The Loss of 1p as a Reliable Marker of Progression in a Child with Aggressive Meningioma: A 16-Year Follow-Up Case Report

<b><i>Background:</i></b> Here, we present the case of a 32-year-old female with a progressing history of meningioma for 16 years starting with an ethmoidal lesion in 2002. The initial tumor specimen of this patient showed a deletion of the short arm of chromosome 1 through a translocation between chromosomes 1 and 11 (t[1; 11]) as well as additional chromosomal aberrations, including partial or complete monosomy of chromosomes 2, 6, 7, 11, 13, and 22. These molecular characteristics were already known to be associated with an aggressive course of the disease, and the patient was, therefore, included in a strict follow-up regime. From 2003 to 2019, the patient suffered multiple relapses and consecutive tumor resections. <b><i>Methods:</i></b> Tumor specimen from 2017 was examined using a genome-wide methylation analysis as well as a whole-genome sequencing. <b><i>Results:</i></b> These analyses confirmed the findings of 2002 and proved genetic alteration in the meningioma to be very stable over the time. Yet <i>SMO</i> and <i>AKT1</i> mutations, which have been described to be paradigmatic in frontobasal meningioma, could not be found. <b><i>Conclusions:</i></b> Genetic characteristics seem to be very stable during progression of the disease. The loss of 1p represents to be a potential marker for the poor clinical course of our child meningioma. In 2019, our patient passed away due to the progress of her meningioma disease.

Primary Melanoma of the Lung Treated with Surgery, Dabrafenib and Trametinib

This is a case report on a 69-year-old woman who was diagnosed with malignant melanoma presenting in the lung. A complete staging workup was performed by her oncologist, with no skin lesion identified as a primary. CT-guided needle biopsy of the lung nodule was completed, with pathology revealing atypical cells consistent with malignant melanoma. Following full body examination by the cutaneous oncologist, a robotic wedge resection and lymph node dissection accompanied by bronchoscopy were performed. Molecular testing (Caris Life Sciences) of the surgical tumor specimen revealed pathological BRAF DNA mutation in exon 15/p.V600K. The patient was initially treated with nivolumab, then treated with a combination of dabrafenib and trametinib at recurrence.

A massive phylloides tumor in the breast: case report and literature review

Phylloides tumor (PT) is a rare fibro epithelial neoplasm comprising <1% of all breast tumors. Clinical spectrum ranges from benign (B), borderline (BL), and locally recurrent to malignant (M) and metastatic type. Phylloides tumors originate from the connective tissue of the breast, so the malignant phylloides are histologically sarcomas. We are reporting a massive phylloides tumor in a 45 years old female. She presented with a huge breast mass occupying almost the whole of the right breast with two areas of pressure necrosis, on the overlying skin. She noticed a small lump 7 months ago in the right breast, which slowly grew to the current dimensions and areas of pressure necrosis appeared recently. FNAC was reported as a complex fibroadenoma; however due to strong suspicion, a core needle biopsy was done. The report came as a phylloides tumor. Simple mastectomy was done. The tumor specimen measured exactly 20×15×10 cm in size; the histopathology report came as benign phylloides tumor.

Pituitary Apoplexy with raised intracranial pressure

Pituitary apoplexy in pre-existing pituitary adenomas occurs as a consequence of acute hemorrhage or infarction. Patients with pituitary apoplexy present with sudden onset headache, vomiting, clouding of consciousness and visual field defects or total oculomotor palsies without any prior diagnosis of pituitary tumor. In this case report, we report a case of 52 years female who presented to the emergency department with headache throughout her head and periorbital area with vomiting. Investigations revealed sellar cystic lesion suggestive of pituitary apoplexy with normal hormonal profile. She underwent endoscopic trans-nasal trans-sphenoidal surgery with complete resection of pituitary adenoma. Histopathological examination of tumor specimen showed large areas of necrosis with blood surrounded by the adenomatous tissue. Post-operatively she had cerebrospinal fluid rhinorrhea with persistent papilledema and hydrocephalus. Sellar floor repair along with theco-peritoneal shunt lead to good recovery.

Soluble PD-L1 as a marker of progressive disease on nivolumab in kidney cancer.

746 Background: Higher levels of soluble PD-L1 (sPD-L1) are associated with poor prognosis in patients with solid tumors including in renal cell carcinoma (RCC). Here we have tested whether in patients with advanced RCC, sPD-L1 levels are associated with PD-L1 expression on tumor tissue or with clinical outcomes on PD-1 blockade. Methods: Serum from 91 patients with advanced clear-cell RCC on a biomarker study of nivolumab (NCT01358721) obtained at baseline (Day 1), Day 29 and Day 63, was tested by SiMoa™ for sPD-L1 (capture mAb 298.12B1, detection mAb 339.4C10; Freeman laboratory and Quanterix). Tumor PD-L1 (tPD-L1) was assessed on pretreatment biopsies (Dako). Association of sPDL1 and tPD-L1 with clinical outcomes was analyzed, including best overall response by RECIST (BOR), objective response of >20% (OR), progression free survival (PFS), and overall survival (OS). Results quote Wilcoxon Rank Sum test or paired t-test with significance at P < 0.05. Results: Median sPD-L1 was highest in patients with progressive disease (PD) at all timepoints (Table). Compared to baseline, sPD-L1 levels significantly increased in patients with PD on Day 29 and Day 63, while sPD-L1 levels significantly decreased in patients with CR/PR on Day 63. In addition, we found significantly higher baseline sPD-L1 in patients with prior therapy compared to those who were treatment-naïve. High tPD-L1 was weakly associated with favorable OR, but also weakly associated with high baseline sPD-L1. Conclusions: Unlike tPD-L1, sPD-L1 levels may show promise for association with clinical response to nivolumab in RCC. In this exploratory study, sPD-L1 increase on-treatment was significantly associated with lack of OR, and may be of utility as an early marker for PD worthy of future validation. Analysis of RNASeq from patients’ tumor specimen is underway to assess whether high sPD-L1 with PD is associated with immune suppressive signatures.[Table: see text]

Cell-Free DNA Genotyping Analysis in Diffuse Large B-Cell Lymphoma; The Correlation between TP53 Gene Mutation and Cereblon Gene Mutation

Introduction: Recently cell-free DNA (cfDNA) genotyping analysis has been utilized as a non-invasive procedure for detecting tumor specific genes or clarifying gene mutations instead of tumor sample biopsies. In diffuse large B-cell lymphoma (DLBCL), cfDNA analysis has been proceeding and the relationships between somatic gene mutation and the disease status have been considered. We retrospectively analyzed somatic gene mutations in DLBCL and examined the correlation between mutant genes and clinical outcomes by using serum cfDNA samples. Patients and Methods: 50 patients newly diagnosed with DLBCL (including 4 patients mixed with follicular components) in our institute between March 2016 and March 2017 were enrolled in this study. All cases were sub-divided into germinal center B-cell (GCB) or non-germinal center B-cell (NGC) through immuno-staining, as CD10, bcl-6, and MUM-1 as Hans algorithm with biopsied tumor specimen. The stage at diagnosis and evaluation of treatment effects were assessed by PET-CT scan and bone marrow aspiration. All patients were treated by R-CHOP-like regimens with or without radiation. The serum samples from the patients were obtained before treatment and the cfDNA was extracted from the serum using a Maxwell RSC cfDNA Plasma kit. Using genomic DNA derived from cfDNA, multiplex polymerase chain reaction (PCR) was performed, and a sequence library was then constructed with an Ion Custom Amplicon panel. The panel for the sequence library was designed using an Ion AmpliSeq DesignerTM. 121 targeted genes were selected. The genomes were sequenced using the Ion ProtonTM System. We compared the validation of the sequence results dependent on the characteristics and prognoses of the patients. Connections between each gene mutation and clinical features were assessed using Fisher's exact test. Mann-Whitney U test was used for evaluating factors associated with the number of gene mutations. Survivals were estimated by the Kaplan-Meier method and differences were compared using the log-rank test. This protocol was approved by the institutional review board and the Genomic Review Board of the Japanese Foundation for Cancer Research. Results: Median age was 65.4 years old (range 33-83), 27 patients were male and 23 were female. The stage of Ⅲ or Ⅳ were 17 (34%), IPI high or high intermediate were 17 (34%), and 20 (40%) had LDH>ULN. 27 patients (54%) were GCB and 23 (46%) were NGC. With a median follow up was 26.6 months (range 6-35). Factors affecting both shorter overall survival (OS) and progression-free survival (PFS) were LDH>ULN (P=0.037 and P<0.001), NGC (P=0.012 and P=0.002), IPI≧3 (P=0.023 and P<0.001) in univariate analysis. According to the cfDNA gene mutation analysis, the mutations of HDAC4 (88%), KDM3B (86%), HDAC6 (86%), KDM1A (84%), CREBBP (80%), JMJD1C (78%), and EGR1 (62%) were frequently detected in all DLBCL patients. CREBBP, PCLO, and KDM5A tended to be relatively abundant in NGC (P=0.084, 0.087, and 0.085, respectively). No other mutations had deviation in either GCB or NGC and correlated with other prognostic factors. 7 patients had TP53 mutation, 6 were TP53 p.N178H and 1 was TP53 p.P58L. All cases with TP53 p.N178H mutation were accompanied by more than 27 types of other gene mutations. This was significantly abundant compared to patients without TP53 p.N178H (mean of 38 types vs 16 types, P<0.001). Patients with 15 or more types of gene mutations tended toward poor PFS (2-year PFS of 89.5% vs 77.2%, P=0.092). Additionally, 7 patients had cereblon (CRBN) p.F101S mutation and 5 of 7 were concurrent with TP53 p.N178H mutation. Discussion and Conclusion: This study showed serum cfDNA could be used as an alternative resource for analysis by tumor specimen. Our results indicated that TP53 mutation occurred in latter period undergoing multistep genetic variation and it showed the tendency that multistep mutations were related to poor prognosis. Interestingly, relative rate in TP53 mutation accompanied by CRBN mutation was high. In some reports, it was described that deletion p53 caused drug resistance including immunomodulator which targets CRBN in multiple myeloma cases. Zijun Y et al mentioned CRBN expression correlated with favorable prognosis in DLBCL with wild type TP53. Further studies are warranted to confirm the relationships between TP53 and CRBN mutations and its prognosis of DLBCL. Disclosures Mishima: Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Yokoyama:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Nishimura:Celgene K.K.: Honoraria; Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Hatake:Takeda Pharmaceutical Co.,Ltd.: Honoraria; Celgene K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Terui:Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Research Funding.