The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine.

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% confidence interval, 13.4-16.3), for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83).

Prognostic value of the international association for the study of lung cancer grading system and its association with the tumor microenvironment in stage I EGFR-muted lung adenocarcinoma.

INTRODUCTION: The International Association for the Study of Lung Cancer (IASLC) grading system predicts early lung adenocarcinoma outcomes. METHODS: The purpose of this study is to examine prognostic value of the IASLC grading system and its association with the tumor microenvironment (TME) in Stage I EGFR-muted lung adenocarcinoma. Based on the IASLC grading system, we compared the clinicopathological characteristics of EGFR-mutated lung adenocarcinoma (n = 296). In addition, we examined the expression level of E-cadherin in tumor cells and counted the number of tumor-infiltrating lymphocytes (TILs; CD8, CD20, CD138, and Foxp3), tumor-associated macrophages (TAMs; CD204), and cancer-associated fibroblasts (CAFs; podoplanin) using semi-automatic digital pathology image analysis. RESULTS: Recurrence-free survival (RFS) curve showed that survival of grade 3 was significantly shorter than that of grade 1 (P < 0.01) and grade 2 (P = 0.03). Multivariate analysis of RFS revealed the invasive size, lymphatic permeation, and grade 3 (P < 0.01) as independent poor prognostic factors. The number of CD204 +TAMs and PDPN+CAFs was significantly higher in grade 3 than in grade 1 or 2 (all P < 0.01). Among the intermediate grade by the predominant subtype based classification, cases classified as grade 3 by the new classification had higher number of CD204 +TAMs (P < 0.01) and PDPN+CAFs (P = 0.02) than those classified as grade 2. CONCLUSION: The IASLC grading system correlated with the outcomes of EGFR-mutated lung adenocarcinoma. Grade 3 was found to have the TME that most contributes to tumor progression, which probably explained their poor prognosis.

Clinicopathological differences between EGFR mutated and EGFR wild-type lung adenocarcinoma with papillary predominant pattern.

OBJECTIVES: We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype. METHODS: This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA). RESULTS: Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01). CONCLUSIONS: The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA.

Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.

Giant retroperitoneal dedifferentiated liposarcoma mimicking ovarian cancer: A case report.

Retroperitoneal liposarcoma is a rare tumor, and its dedifferentiated subtype and a larger diameter are associated with a poor prognosis. However, there are few reports of retroperitoneal liposarcomas, both with a dedifferentiated subtype and a diameter of >30 cm. We report a case of a giant retroperitoneal liposarcoma with a dedifferentiated subtype. A 78-year-old woman presented to our hospital with abdominal distension and loss of appetite. Computed tomography and magnetic resonance imaging findings revealed a 35-cm-diameter solid tumor in the peritoneal cavity. CA125 (64.8 U/mL) and HE4 (229.0 pmol/L) were elevated preoperatively raising suspicion for ovarian malignancy. However, intraoperative findings revealed that the tumor originated in the retroperitoneal cavity. Reductive surgery for the tumor and partial resection of the sigmoid colon and left ureter were performed, and pathological examination confirmed a retroperitoneal dedifferentiated liposarcoma. Although her symptoms improved postoperatively, she died 11 months after surgery due to disease progression.

Cellular debris on negative liquid-based cytology cervicovaginal smears.

OBJECTIVES: To determine the prevalence of cellular debris (CD) on benign cervicovaginal liquid-based cytology (LBC) smears and which factors predict the presence and larger amount of CD. METHODS: Cervicovaginal smears evaluated as negative for intraepithelial lesion or malignancy (NILM) between 1 January and 31 March 2020 were retrospectively reviewed to record the presence and amount of CD. All smears were prepared with the SurePath platform. Patient ages and past medical and surgical histories were also retrieved. Multivariate regression analyses were performed to find positive predictors of a larger amount of CD. RESULTS: Three hundred forty-nine NILM smears were included in this study. The cohort consisted of 222 cervical smears (CS), and 127 vaginal smears (VS) taken from patients who had undergone hysterectomy. Overall, CD was observed in 111 (31.8%) cases. The positive predictors of CD were increasing age, specimen type (VS compared to CS), history of chemotherapy or radiation therapy (CRT), and more than mild background inflammation. Among the VS group, CD was present in 64 cases (50.4%) regardless of the time between the hysterectomy and specimen collection. Positive predictors in the VS group were age and more than mild inflammation. By contrast, the prevalence of CD in the CS group was 21.2%, and age was the only positive predictor. Histories of CRT, conisation, and inflammation were not statistically significant positive predictors for CD among CS. CONCLUSIONS: Cellular debris could be seen in as much as 50% of NILM smears taken after hysterectomy, regardless of the time since the procedure. Increasing age was a positive predictor of the presence and a larger quantity of CD. These findings are helpful when evaluating smears with moderate to abundant debris in the background with questionable cellular atypia.

A clinicopathologic and molecular analysis of five cases of bronchiolar adenoma with rare mutations.

Bronchiolar adenoma (BA) is a rare benign lung tumor that shows proliferation of bland bronchiolar-type epithelium containing a continuous layer of basal cells. This tumor entity has been newly added to the recent World Health Organization (WHO) classification 5th edition. This entity encompasses a spectrum of lesions: the classic ciliated muconodular papillary tumor (CMPT) and the non-classic CMPT. Although BA is reported to have driver mutations including BRAF V600E, EGFR, and KRAS, the molecular profile of BA is still incompletely understood. Five resected BAs at our institutions were analyzed. The BA lesions were subdivided into two groups: three proximal-type BAs and two distal-type BAs. NRAS codon 12/13 mutation and EML4 exon 20-ALK exon 20 fusion were found in two of the three proximal-types. BRAF V600E mutation was found in one of the two distal-types. Two cases coexisted with lung adenocarcinoma, with EGFR exon 19 deletion and KRAS mutation, respectively. No recurrence was observed at a median of 12 months (range 2-84 months) of follow-up. BA has uncommon variants of mutation seen in lung adenocarcinoma. NRAS mutation and ALK fusion partner has not been reported previously. The present cases may reinforce the distinctive biology of BA from lung adenocarcinoma.

Mesectodermal Leiomyoma of the Ciliary Body: A Unique Variant of Leiomyoma with Myogenic and Neurogenic Histological Features.

Mesectodermal leiomyoma of the ciliary body is a rare benign tumor, showing both neurogenic and myogenic characteristics. This tumor typically shows predilection for women of reproductive age. Because it is almost impossible to clinically distinguish this tumor from malignant melanoma, unnecessary eye enucleations have been unfortunately performed. Herein, we report a case of mesectodermal leiomyoma of the ciliary body in a young Japanese woman. She was referred to our hospital due to a slow-growing mass in her left iris. A malignant tumor could not be clinically ruled out and surgery with intraoperative pathology consultation was performed. Intraoperative frozen section diagnosis was a benign tumor with neurogenic features, and a simple excision of the tumor was performed. Histologically, the tumor was composed of diffuse growth of spindle cells with fibrillary indistinctive cytoplasm. Immunohistochemical examination showed diffuse positive staining of α-smooth muscle actin, h-caldesmon, calponin, and CD56. Scattered tumor cells were weakly positive for desmin. Neither melanocytic markers nor neural markers except for CD56 were positive. We diagnosed this tumor as mesectodermal leiomyoma. Mesectodermal leiomyoma is rare and often misdiagnosed as malignant melanoma. To avoid overtreatment, a correct preoperative diagnosis is essential.

Clinicopathological analysis of myeloid sarcoma with megakaryocytic differentiation.

Myeloid sarcoma (MS) is defined as a tumour mass consisting of myeloid blasts that occurs at an anatomical site other than bone marrow. MS with megakaryocytic differentiation (MSmgk) is extremely rare and its clinicopathological features have not been well described. We reviewed 11 cases in 11 patients of extramedullary mass-forming malignant tumours composed of immature non-lymphoid haematopoietic cells expressing CD41 with or without concurrent bone marrow lesions. The patients consisted of seven men and four women (1.75:1 male-to-female ratio). The mean and median ages at diagnosis were 50 and 62 years, respectively, ranging from 2 to 78 years. Extramedullary mass lesions were solitary in three cases (27%) and multiple in eight cases (73%). Tumour locations were lymph nodes (6 cases), subcutaneous tissue (3 cases), intramuscular (1 case), and bone (1 case). Seven of the 11 patients (64%) had a history of myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). Three patients (27%) developed MS during remissions of acute myelogenous leukaemia, and one patient had a recurrence of MS at other sites. Follow-up data were available for four cases. Tumour cells were positive for CD41, CD33, CD34, MPO, and CD68 in 11 (100%), three (27%), seven (64%), four (36%), and seven (64%) cases, respectively. Cytogenetic analysis was successfully performed in two cases. Complex but inconsistent abnormalities were evident. When compared with cases of MS without megakaryocytic differentiation, the survival of MSmgk was significantly shorter (p=0.0033). Compared to MS without megakaryocytic differentiation, MSmgk is more likely to follow MDS/MPN, to involve multiple sites, and to be associated with poorer outcomes. More detailed studies, including genomic or gene expression analyses, could confirm the characteristics of MSmgk.

[Necrotic Thymoma;Report of a Case].

A 36-year-old man, who had never been detected abnormalities on an annual chest X-ray check up, presented with a sudden onset of right-sided chest pain and fever. Contrast-enhanced computed tomography showed an anterior mediastinal mass with necrosis or hemorrhage and right pleural effusion. Neither computed tomography-guided biopsy nor video-assisted thoracic surgery (VATS) yielded definitive histological diagnosis due to insufficiency of the sample. For diagnosis and treatment, we performed thymectomy. Histopathologically, the tumor was almost entirely necrotic with few viable tumor cells on periphery. A diagnosis of B2 thymoma was rendered.

Ovarian Seromucinous Tumors: Pathogenesis, Morphologic Spectrum, and Clinical Issues.

Ovarian seromucinous tumors were introduced in the 2014 World Health Organization (WHO) classification as one of the seven types of ovarian epithelial tumors. They are characterized by frequent association with endometriosis and bilaterality, microscopic appearance of papillary architecture, and admixture of a variety of müllerian-type epithelium. They are considered to be endometriosis-related ovarian neoplasms, along with endometrioid and clear cell tumors; recent molecular studies suggest this particular tumor is a variant of endometrioid tumor. Discrepancies in nomenclature, definition, and morphology of seromucinous tumors appear to be a source of confusion, for both clinicians and general surgicalpathologists. This review summarizes the clinicopathological features of benign, borderline, and malignant seromucinous tumors, as well as controversies regarding these tumors.

Calcified Cerebral Embolism Due to a Calcified Amorphous Tumor.

A 59-year-old man developed brain embolism in the frontal and parietal cortex. Brain CT showed a high-density spot in the upper branch of the left middle cerebral artery, indicating calcified cerebral embolism. Calcified amorphous tumor attached to the mitral valve was identified as the cause of embolism. After surgical resection, anticoagulation was started and recurrent stroke did not occur.

A case of poorly differentiated mucinous carcinoma of the gallbladder that exhibited a peculiar morphology.

A 65-year-old female presented with an elevated lesion that was identified in the gallbladder fundus via abdominal ultrasound during a medical checkup. The tumor was a pedunculated lesion, measuring 30mm in diameter, that exhibited a blood flow pattern with gradual dense staining throughout the equilibrium phase on the abdominal contrast computed tomography and a high signal intensity on T2-weighted magnetic resonance imaging. Histopathological findings revealed the proliferation of poorly differentiated adenocarcinoma, including signet ring cells, throughout the tumor along with the formation of a mucous lake. The patient was consequently diagnosed with poorly differentiated mucinous carcinoma of the gallbladder.

A spontaneous superficial temporal artery pseudoaneurysm possibly related to atherosclerosis: Case report and review of literature.

BACKGROUND: Spontaneous superficial temporal artery (STA) pseudoaneurysms are very rare; only four cases, including ours, have been reported to date. Therefore, the cause of them has not been studied. CASE DESCRIPTION: A 57-year-old woman was admitted to our hospital with a pulsatile mass in the left preauricular region. Her medical history included hypertension, dyslipidemia, and angina pectoris. She denied a history of head injury or minor head trauma. Three-dimensional computed tomography angiography showed a well-enhanced saccular aneurysm on the main trunk of the STA. To prevent rupture it was removed surgically. The histological diagnosis was pseudoaneurysm with atherosclerosis. By the 2(nd) postoperative day, she had completely recovered and was discharged home. There has been no relapse. CONCLUSIONS: As all four documented patients were at high risk for atherosclerosis, we posit that a causal factor was weakening of the arterial wall due to atherosclerosis and chronic pressure on the STA from anatomical structures. Here, we present histological evidence to support this hypothesis.

A case report of primary neuroendocrine carcinoma of the perihilar bile duct.

BACKGROUND: Although neuroendocrine tumors are most commonly found in the digestive system, neuroendocrine tumors originating from the bile duct are rare, and neuroendocrine carcinomas derived from the perihilar bile duct are extremely rare. This report presents the clinical course and clinicopathological features of neuroendocrine carcinomas arising from the extrahepatic bile duct. CASE PRESENTATION: A 70-year-old Japanese woman was preoperatively diagnosed with perihilar cholangiocarcinoma, and a radical resection with an extended left hepatic lobectomy and a choledochojejunostomy was performed. From the histopathological findings, we diagnosed the tumor as a neuroendocrine carcinoma of the bile duct (small cell type) with lymph node metastasis. The patient was treated with the same adjuvant chemotherapy as that used for small cell carcinoma of the lung. At 10 months after surgery, there was no recurrence of the disease. CONCLUSION: Neuroendocrine carcinoma of the extrahepatic biliary tracts is a very rare and highly malignant disease with a poor prognosis. A multidisciplinary approach could improve the prognosis for this neoplasm.

Prognostic Factors and Outcomes of Adult-Onset Hemophagocytic Lymphohistiocytosis: A Retrospective Analysis of 34 Cases.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) has features that are distinct from that of HLH in pediatric patients. The clinical records at the Japanese Red Cross Kumamoto Hospital were reviewed. We retrospectively analyzed 34 patients who fulfilled the diagnostic criteria of HLH-2004. The median age of patients was 60.0 (range 15-86). Underlying diseases were diagnosed in 17 patients. They consisted of malignant lymphoma (n=3), other neoplastic disease (n=3), viral infection (n=4), collagen vascular disease (n=3), Kikuchi's disease (n=3) and drug (n=1). Underlying diseases were not diagnosed in 17 patients despite examination. The treatments were steroids (n=18), dexamethasone + cyclosporine A (CSA) + etoposide (n=4), multidrug chemotherapy (n=2), steroids and CSA (n=3). Eleven patients died during observation. In a multivariate analysis, the significant predictor for death was age at onset (hazard ratio, 1.22; 95%CI, 1.02-1.44; P=0.027). Autopsy was performed in 4 cases, but the underlying disease remained unknown in 3 of those cases. Adult-onset HLH has high diversity and various outcomes. The mechanism of adult-onset HLH is not fully understood and further research is required.

[On-the-street DOTS for a homeless tuberculosis patient--case report of a patient who had difficulties with TB treatment adherence].

PURPOSE: A homeless patient with tuberculosis (TB), who had often quit his TB treatment in mid-course and then gone homeless again, succeeded in completing his treatment for over 10 months through on-the-street DOTS ("Bluesky DOTS" is another expression). Based on the analysis of this case, we have discussed how to provide effective countermeasures to non-compliant TB patients. METHOD: An episode of a successful on-the-street DOTS for a 70-year-old homeless man with sputum smear positive pulmonary TB was qualitatively analyzed, with a view toward patient's empowerment. RESULT: The patient had had human-relations problems in his life, and trouble with medical and welfare service staff. During his hospital admissions, he repeatedly self-discharged or was forced to discharge due to violent behavior against staff. Public health nurses at Shinjuku public health center visited the patient frequently at the hospital, and tried to build a good relationship with the patient from the beginning of the treatment. Following a two and half month interruption of the TB treatment after he disappeared from the hospital, he was discovered staying outside at a canal side in the area, and on-the-street TB treatment was carried out, with good cooperation with the hospital and social welfare office. Directly observed TB medication was given to him by a public health nurse and another health center staff member for 293 days, at the park near his living place. The patient often rejected the medication, particularly when he was hungry, but offering lunch to him was a very effective incentive. Through comprehensive supports to the patient, he gradually changed his attitude, and on his own came to consider his health and his future. DISCUSSION: We have analyzed a successfully treated case of a homeless TB patient who had difficulties in maintaining a social life and had not been cooperative in complying with the medication. The level of independence improved during the course of on-the-street DOTS with incentive and other supports. He became receptive to TB treatment and became self-supportive during the course of DOTS, with food as an incentive. This indicates that on-the-street DOTS was successful not only for the treatment completion but also contributed to empowering the TB patient. This approach of adjusting the service to the patient's needs fostered a positive relationship with all stakeholders.