Cancer Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients’ peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

An Analysis of 20 Cases of Radiation-Associated Sarcoma, Including 4 Cases Treated by Carbon Ion Radiotherapy

Introduction Radiation-associated sarcoma (RAS) is one of the most life-threatening complications associated with the treatment of malignant neoplasms. Because all RAS patients have a history of radiotherapy, there have been no effective treatment options when RAS is not completely resected. Methods We retrospectively reviewed 20 RAS patients, including 4 unresectable cases treated by carbon ion radiotherapy (CIRT). Results The primary diseases targeted by radiotherapy included malignant lymphoma (n=4), cervical cancer (n=3), pharyngeal cancer (n=3), breast cancer (n=2), lung cancer (n=1), rectal cancer (n=1), maxillary cancer (n=1), synovial sarcoma (n=1), and benign neoplasms (n=4). The histological diagnoses of RAS included osteosarcoma (n=8), leiomyosarcoma (n=3), undifferentiated pleomorphic sarcoma (n=3), rhabdomyosarcoma (n=1), angiosarcoma (n=1), malignant peripheral nerve sheath tumor (n=1), spindle cell sarcoma NOS (n=1), and sarcoma not further specified (n=2). The median survival time from the diagnosis of RAS was 26 months. Eleven patients underwent surgery. Five of these patients achieved a continuous disease free status or showed no evidence disease. Four patients underwent CIRT. One of these patients with leiomyosarcoma achieved a continuous disease free status, and the other patient with osteosarcoma achieved a partial response. On the other hand, 2 patients experienced Grade 3 toxicities that required surgical treatment. Conclusion RAS originates from various types of diseases that are treated by radiotherapy and shows diverse pathological features. Complete resection achieves a good prognosis. CIRT can be an effective and feasible option for unresectable RAS.

Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

Evaluation of Clinical Significance of Lymphovascular Space Invasion in Stage IA Endometrial Cancer

Introduction: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. Methods: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. Results: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and four patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and -negative groups (P=0.07 and P=0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (P=0.11 and P=0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (P=0.92 and P=0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. Conclusion: LVSI was not a prognostic factor of not only stage IA endometrial cancer, but also stage IA low-grade cancer.

Comparison of the Modified IHC4 Score and 21-Gene Recurrence Score Assay in Patients with Estrogen Receptor-Positive Breast Cancer

Introduction: Not only the 21-gene recurrence score (RS) assay but also online prognostic tools and immunohistochemical prognostic models predict chemotherapy benefits for women with early breast cancer. Multi-gene assays, including Oncotype DX, are expensive and not covered by insurance in some countries. Methods: In this study, we retrospectively analyzed a series of 155 patients with estrogen receptor-positive primary breast cancer for whom an Oncotype DX assay was performed between January 2016 and August 2021. The patients’ modified immunohistochemical marker (mIHC4) scores were calculated on the basis of their pathological reports. The correlations of the RS with the online tool PREDICT and mIHC4 scores were evaluated. Results: Of the patients, 43.9% were premenopausal, 147 (94.8%) had T1 or T2 tumor, and 55.5% had no positive lymph nodes. Low (0–10), intermediate (11–25), and high RSs (26–100) were obtained in 16.1%, 61.9%, and 21.9% of the patients, respectively. The RS showed no correlation with the PREDICT score (r = 0.2720) but correlated with the mIHC4 score (r = 0.6356). In addition, a stronger correlation was observed in the patients with no node involvement and in the postmenopausal patients (r = 0.6609 and r = 0.7277, respectively). Conclusions: A relatively strong correlation was observed between the RS and the mIHC4 score. The mIHC4 score is a potentially easy and useful tool to guide adjuvant chemotherapy decision making especially for postmenopausal patients with no node involvement if a genomic test could not be performed for some reason.

Post-Progression Treatments after Palbociclib plus Endocrine Therapy in HR+/HER2– Metastatic Breast Cancer Patients: What Is the Better Choice?

Background: To date, a consensus has not yet been reached about the therapy sequence after disease progression (PD) on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer (MBC). Objectives: The present study assesses, in a real-world setting, the activity of different subsequent therapies in patients who experienced a PD on palbociclib (P) + endocrine therapy (ET), to evaluate the best therapy sequence. Methods: This is a multicenter retrospective observational study. Records of consecutive HR+/HER2- MBC patients from January 2017 to May 2019 were reviewed. The primary endpoint was the evaluation of progression-free survival (PFS) according to subsequent treatment lines after progression on P+ET. Toxicity data were also collected. Results: The outcomes were analyzed in 89 MBC patients that had progressed on previous P+ET: 17 patients were on hormone therapy (HT) and 31 patients on chemotherapy (CT) as second-line treatments; seven patients were on HT and 34 on CT as third-line therapies. PFS of patients treated with HT as second-line therapy is significantly improved when compared with patients treated with CT (p=0.01). Considering third-line settings, the difference in PFS was not statistically different between HT and CT. A better outcome in terms of toxicity is observed among HT patients for both second- and third-line therapies. Conclusions: patients who were progressive on P+ET could still benefit from a subsequent ET. In patients who experienced a good efficacy from prior ET, without visceral metastatic sites, HT seems the most suitable option, when compared to CT, also in terms of safety.

Soluble PD-L1 Concentration Is Proportional to the Expression of PD-L1 in Tissue and Is Associated with a Poor Prognosis in Esophageal Squamous Cell Carcinoma

<b><i>Introduction:</i></b> We determined the soluble programmed cell death-1 ligand-1 (sPD-L1) concentration in patients with esophageal squamous cell carcinoma (ESCC), and confirmed the PD-L1 expression in resected specimens. <b><i>Methods:</i></b> Blood samples were collected from 73 patients with histologically proven ESCC. The serum levels of sPD-L1 were measured using an enzyme-linked immunosorbent assay. The correlations between the sPD-L1 concentration and the expression of PD-L1 in tumor specimens and tumor depth, lymph node metastasis, disease stage, and various laboratory data were assessed. <b><i>Results:</i></b> sPD-L1 levels in patients with high PD-L1 expression levels in tumor tissue were significantly higher than in patients with low PD-L1 expression levels (<i>p</i> = 0.042). The OS of the sPD-L1-high group was significantly worse than that of the low group (<i>p</i> = 0.028). Similarly, patients in whom a tissue specimen was PD-L1-positive group showed significantly poorer OS. <b><i>Conclusion:</i></b> The sPD-L1 concentration was correlated with the PD-L1 expression in tissues. Patients with PD-L1-positive tissue specimens showed significantly higher sPD-L1 levels in comparison to PD-L1-negative cases. Furthermore, patients with high sPD-L1 expression levels had a significantly worse prognosis than those with low sPD-L1 expression levels, and patients with a PD-L1-positive tissue specimen had a significantly worse prognosis than patients in whom the tissue specimen showed a low PD-L1 expression level.

The Impact of Routine Molecular Screening for SARS-CoV-2 in Patients Receiving Anti-Cancer Therapy: An Interim Analysis of the Observational COICA Study

Introduction: Cancer aggravates COVID-19 prognosis. Nosocomial transmission of SARS-CoV-2 is particularly frequent in cancer patients, who need to attend hospitals regularly. Since March, 2020, all cancer patients having access to the Oncology Unit at the “Andrea Tortora” Hospital (Pagani, Salerno - referred to as “the Hospital”) as inpatients or outpatients receiving intravenous therapy have been screened for SARS-CoV-2 using RT-PCR nasal swab. The ongoing COICA (COVID-19 Infection in Cancer Patients) study is an ambispective, multicenter, observational study designed to assess the prognosis of SARS-CoV-2 infection in cancer patients. The aim of the study presented here was to explore potential differences in COVID-19 related outcomes among screening-detected vs. non-screening detected SARS-CoV-2 infected patients. Methods: The COICA study enrolled cancer patients who had received any anti-cancer systemic therapy within 3 months since the day they tested positive for SARS-CoV-2 on RT-PCR. The target accrual is 128 patients, and the study was approved by the competent Ethics Committee. Only the sub-group of patients enrolled at the Hospital was considered in this unplanned interim analysis. Logistic regression analysis was used to evaluate the association of screening-based vs. non screening based diagnosis. Results: Since March, 15 2020 until August, 15 2021, a total of 931 outpatients and 230 inpatients were repeatedly screened for SARS-CoV-2 using RT-PCR nasal swab at the Hospital. Among these, 71 asymptomatic patients were positive on routine screening and five patients were positive for SARS-CoV-2 outside the institutional screening. Seven patients died because of COVID-19. At univariate analysis, non-screening vs. screening detected SARS-CoV-2 infection was associated with significantly higher odds of O2 Therapy (OR= 16.2; 95% CI =2.2 to 117.1; p =0.006),hospital admission (OR=31.5; 95% CI=3.1 to 317.8; p=0.003 ), admission to ICU (OR=23.0; 95% CI = 2.4 to 223.8; p= 0.007) and Death (OR=8.8; 95%CI= 1.2 to 65.5; p =0.034). Conclusion: Routine screening with RT-PCR may represent a feasible and effective strategy in reducing viral circulation and possibly COVID-19 mortality in patients with active cancer having repeated access to hospital facilities.

Prognoses in Pathologically Confirmed T1 Lower Rectal Cancer Patients with or without Preoperative Therapy: An Analysis Using the Surveillance, Epidemiology, and End Results Database

Introduction Preoperative chemoradiotherapy (CRT) is the standard therapy for downstaging in locally advanced lower rectal cancer. However, it remains unclear whether rectal cancers down-staged by preoperative therapy show similar prognoses to those of the same stage without preoperative therapy. We previously demonstrated that preoperative CRT did not affect prognosis of rectal cancer with pathological T1N0 (pT1N0) stage in a single institute. Here, using a larger dataset, we compared prognoses of (y)pT1 rectal cancer stratified by the use of preoperative therapy and analyzed prognostic factors. Methods Cases of pT1N0 rectal cancer, registered between 2004 and 2016, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized as the ‘ypT1 group’ if they had undergone preoperative therapy before surgery or as the ‘pT1 group’ if they had undergone surgery alone. overall survival (OS) and cancer-specific survival (CSS) between these groups of patients was compared. Factors associated with CSS and OS were identified by univariate and multivariate analyses. Results Among 3,757 eligible patients, ypT1 and pT1 groups comprised 720 and 3,037 patients, respectively. While ypT1 patients showed poorer CSS than ypT1 patients, there was no significant difference in OS. Preoperative therapy was not an independent prognostic factor for CSS or OS. Multivariate analysis identified age and histological type as significant factors associated with CSS. Sex, age, race, and number of lymph nodes dissected were identified as significant factors associated with OS. Conclusions Prognosis among patients with (y)p T1N0 rectal cancer was similar irrespective of whether they underwent preoperative therapy, which is consistent with our previous observations.

Systemic Immune-Inflammatory Index Association with Survival in Patients Undergoing Trimodality Therapy for Lung Cancer

Purpose: The systemic immune-inflammation index (SII) is correlated with patient survival in various solid malignancies including non-small cell lung cancer (NSCLC). However, limited information is available on the prognostic implication of SII in patients undergoing trimodality therapy for stage III Non-Small Cell Lung Carcinoma (NSCLC). Methods: At our institution, 81 patients underwent curative intent trimodality therapy (neoadjuvant chemoradiotherapy followed by surgical resection) for stage III NSCLC from 2004-2019. SII was calculated at the time of diagnosis as platelet count × neutrophil count/lymphocyte count. Chi-squared analysis was used to compare categorical variables. A Kaplan-Meier analysis was performed to estimate disease free survival (DFS), overall survival (OS), and freedom from recurrence (FFR) rates, with Cox regression used to determine absolute hazards. Results: Patients underwent neoadjuvant radiation therapy to a median dose of 4500 cGy concurrent with a median of 3 cycles of chemotherapy (most commonly carboplatin and paclitaxel) followed by surgical resection (86.4% lobectomy and 13.6% pneumonectomy) with mediastinal lymph node dissection. At a median follow-up of 68.4 months, a low SII (<1260) at diagnosis was independently associated with an improved OS (HR: 0.448, p=0.004), DFS (HR: 0.366, p<0.001), and FFR (HR: 0.325, p=0.002). Conclusions: We identified that a low SII was associated with improved OS, DFS, and FFR in patients undergoing trimodality therapy for stage III NSCLC. The interplay of the immune system and lung cancer outcomes remains an active area of investigation for which further study is warranted.