Kenta Kawasaki

Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis

Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers.

Positive relationship between subsequent chemotherapy and overall survival in pancreatic cancer: meta-analysis of postprogression survival for first-line chemotherapy

PurposeTo gain a better understanding of the impact of postprogression survival (PPS) and post-trial anticancer therapy on overall survival (OS) in first-line pancreatic cancer patients.MethodsA literature search identified 54 randomized trials, focusing on gemcitabine monotherapy to eliminate effects of heterogeneity of first-line regimens. We evaluated the relation between OS and either progression-free survival (PFS) or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment.ResultsFor all 54 trials, PPS was strongly associated with OS (r = 0.844), whereas PFS was moderately associated with OS (r = 0.623). Average OS and PPS were significantly longer in recent trials than in older trials, (7.29 versus 6.15 months, p < 0.001) and (3.64 versus 2.86 months, p < 0.001), respectively. The correlation between OS and PPS in recent trials was much stronger than that in older trials (r = 0.846 versus 0.729). The relation between OS and PFS in recent and older trials did not differ (r = 0.595 versus 0.563). The percentage of patients with post-trial treatment was significantly higher in recent trials than in older trials (52.7 versus 39.7%, p < 0.001). The rate of post-trial anticancer therapy was significantly associated with OS (r = 0.910).ConclusionsWe found an increase in median PPS in accordance with an increase in median OS in recent trials compared with older trials and that rate of post-trial anticancer therapy was strongly associated with median OS. It is important that researchers be aware of these findings in designing clinical trials of first-line chemotherapy for pancreatic cancer patients.

Fatal hemorrhage in a patient with advanced soft tissue sarcoma following radiation and pazopanib treatment: A case report

A 71-year-old Japanese woman presented to the Department of Neurosurgery of Keio University School of Medicine (Tokyo, Japan) with a leiomyosarcoma originating in the infratemporal fossa and an 85-mm metastasis to the right lung. Since the pulmonary lesion was associated with risk of airway obstruction, radiation therapy (50 Gy/20 fractions) was administered to the patient, which resulted in remarkable tumor shrinkage. Subsequently, the patient was administered 800 mg/day pazopanib for 10 weeks, which resulted in further reduction in tumor size. However, the patient succumbed to a massive hemorrhage of sudden onset. Three possible explanations for the fatal hemorrhage are: i) adverse reaction to pazopanib; ii) side effects of radiation; and iii) remarkable tumor shrinkage. As a result, it may be proposed that the synergic effects of the aforementioned hypotheses may have been responsible for the bleeding observed in the present case. Therefore, clinicians should be alert to the possibility of this adverse event. In the present study, the first case of mortality due to massive hemorrhage following remarkable tumor shrinkage induced by radiation therapy and subsequent pazopanib treatment is reported.

Benefit of rebiopsy for deciding treatment strategy in rectal cancer: A case report

Rebiopsy is considered an option for specific types of cancer, such as breast, non-small cell lung, and prostate cancer, in clinical trials and in practice. The benefit of rebiopsy comes from the selection of a new treatment strategy based on the genetic profile of the cells, which may reflect the development of drug resistance or hormonal changes. For colorectal cancer, the presence of different genomic mutations between the primary tumor and its metastases is rare, and rebiopsy is therefore not generally performed. The present study reports the case of a 68-year-old man who was initially diagnosed with metastatic adenocarcinoma from a primary colorectal cancer, but was subsequently rediagnosed with metastatic neuroendocrine carcinoma based on the pathological rebiopsy results. The patient responded well to cisplatin and etoposide treatment, after not responding to initial FOLFOX treatment. In this case, rebiopsy resulted in a change in treatment regimen and improved the patients quality of life and his long-term survival. This case indicates that, when a colorectal cancer patient is unresponsive to standard treatment, it may be beneficial for the clinician to suspect an atypical histological type, and to consider rebiopsy.

Inter-evaluator heterogeneity of clinical diagnosis for locally advanced esophageal squamous cell carcinoma

BackgroundIdentifying clinical resectability of locally advanced esophageal squamous cell carcinoma (ESCC) is important, although inter-evaluator heterogeneity (IEH) could exist, especially in borderline resectable (BLR) cases. To investigate the extent of heterogeneity, we conducted clinical diagnostic imaging questionnaires.Materials and methodsFive cases with clinical T3 or T4 cases, which were treated with neo-adjuvant triplet chemotherapy followed by surgery, were selected as the model. These cases were divided into two groups: curative resected cases (#1–#3) and non-curative resected cases (#4 and #5). Only imaging slides were shown without any information about patient characteristics or clinical course. The evaluators consisted of surgeons (staff and non-staff), medical oncologists, and an imaging radiologist; a total of 25 medical staff answered the questionnaire. Two questions (1: clinical T stage before chemotherapy, 2: resectability after chemotherapy) were answered. Occupational differences were assessed by comparing the results to the imaging radiologist.ResultsIEH was observed for clinical diagnosis before chemotherapy in one case (clinical T4: 52%, clinical T3: 48%). In the other cases, most evaluators diagnosed them as clinical T4, with 76–88% agreement. IEH for clinical resectability after chemotherapy was relatively small. Occupational IEH was observed in both before and after chemotherapy.ConclusionIEH in decisions about treating BLR cases in ESCC should be considered in clinical practice. Multi-disciplinary teams are essential to overcome this problem.

Early tumor cavitation with regorafenib in metastatic colorectal cancer: A case report.

Tumoral cavity formation is a characteristic phenomenon reported in anti-angiogenic therapy in lung lesions. A 57-year-old male with multiple pulmonary metastases from colorectal cancer treated with an oral tyrosine kinase inhibitor, regorafenib, exhibited a characteristic cavity formation after the first two cycles. The decrease in the size of tumors was calculated as 38%, and there were associated decreases in the serum concentrations of the tumor markers carcinoembryonic antigen and CA19-9. After eight cycles of treatment, the cavity gradually disappeared through filling-in. This unique morphological response is not only reported in lung cancer but also in liver metastasis in colorectal cancer. However, the association between morphological changes including cavity formation and clinical benefit remains controversial. Pulmonary hemorrhage and pneumothorax are well-known consequences of cavitation, as reported with the other anti-angiogenic inhibitors. Early tumor cavitation in lung metastasis may demonstrate the predictive potential of regorafenib in colorectal cancer, although it is necessary to be mindful of toxicity.

Arrhythmogenic right ventricular cardiomyopathy in a patient with schizophrenia

People with schizophrenia are at greater risk of cardiovascular morbidity and mortality than the general population. Arrhythmogenic right ventricular cardiomyopathy is a recognized cause of sudden cardiac death in young people. This report discusses the necessity for close cardiac evaluation to reduce incidence of sudden death in people with schizophrenia.

Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models

ABSTRACT Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) refer to a group of heterogeneous cancers of neuroendocrine cell phenotype that mainly fall into one of two subtypes: gastroenteropancreatic neuroendocrine tumors (GEP-NETs; well differentiated) or gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs; poorly differentiated). Although originally defined as orphan cancers, their steadily increasing incidence highlights the need to better understand their etiology. Accumulating epidemiological and clinical data have shed light on the pathological characteristics of these diseases. However, the relatively low number of patients has hampered conducting large-scale clinical trials and hence the development of novel treatment strategies. To overcome this limitation, tractable disease models that faithfully reflect clinical features of these diseases are needed. In this Review, we summarize the current understanding of the genetics and biology of these diseases based on conventional disease models, such as genetically engineered mouse models (GEMMs) and cell lines, and discuss the phenotypic differences between the models and affected humans. We also highlight the emerging disease models derived from human clinical samples, including patient-derived xenograft models and organoids, which may provide biological and therapeutic insights into GEP-NENs. Summary: Gastroenteropancreatic neuroendocrine neoplasms have been an understudied entity with limited treatment options. We discuss the disease models, including emerging organoids, that may provide biological and therapeutic insight into these diseases.

Curative resectability of gastrointestinal cancer identified from iron deficiency anemia

The present study aimed to clarify the staging and curative resectability of gastrointestinal cancer found through iron deficiency anemia (IDA). An electronic database was used and females >51 and males >18 years old were identified who had been diagnosed with IDA at the internal medicine outpatient clinic of Asahi General Hospital (Chiba, Japan) from 1 April 2010 to 31 March 2012. IDA was defined as a hemoglobin level of <135 g/l for males and <120 g/l for females, combined with a serum ferritin level of <33.71 pmol/l. Of the 472 patients who had been diagnosed with IDA, 347 patients underwent either a gastroscopy and/or colonoscopy, including 120 patients who had undergone both gastroscopy and colonoscopy, 197 patients who only underwent gastroscopy, and 30 patients who only underwent colonoscopy. In total, 125/472 patients diagnosed with IDA did not undergo a gastroscopy or a colonoscopy. From the 50 patients who were diagnosed with cancer as a result of the investigation, 24 patients had gastric cancer and 23 patients had colorectal cancer. Of the gastric cancer patients, 6 patients were stage I, 3 patients stage II, 5 patients were stage III and 9 patients were stage IV. In colorectal cancer, 9 patients were stage II, 8 patients were stage III and 4 patients were stage IV. Curative surgery including endoscopic treatment was performed on 14 gastric cancer patients and 17 colorectal cancer patients of stage III or lower. Malignancies were found in 50 patients with IDA, and curative surgery was performed on >50% of the patients.

Surgery and radiation therapy for brain metastases from classic biphasic pulmonary blastoma

Pulmonary blastoma, a rare malignant lung tumour, can metastasise to the brain. However, there is no evidence for any effective treatment. The aim of this report is to discuss the treatment options for pulmonary blastoma and confirm the necessity for a pathological diagnosis. A 75-year-old man was admitted with progressive right-sided hemiplegia and aphasia. MRI showed multiple brain tumours. A left frontal lobe lesion was surgically resected, after which he underwent whole brain radiation (30 Gy/10 fractions). He died of an acute exacerbation of interstitial pneumonia. On performing autopsy, partial responses in the brain metastases that had been irradiated were confirmed pathologically. Thus, we present pathological confirmation that surgery and radiation therapy have therapeutic effects on brain metastases from pulmonary blastoma.