Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma

Background Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. Methods We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. Results The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. Conclusions We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

TGFβ signaling modifies hematopoietic acute inflammatory response to drive bone marrow failure

Bone marrow failure syndromes (BMF) are characterized by ineffective hematopoiesis due to impaired fitness of hematopoietic stem cells (HSC). BMFs can be acquired during bone marrow stress or innate are associated with driver genetic mutations. BMFs are at higher risks of developing secondary neoplasms, including myelodysplastic syndromes and leukemia. Despite the identification of genetic driver mutations, the hematopoietic presentation of the disease is quite heterogeneous raising the possibility that non-genetic factors contribute to the pathogenesis of the disease. The role of inflammation has emerged as an important contributing factors, but remain to be understood in detail. In this study, we examined the effect of increased TGFβ signaling in combination or not with an acute innate immune challenge using polyinosinc:polycytidilic acid (pIC) on the hematopoietic system without genetic mutations. We show that acute rounds of pIC alone drive a benign age-related myeloid cell expansion, increased TGFβ signaling alone causes a modest anemia on old mice. In sharp contrast, increased TGFβ signaling plus acute pIC challenge result in chronic pancytopenia, expanded hematopoietic stem and progenitor pools, and increased bone marrow dysplasia 3-4 months after stress, phenotypes similar to human bone marrow failure syndromes. Mechanistically, this disease phenotype is uniquely associated with increased mitochondrial content, increased reactive oxygen species and enhanced caspase-1 activity. Our results suggest that chronic increased TGFβ signaling modifies the memory of an acute immune response to drive bone marrow failure without the need for pre-existing genetic insult. Hence, non-genetic factors in combination are sufficient to drive bone marrow failure.

Restoration of the immune function as a complementary strategy to treat Chronic Lymphocytic Leukemia effectively

Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by uncontrolled proliferation of B-cells and severe immune dysfunction. Chemo(immuno)therapies (CIT) have traditionally aimed to reduce tumor burden without fully understanding their effects on the immune system. As a consequence, CIT are usually associated with higher risk of infections, secondary neoplasms and autoimmune disorders. A better understanding of the biology of the disease has led to the development of therapeutic strategies which not only act against malignant B-cells but also reactivate and enhance the patient’s own anti-tumor immune response. Here, we review the current understanding of the underlying interplay between the malignant cells and non-malignant immune cells that may promote tumor survival and proliferation. In addition, we review the available evidence on how different treatment options for CLL including CIT regimens, small molecular inhibitors (i.e, BTK inhibitors, PI3K inhibitors, BCL-2 inhibitors) and T-cell therapies, affect the immune system and their clinical consequences. Finally, we propose that a dual therapeutic approach, acting directly against malignant B-cells and restoring the immune function is clinically relevant and should be considered when developing future strategies to treat patients with CLL.

An Analysis of the Social and Economic Costs of Breast Cancer in Italy

Background: Breast cancer is the most prevalent cancer affecting women and it represents an important economic burden. The aim of this study was to estimate the socio-economic burden of breast cancer (BC) in Italy both from the National Health Service (NHS) and the government perspectives (costs borne by the social security system). Methods: The economic analysis was based on the costs incurred by the NHS from 2008 to 2016 (direct costs related to hospitalizations) and by the National Social Security Institute (INPS) from 2009 to 2015 (costs of social security benefits) for patients with breast cancer. The analysis was based on the Hospital Information System (HIS) and Disability Insurance Awards databases. For both databases, patients affected by a malignant neoplasm of the female breast, carcinoma in situ, or secondary malignant neoplasm of the breast were considered. Results: Results show that more than 75,000 women were hospitalized for breast cancer every year, with an overall cost for hospitalization of about €300 million per year. From the Social Security analysis, a number of 29,000 beneficiaries each year was estimated. Considering per patient social costs, breast cancer at the primary stage cost €8828 per year, while secondary neoplasms cost €9780, with an average total economic burden of €257 million per year. Conclusions: This analysis focused on the economic impact of breast cancer in Italy, showing that an advanced stage of the disease was associated with a higher cost.

Safety of growth hormone (GH) treatment in GH deficient children and adults treated for cancer and non-malignant intracranial tumors—a review of research and clinical practice

Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking.

Real-world Evidence for Preventive Effects of Statins on Cancer Incidence: A Trans-Atlantic Analysis

Background: Numerous clinical trials have considered the potential linkages between statins and cancer. Despite some evidence for reduced mortality associated with statin use, the results thus far have been somewhat inconclusive and not easily comparable, thus hampering the emergence of a consensus. We suspect that this uncertainty would be reduced, and greater clarity achieved (e.g. regarding clinical best practices and standards-of-care), were we to have a reliable, causal biomarker that could help identify those individual patients who might benefit from statin use during cancer treatment. Methods and Findings: In the joint experimental and statistical analysis reported here, we assessed the inhibitory potential of various statins on the expression of a tumor enhancer known as MACC1, taking into account the molecular functions of this key metastasis-associated protein. To assess any effects of statins in cancer prevention (observationally), we also performed a retrospective, two-center, nested case-control study, focusing on medical centers in Berlin, Germany and Virginia, USA. Among nearly a half-million patient visits, over a decade-long period, cancer patients were identified and analyzed in comparison to patients without cancer diagnoses. Odds ratios (OR) and hazard ratios (HR) for cancer were computed for patients with and without statin intake, accounting for potential confounders. Finally, we also extended these analyses of our trans-Atlantic cohort by utilizing real-world data from 132,072 cancer patients with statins available on the TriNetX platform. Experimental work revealed that statins inhibit MACC1 mRNA levels and protein expression, resulting in reduced MACC1-induced phenotypic functions, such as motility and proliferation. Moreover, we found that statins restrict colorectal cancer (CRC) growth and metastasis in xenografted mice. The cohort data that we gathered at the German and U.S. centers enabled analysis of 53,113 cancer patients and matched controls. These were extracted, aggregated, and 1:1 matched (by age/gender) in order to build propensity-score matched sub-cohorts, to mitigate confounder bias. Based on this real-world evidence (RWE), we found that atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin were associated with a 50% reduced overall risk for developing cancer (OR 0.5, CI 0.48-0.51). The strongest association of reduced cancer risk was found for (i) liver cancer (OR 0.35, 0.29-0.43), (ii) secondary neoplasms of respiratory and digestive organs (OR 0.42, 0.34-0.45), and (iii) colorectal cancer (OR 0.44, 0.39-0.5). The effect of atorvastatin (OR 0.3, 0.28-0.32) exceeded other considered statins, even after exclusion of aspirin as the strongest confounder (OR 0.63, CI 0.57-0.7). Additionally, we note that those patients taking statins have a 38% decreased risk of death (HR 0.64, 0.48-0.86). Conclusions: Our data, which offer evidence for cancer-preventative and anti-metastatic effects of statins, lead us to suggest that these medications should be considered in treating some types of cancers. In addition, MACC1 may serve as a potentially helpful biomarker for purposes of patient stratification (and personalized treatment). A more definitive test of these proposed ideas could come from prospective, randomized clinical trials.

Recurrence of Adult Granulosa Cell Tumor in the Greater Omentum 11 Years after Surgery

Adult-type ovarian granulosa cell tumors (AGCTs) are very rare tumors that account for <5% of all ovarian carcinomas. AGCTs have low malignancy potential and rarely metastasize 5–30 years after the initial diagnosis. Because time has passed from the first surgery and because recurrence develops in various locations, the differential diagnosis is difficult. In particular, tumors developing in the greater omentum are encountered rarely, and it is necessary to carefully consider the differential diagnosis, including primary and secondary neoplasms. Although CT is useful to detect omental tumors, the diagnosis requires invasive procedures. We report a case of AGCT recurrence in the greater omentum that was resected during laparoscopic cholecystectomy. A patient visited our hospital with right-sided abdominal pain. The CT revealed gallbladder stones, a ureteral stone, and a right abdominal mass. The diagnosis of the abdominal tumor was difficult on the basis of blood biochemical testing, gastrointestinal endoscopy, or image inspection. Although the patient underwent several previous surgeries and there were no findings of malignancy with positron emission tomography, we chose to resect the tumor for combined diagnosis and treatment during laparoscopic cholecystectomy. Intraoperative findings showed that the tumor originated from the greater omentum, and the tumor was diagnosed as AGCT recurrence by pathology. A recurrence of AGCT in the greater omentum is very rare, and laparoscopic surgery was safe and useful for resection, in our case.

Analysis of Patients Undergoing Splenectomy for Spleen Masses

Aims: Spleen masses, which are discovered on imaging studies, usually create difficulty in diagnosis and treatment. Except for lymphomas involving the spleen, primary and secondary neoplasms are rare and discovered by chance. This study analyses a series of splenectomies in a surgical clinic to evaluate the management of incidentally diagnosed splenic masses. Study Design: This retrospective study included patients operated for spleen masses between 2010 and 2021. Patients with a history of lymphoproliferative disease and splenectomy performed as part of a larger resection were excluded. Methodology: The patients were divided into three groups, i.e. cystic, benign and malignant, based on the results of pathological examinations. The groups were compared in terms of age, gender, tumor size, and previous history of malignancy. Results: Splenectomy was performed in 512 patients in 11 years, 62 of whom had solid and cystic lesions detected on imaging. Thirty-five patients (56,5%) were female and the median age was 40 years (range: 18-80 years). Forty-four patients (71%) had distinct symptoms. Radiological evaluations of all the patients were made. Diagnostic biopsy could not be performed in any of the patients. The final pathological examination showed cysts in 38 patients (61,3%), benign lesions in nine patients (14,5%) and malignant lesions in 15 patients (24,2%). Out of 15 patients with malignant lesions, one patient had Hodgkin’s lymphoma, four patients had diffuse large B cell lymphoma and ten patients had metastatic tumors. There was a significant difference in age between the groups and the malignant group was older (p = 0.017). The size of the lesions also significantly differed and the malignant lesions had a significantly smaller diameter (p = 0.014). A significantly higher rate of the malignant group had a previous history of cancer (p˂0,001). Conclusion: Spleen neoplasms are masses that are difficult to diagnose. Most of them are asymptomatic and are found after splenectomies by coincidence. Splenectomy can be utilized as both a diagnostic and curative method. It should be kept in mind that the lesions detected in the spleen in patients with a history of malignancy can be metastatic.

Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies

Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry. Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms. Circulating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies. Our data suggest that expression of CaSR variants at rs1801725 is associated with a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part to cancer-induced hypercalcemia and/or tumor immune suppression. Screening of patients for CASR variants at this locus may lead to improved management of high calcium associated tumor progression.

Risk of secondary neoplasms after external-beam radiation therapy treatment of pediatric low-grade gliomas: a SEER analysis, 1973–2015

OBJECTIVE Although past studies have associated external-beam radiation therapy (EBRT) with higher incidences of secondary neoplasms (SNs), its effect on SN development from pediatric low-grade gliomas (LGGs), defined as WHO grade I and II gliomas of astrocytic or oligodendrocytic origin, is not well understood. Utilizing a national cancer registry, the authors sought to characterize the risk of SN development after EBRT treatment of pediatric LGG. METHODS A total of 1245 pediatric patient (aged 0–17 years) records from 1973 to 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable subdistribution hazard regression models were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Cumulative incidence analyses measured the time to, and rate of, SN development, stratified by receipt of EBRT and controlled for competing mortality risk. The Fine and Gray semiparametric model was used to estimate future SN risk in EBRT- and non–EBRT-treated pediatric patients. RESULTS In this study, 366 patients received EBRT and 879 did not. Forty-six patients developed SNs after an LGG diagnosis, and 27 of these patients received EBRT (OR 3.61, 95% CI 1.90–6.95; p < 0.001). For patients alive 30 years from the initial LGG diagnosis, the absolute risk of SN development in the EBRT-treated cohort was 12.61% (95% CI 8.31–13.00) compared with 4.99% (95% CI 4.38–12.23) in the non–EBRT-treated cohort (p = 0.013). Cumulative incidence curves that were adjusted for competing events still demonstrated higher rates of SN development in the EBRT-treated patients with LGGs. After matching across available covariates and again adjusting for the competing risk of mortality, a clear association between EBRT and SN development remained (subhazard ratio 2.26, 95% CI 1.21–4.20; p = 0.010). CONCLUSIONS Radiation therapy was associated with an increased risk of future SNs for pediatric patients surviving LGGs. These data suggest that the long-term implications of EBRT should be considered when making treatment decisions for this patient population