social adjustment scores (M = 106.91, SD = 11.69) compared to nonrepressors (M = 99.57, SD = 13.45). Conclusions: Repressive adaptive style explains some of the variance in survivors and siblings' self-reports of social adjustment. Future research should aim to better understand the role of the repressive adaptive style in survivors and siblings of children with cancer.     

Feasibility of clinical psychosocial screening in pediatric oncology: Implementing the PAT2.0

ABSTRACT

This study examined the feasibility of implementing the Psychosocial Assessment Tool (PAT2.0) from the perspectives of families and health-care providers (HCPs). PAT2.0 data were collected from 104 families. Individual and focus group interviews were conducted with HCPs. Parents reported that the PAT2.0 was brief and easy to complete. HCPs' perspectives on the utility of the PAT2.0 were mixed and varied according to clinical roles. A major perceived benefit was the PAT2.0 as a communication tool. Barriers included timing and an increased workload for social workers. Psychosocial screening represents a significant practice change for oncology HCPs and is an important area of ongoing research.