Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Reduced healthcare access contributes to delay of care in endometrial cancer.

OBJECTIVE: We aimed to characterize delays to care in patients with endometrioid endometrial cancer and the role healthcare access plays in these delays. METHODS: A chart review was performed of patients with endometrioid endometrial cancer who presented with postmenopausal bleeding at a diverse, urban medical center between 2006 and 2018. The time from symptom onset to treatment was abstracted from the medical record. This interval was subdivided to assess for delay to presentation, delay to diagnosis, and delay to treatment. RESULTS: We identified 484 patients who met the inclusion criteria. The median time from symptom onset to treatment was 4 months with an interquartile range of 2 to 8 months. Most patients had stage I disease at diagnosis (88.6%). There was no significant difference in race/ethnicity or disease stage at time of diagnosis between different groups. Patients who had not seen a primary care physician or general obstetrician-gynecologist in the year before symptom onset were more likely to have significantly delayed care (27.7% vs 14.3%, p = 0.02) and extrauterine disease (20.2% vs 4.9%, p < 0.01) compared to those with established care. Black and Hispanic patients were more likely to experience significant delays from initial biopsy to diagnosis. CONCLUSIONS: Delays exist in the evaluation of endometrial cancer. This delay is most pronounced in patients without an established outpatient primary care provider or obstetrician-gynecologist.

Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration.

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Screening for Chemotherapy-induced Peripheral Neuropathy and Utilization of Physical Therapy in Pediatric Patients Receiving Treatment for Hematologic Malignancies.

Physical therapy (PT) has been shown to be a helpful intervention in the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Our aim was to screen for CIPN in patients with hematologic malignancies receiving vincristine chemotherapy and obtain a baseline assessment on the percentage of patients utilizing PT in the treatment of CIPN. A retrospective review of surveys administered to parents and patients regarding the severity of peripheral neuropathy symptoms from October 2016 through March 2018 was conducted. Of 116 patients, a total of 102 patients (67 male and 35 female; 4 to 10 y of age, N=63; 11 to 15 y of age, N=19; 16 to 20 y of age, N=20) were eligible for the study, with 67.6% (N=69) reporting symptoms of CIPN. Of these patients, 16.7% scored 4 or greater on the surveys, suggesting clinically severe CIPN. Common parental concerns included decreased strength, difficulty walking up stairs, tripping, and foot drops. Approximately 55.1% of the 69 patients who reported CIPN symptoms were referred to outpatient PT, while 44.9% were not referred. A simple survey consisting of 4 questions that only took several minutes to administer was capable of identifying CIPN in 67.6% of patients receiving vincristine chemotherapy.

Improving vitamin D testing and supplementation in children with newly diagnosed cancer: A quality improvement initiative at Rady Children's Hospital San Diego.

BACKGROUND: Vitamin D deficiency and insufficiency have been associated with poorer health outcomes. Children with cancer are at high risk for vitamin D deficiency and insufficiency. At our institution, we identified high variability in vitamin D testing and supplementation in this population. Of those tested, 65% were vitamin D deficient/insufficient. We conducted a quality improvement (QI) initiative with aim to improve vitamin D testing and supplementation among children aged 2-18 years with newly diagnosed cancer to ≥80% over 6 months. METHODS: An inter-professional team reviewed baseline data, then developed and implemented interventions using Plan-Do-Study-Act (PDSA) cycles. Barriers were identified using QI tools, including lack of automated triggers for testing and inconsistent supplementation criteria and follow-up testing post supplementation. Interventions included an institutional vitamin D guideline, clinical decision-making tree for vitamin D deficiency, insufficiency and sufficiency, electronic medical record triggers, and automated testing options. RESULTS: Baseline: N = 26 patients, four (15%) had baseline vitamin D testing; two (8%) received appropriate supplementation. Postintervention: N = 33 patients; 32 (97%) had baseline vitamin D testing; 33 (100%) received appropriate supplementation and completed follow-up testing timely (6-8 weeks post supplementation). Change was sustained over 24 months. CONCLUSIONS: We achieved and sustained our aim for vitamin D testing and supplementation in children with newly diagnosed cancer through inter-professional collaboration of hematology/oncology, endocrinology, hospital medicine, pharmacy, nursing, and information technology. Future PDSA cycles will address patient compliance with vitamin D supplementation and impact on patients' vitamin D levels.

The Application of Next-generation Sequencing Tumor Molecular Profiling in the Diagnosis and Management of a Case of Acute Myelogenous Leukemia With MLL-PTD in a Pediatric Heart Transplant Recipient.

A 6-year-old girl with a history of heart transplantation was diagnosed with myelodysplastic syndrome, which progressed to acute myelogenous leukemia. Comprehensive genomic profiling of her tumor discovered an MLL-PTD (partial tandem duplication) and she received chemotherapy and a hematopoietic stem cell transplant (HSCT). She subsequently relapsed and tumor molecular profiling was repeated, revealing 2 new potentially targetable mutations (FLT3 and IDH2). A novel treatment regimen targeting these mutations with sorafenib and azacitidine without using cytotoxic chemotherapy produced remission and she subsequently pursued a second HSCT. She remains disease-free 17 months after HSCT. This case report demonstrates how repeated tumor molecular profiling provided novel actionable information for the diagnosis and management at 2 timepoints.

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer.

Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.

Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia.

BACKGROUND: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML). METHODS: To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2 ) before and in combination with fludarabine and cytarabine. RESULTS: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status. CONCLUSIONS: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.

Risk factors associated with delayed discharge following robotic assisted surgery for gynecologic malignancy.

BACKGROUND: The risk factors for extended length of stay (LOS) have not been examined in a cohort of patients with complex social and medical barriers who undergo robotic assisted (RA) surgery for gynecologic malignancies. We sought to identify those patients with a LOS > 24 h after robotic surgery and the risk factors associated with delayed discharge. Then we aimed to develop a predictive model for clinical care and identify modifiable pre-operative risk factors. METHODS: After IRB approval, data was abstracted from medical records of all patients with a gynecologic malignancy who underwent a RA laparoscopic surgery from 2010 to 2015. Univariable and multivariable logistic regression was performed to identify independent risk factors associated with delayed discharge defined as LOS > 24 h. A multi-variable logistic regression model was performed using a stepwise backward selection for the final prediction model. All testing was two-sided and a p-value < 0.05 was considered statistically significant. RESULTS: Of the 406 eligible and evaluable patients, 194 (48%) had a LOS > 24 h. Age ≥ 60 years, a higher usage of narcotic medication, a longer surgical time, and a larger estimated blood loss were all associated with LOS > 24 h (p < 0.05). Many of these women had a social work consultation and went home with home care services despite no surgical or post-operative complications. Our prediction model has the potential to correctly classified 75% of the patients discharged within 24 h. CONCLUSIONS: The development of a pre-hospitalization risk stratification and anticipating the possible need for home care services pre-operatively shows promise as a strategy to decrease LOS in patients classified as high-risk. These findings warrant prospective validation through the use of this prediction model in our institution.

Acute Pancreatitis Associated With Cytarabine During the Treatment of Pediatric Acute Myeloid Leukemia.

Pancreatitis is a common complication of many pediatric oncology drugs - most commonly asparaginase, followed by pentamidine, mercaptopurine, corticosteroids, and trimethoprim-sulfamethoxazole. Cytarabine-associated pancreatitis is not often mentioned in the pediatric oncology literature. We report the case of a 10-year-old female with acute myeloid leukemia who developed cytarabine-associated pancreatitis.

Leiomyosarcoma in Birt-Hogg-Dubé Syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis characterized by benign cutaneous tumors (fibrofolliculomas, trichodiscomas, and acrochordons), basal lung cysts, pneumothoraces, and a 20% to 30% lifetime risk for renal cancer. There are isolated cases of other cancers in BHDS reported in the literature, including oncocytoma, rhabdomyoma, melanoma, thyroid cancer, meningioma, colon cancer, and breast cancer, but only the increased renal cancer risk has been substantiated. This is the case of a 9-year-old girl who presented with a leiomyosarcoma whose tumor genetic analysis showed FLCN c.365_372del, p.Arg122Leufs*8. She was diagnosed with BHDS when the same mutation was confirmed in her germline lymphocytes. This is the second known reported case of leiomyosarcoma in BHDS.

To test or not to test: genetic cancer predisposition testing in paediatric patients with cancer.

Genetic cancer predisposition testing in the paediatric population poses unique ethical dilemmas. Using the hypothetical example of a teenager with cancer with a high probability of having an underlying cancer predisposition syndrome, we discuss the ethical considerations that affect the decision-making process. Because legally these decisions are made by parents, genetic testing in paediatrics can remove a child's autonomy to preserve his or her own 'open future'. However, knowledge of results confirming a predisposition syndrome can potentially be beneficial in modifying treatment and surveillance plans and enabling at-risk family members to obtain cascade testing for themselves. Considering virtue ethics to envision the best characters of the patient, parents and healthcare providers can guide them to the better choice to test or not to test, with the ultimate goal of achieving the best outcome for survival and eudaimonia, human flourishing reliably sought out.

Healthcare access and adverse family impact among U.S. children ages 0-5 years by prematurity status.

BACKGROUND: Many children and their families are affected by premature birth. Yet, little is known about their healthcare access and adverse family impact during early childhood. This study aimed to (1) examine differences in healthcare access and adverse family impact among young children by prematurity status and (2) determine associations of healthcare access with adverse family impact among young children born prematurely. METHODS: This was a secondary analysis of cross-sectional 2016 and 2017 National Survey of Children's Health data. The sample included 19,482 U.S. children ages 0-5 years including 242 very low birthweight (VLBW) and 2205 low birthweight and/or preterm (LBW/PTB) children. Prematurity status was defined by VLBW (i.e., < 1500 g at birth) and LBW/PTB (i.e., 1500-2499 g at birth and/or born at < 37 weeks with or without LBW). Healthcare access measures were adequate health insurance, access to medical home, and developmental screening receipt. Adverse family impact measures were ≥ $1000 in annual out-of-pocket medical costs, having a parent cut-back or stop work, parental aggravation, maternal health not excellent, and paternal health not excellent. The relative risk of each healthcare access and adverse family impact measure was computed by prematurity status. Propensity weighted models were fit to estimate the average treatment effect of each healthcare access measure on each adverse family impact measure among children born prematurely (i.e., VLBW or LBW/PTB). RESULTS: Bivariate analysis results showed that VLBW and/or LBW/PTB children generally fared worse than other children in terms of medical home, having a parent cut-back or stop working, parental aggravation, and paternal health. Multivariable analysis results only showed, however, that VLBW children had a significantly higher risk than other children of having a parent cut-back or stop work. Adequate health insurance and medical home were each associated with reduced adjusted relative risk of ≥$1000 in annual out-of-pocket costs, having a parent cut-back or stop work, and parental aggravation among children born prematurely. CONCLUSIONS: This study's findings demonstrate better healthcare access is associated with reduced adverse family impact among U.S. children ages 0-5 years born prematurely. Population health initiatives should target children born prematurely and their families.

Association of Home Respiratory Equipment and Supply Use with Health Care Resource Utilization in Children.

OBJECTIVE: To compare health care use and spending in children using vs not using respiratory medical equipment and supplies (RMES). STUDY DESIGN: Cohort study of 20 352 children age 1-18 years continuously enrolled in Medicaid in 2013 from 12 states in the Truven Medicaid MarketScan Database; 7060 children using RMES were propensity score matched with 13 292 without RMES. Home RMES use was identified with Healthcare Common Procedure Coding System and International Classification of Diseases codes. RMES use was regressed on annual per-member-per-year Medicaid payments, adjusting for demographic and clinical characteristics, including underlying respiratory and other complex chronic conditions. RESULTS: Of children requiring RMES, 47% used oxygen, 28% suction, 22% noninvasive positive-pressure ventilation, 17% tracheostomy, 8% ventilator, 5% mechanical in-exsufflator, and 4% high-frequency chest wall oscillator. Most children (93%) using RMES had a chronic condition; 26% had ≥6. The median per-member-per-year payments in matched children with vs without RMES were $24 359 vs $13 949 (P < .001). In adjusted analyses, payment increased significantly (P < .001 for all) with mechanical in-exsufflator (+$2657), tracheostomy (+$6447), suction (+$7341), chest wall oscillator (+$8925), and ventilator (+$20 530). Those increased payments were greater than the increase associated with a coded respiratory chronic condition (+$2709). Hospital and home health care were responsible for the greatest differences in payment (+$3799 and +$3320, respectively) between children with and without RMES. CONCLUSION: The use of RMES is associated with high health care spending, especially with hospital and home health care. Population health initiatives in children may benefit from consideration of RMES in comprehensive risk assessment for health care spending.

Association of obesity with survival in patients with endometrial cancer.

BACKGROUND: Obesity confers an overall increased risk for development of endometrial cancer. However there are conflicting reports regarding the effect of obesity on patients' overall and disease specific survival. The purpose of this study was to evaluate the effect of obesity on survival in women with endometrial cancer. METHODS: After IRB approval, records of women with diagnosis and treatment of endometrial cancer from 1999 to 2016 were abstracted for histopathological, treatment and demographic data. Death was confirmed by query of the Social Security Death Index. Kaplan Meier survival curves and Cox regression modeling was performed with Stata version 14.0. RESULTS: Of 1732 evaluable patients, there were significant differences in age at diagnosis, histology (endometrioid versus non-endometrioid), stage, race, grade, hypertension, hyperlipidemia, diabetes, and treatment between normal weight, overweight, obese, and morbidly obese patients (p < 0.01). There was a linear association of younger age at diagnosis with increasing obesity (p < 0.01) R2 = 0.04. Younger age, endometrioid histology, lower stage, and statin use were independently associated with decreased hazard of death (p < 0.01). However, in stratified analysis of non-endometrioid histologies, patients with Stage 3 and 4 disease over the age of 65 showed a survival benefit for women associated with obesity (p = 0.02). CONCLUSIONS: Obesity is associated with younger age at diagnosis and earlier stage disease. Obesity is associated with improved disease specific survival for stage 3 and 4 non-endometrioid endometrial cancers.

Deep Vein Thrombosis in a Young, Healthy Baseball Catcher: A Case Report and Review of the Literature.

Venous thromboembolism is becoming increasingly recognized as a significant cause of morbidity and mortality in the hospitalized pediatric population. However, young healthy athletes can present with unique risk factors for deep vein thrombosis (DVT) that can be overlooked. Here we report a case of an adolescent male with no inherited risk factors or prior history of DVTs who developed a right femoral vein DVT in the context of playing catcher in baseball after recovering from a bout of streptococcal pharyngitis. We review the evidence that suggests that repetitive squatting-induced compression of the femoral vein can cause the venous stasis and endothelial microtrauma that contributed to the formation of this thrombus.

Treatment of Recurrent Refractory Pediatric Pre-B Acute Lymphoblastic Leukemia Using Inotuzumab Ozogamicin Monotherapy Resulting in CD22 Antigen Expression Loss as a Mechanism of Therapy Resistance.

BACKGROUND: Inotuzumab ozogamicin is a novel antibody-drug conjugate that targets CD22, a common antigen on pre-B acute lymphoblastic leukemia cells. OBSERVATIONS: A 7-year-old boy with pre-B acute lymphoblastic leukemia in his second relapse was given 2 cycles of inotuzumab ozogamicin. He responded morphologically with a negative bone marrow evaluation. However, he relapsed in cycle 3 of therapy with a loss of CD22 expression on his lymphoblast population. CONCLUSION: To our knowledge, this is the first published case of CD22 expression loss as a mechanism of therapy resistance for inotuzumab ozogamicin.

'I just need an opiate refill to get me through the weekend'.

In this article, we discuss the ethical dimensions for the prescribing behaviours of opioids for a chronic pain patient, a scenario commonly witnessed by many physicians. The opioid epidemic in the USA and Canada is well known, existing since the late 1990s, and individuals are suffering and dying as a result of the easy availability of prescription opioids. More recently, this problem has been seen outside of North America affecting individuals at similar rates in Australia and Europe. We argue that physicians are also confronted with an ethical crisis where a capitalist-consumerist society is contributing to this opioid crisis in which societal, legal and business interests push physicians to overprescribe opioids. Individual physicians often find themselves unequipped and unsupported in attempts to curb the prescribing of opioid medications and balance competing goals of alleviating pain against the judicious use of pain medications. Physicians, individually and as a community, must reclaim the ethical mantle of our profession, through a more nuanced understanding of autonomy and beneficence. Furthermore, physicians and the medical community at large have a fiduciary duty to patients and society to play a more active role in curbing the widespread distribution of opioids in our communities.

Correction to: Do Insurance Mandates Affect Racial Disparities in Outcomes for Children with Autism?

The original version of this article unfortunately contained a mistake in the analysis of the Tables 4 and 5.