Statistics of bone sarcoma in Japan: report from the population-based cancer registry in Japan.

BACKGROUND: No previous reports have characterized national bone sarcoma profiles overall. We examined the nationwide statistics for bone sarcoma in Japan using data from the National Cancer Registry (NCR), a population-based cancer registry. METHODS: We identified 3,755 patients with bone sarcomas entered in the NCR during 2016-2019 using International Classification of Diseases-Oncology, Third Edition codes for cancer topography and morphology. We extracted data on patient demographics, tumor details (reason for diagnosis, tumor location, histology, extent of disease), hospital volume/type, treatment, and prognosis for each patient. RESULTS: Bone sarcoma showed a slight male preponderance. The age distribution peaked at ages 10-20 and 60-80; approximately 44% of patients were aged over 60 years. Chordoma, chondrosarcoma, and malignant fibrous histiocytoma of bone peaked in the elderly, and Ewing's sarcoma peaked in children. Osteosarcoma had two peaks in Japan as well as in Western countries. The most frequent tumor locations were the limb (45%) and the pelvis (21%). Extent of disease was categorized as: "localized" (39%), "regional" (27%), and "distant" (11%). We found significant associations between overall survival and age, tumor location, facility type, hospital volume, histologic subtype, reason for diagnosis, and extent of disease. The latter had the poorest survival. CONCLUSIONS: This is the first study to outline the epidemiology, clinical features, treatment, prognosis, and significant factors affecting prognosis of bone sarcoma in Japan using the NCR. Documenting our data regarding elderly patients' outcomes is essential so other countries showing similar population-aging trends can learn from our experiences. LEVEL OF EVIDENCE: Prognostic studies, Level III.

Treatment outcomes of gemcitabine plus nab-paclitaxel in pancreatic cancer patients with malignant ascites.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) therapy has been shown to improve the prognosis in patients with metastatic pancreatic cancer (PC); however, the efficacy and safety of GnP in PC patients with malignant ascites (MA) remains unknown. METHODS: We retrospectively investigated PC patients with peritoneal dissemination who had received GnP as first-line chemotherapy at our institution between March 2015 and August 2021. The following patient data were reviewed: patient characteristics, overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and relative dose intensity (RDI). The severity of MA was categorized based on the CT findings as grade 1 (small), grade 2 (moderate), or grade 3 (massive). RESULTS: A total of 189 patients were included; the study endpoints were compared between patients with each ascites grade and 41 patients without MA. The MA was classified as grade 1 in 85 patients, grade 2 in 41 patients, and grade 3 in 22 patients. In the patients with MA, the median OS, PFS and ORR were 11.2 months, 5.7 months and 24.3%, respectively. The OS and PFS decreased with increasing the severity of MA; in particular, patients with grade 2 and 3 showed a poorer prognosis. There were no differences in AEs, except for anorexia, or the RDI according to the severity of MA. CONCLUSION: GnP showed moderate efficacy with manageable safety profile in PC patients with MA. However, PC patients with moderate to massive ascites still have a dismal prognosis, and further development of effective treatments is needed.

Covered self-expandable metallic stent placement for tumor bleeding from duodenal invasion in patients with unresectable pancreatic cancer.

Patients with unresectable pancreatic cancer often present with duodenal bleeding, a potentially life-threatening complication. In our case series of six unresectable pancreatic cancer patients with tumor bleeding, we explored the efficacy and safety of placement of a covered self-expandable metallic stent in the duodenum as a treatment option; we achieved a hemostasis rate of 67% (4/6), with a rebleeding rate of 50% (2/4). No complications occurred with stent placement, except for food impaction in one patient. Covered self-expandable metallic stent placement is a moderately effective treatment option for tumor bleeding in patients with unresectable pancreatic cancer. Although its hemostatic efficacy is limited, covered self-expandable metallic stent placement is safe and beneficial in some cases, warranting consideration in this disease setting with limited treatment options.

Current status of head and neck sarcomas in Japan in 2016-2019: an analysis using the national cancer registry.

BACKGROUND: Head and neck sarcomas are especially rare in Asia, leading to limited clinical evidence. This study aimed to investigate the incidence, clinical features, treatment status, and outcome of these sarcomas using data from the National Cancer Registry in Japan. METHODS: All head and neck sarcomas diagnosed between 2016 and 2019 and recorded in the National Cancer Registry were analyzed. Data on sex, age, primary site, histological type, stage, treatment modality, and prognostic information were collected. Age-adjusted incidence and 3-year survival rates of patients with head and neck sarcomas were calculated. RESULTS: Overall, 635 head and neck sarcoma patients were identified. Head and neck sarcoma occurred more frequently in men and patients in their 70 s. The age-adjusted annual incidence rate was 0.125 per 100,000 patients in the 2015 Japanese model or 0.089 per 100,000 patients in the world population model. The nasal cavity and paranasal sinuses were the most frequent primary sites, with rhabdomyosarcoma as the most common histologic type. Treatment typically involved chemotherapy and/or radiation therapy for rhabdomyosarcoma and Ewing's sarcoma, whereas surgical approaches for other types. Three-year survival rate of head and neck sarcoma patients was 64.8%. CONCLUSIONS: Head and neck sarcomas occurred rarely, but most frequently in the nasal cavity and paranasal sinuses in Japan. Poor outcomes were observed for sarcoma patients than for non-sarcoma head and neck cancer patients.

Pathogenic Germline Variants in BRCA1/2 and p53 Identified by Real-world Comprehensive Cancer Genome Profiling Tests in Asian Patients.

Cancer genome profiling (CGP) occasionally identifies pathogenic germline variants (PGV) in cancer susceptibility genes (CSG) as secondary findings. Here, we analyzed the prevalence and clinical characteristics of PGVs based on nationwide real-world data from CGP tests in Japan. We analyzed the genomic information and clinical characteristics of 23,928 patients with solid cancers who underwent either tumor-only (n = 20,189) or paired tumor-normal (n = 3,739) sequencing CGP tests between June 2019 and December 2021 using the comprehensive national database. We assigned clinical significance for all variants and highlighted the prevalence and characteristics of PGVs. Our primary analysis of the tumor-normal sequencing cohort revealed that 152 patients (4.1%) harbored PGVs in 15 CSGs. Among 783 germline variants, 113 were annotated as PGVs, 70 as benign variants, and 600 as variants of uncertain significance. The number of PGVs identified was highest in BRCA1/2, with 56, followed by TP53, with 18. PGVs were the most prevalent in ovarian and peritoneal cancers, including among cancer types common in Asia. In the tumor-only sequencing cohort, of the 5,184 pathogenic somatic variants across 26 CSGs, 784 (15.1%) were extracted according to the European Society for Medical Oncology recommendations for germline-focused tumor analysis. The prevalence of PGVs was similar to that previously reported in Europe and the United States. This is the largest analysis based on real-world tumor-normal sequencing tests in Asia. The more widespread use of the tumor-normal sequencing CGP test could be reasonable for evaluating PGVs. SIGNIFICANCE: We analyzed real-world data from over 23,000 patients in Japan, revealing 4.1% harbored PGVs, particularly in BRCA1/2 and TP53, in CSGs. It highlights the prevalence of PGVs in Asian populations and supports the broader adoption of tumor-normal sequencing CGP tests for PGV evaluation.

Palliative radiotherapy for tumor bleeding in patients with unresectable pancreatic cancer: a single-center retrospective study.

BACKGROUND: Patients with unresectable pancreatic cancer (PC) sometimes experience gastrointestinal bleeding (GIB) due to tumor invasion of the gastrointestinal tract (tumor bleeding); no standard treatment has been established yet for this complication. Palliative radiotherapy (PRT) could be promising, however, there are few reports of PRT for tumor bleeding in patients with unresectable PC. Therefore, we evaluated the outcomes of PRT for tumor bleeding in patients with unresectable PC. METHODS: We reviewed the medical records of patients with unresectable PC diagnosed at our institution between May 2013 and January 2022, and identified patients with endoscopically confirmed tumor bleeding who had received PRT. PRT was administered at a total dose of 30 Grays (Gy) in 10 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction, and the dose selection was left to the discretion of the attending radiation oncologists. RESULTS: During the study period, 2562 patients were diagnosed as having unresectable PC at our hospital, of which 225 (8.8%) developed GIB. Among the 225 patients, 63 (2.5%) were diagnosed as having tumor bleeding and 20 (0.8%) received PRT. Hemostasis was achieved in 14 of the 20 patients (70%) who received PRT, and none of these patients developed grade 3 or more adverse events related to the PRT. The median time to hemostasis was 8.5 days (range 7-14 days). The rebleeding rate was 21.4% (3/14). The median hemoglobin level increased significantly (p < 0.001) from 5.9 to 9.1 g/dL, and the median volume of red blood cell transfusion tended (p = 0.052) to decrease, from 1120 mL (range 280-3360 mL) to 280 mL (range 0-5560 mL) following the PRT. The median overall survival (OS) was 52 days (95% confidence interval [CI] 39-317). Of the 14 patients in whom hemostasis was achieved following PRT, chemotherapy could be started/resumed in seven patients (50%), and the median OS in these patients was 260 days (95% CI 76-not evaluable [NE]). Three patients experienced rebleeding (21.4%), on days 16, 22, and 25, after the start of PRT. CONCLUSION: This study showed that PRT is an effective and safe treatment modality for tumor bleeding in patients with unresectable PC.

Case Report: Atezolizumab plus bevacizumab for combined hepatocellular-cholangiocarcinoma.

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare subtype of primary liver cancers. Therapeutic strategies for patients with cHCC-CCA are limited, and no standard systemic treatment has been established for unresectable cHCC-CCA. Here, we present six cases of cHCC-CCA treated with atezolizumab plus bevacizumab. We observed three partial responses and one stable disease as the best responses; two of these patients were still being treated with atezolizumab plus bevacizumab at the time of reporting (at least five months of treatment), whereas the remaining two patients were unable to continue treatment owing to adverse events. Atezolizumab plus bevacizumab may be an effective treatment for unresectable cHCC-CCA.

The epidemiology of rare types of hepatobiliary and pancreatic cancer from national cancer registry.

BACKGROUND: Information on rare hepatobiliary and pancreatic (HBP) subtypes of cancer is scarce. We aimed to elucidate the incidence and clinical features of rare tumors in Japan using the National Cancer Registry (NCR), a new nationwide integrated population-based registry. METHODS: The data of patients diagnosed in 2016-2017 were extracted from the NCR database, and classified by topography: liver cells, intrahepatic bile duct, gallbladder, extrahepatic bile duct, ampulla of Vater, and pancreas. Data were described and analyzed using the World Health Organization and General Rules tumor classifications. The incidences for all rare tumors including hepatoblastoma and adenosquamous cell carcinoma were calculated as the number of new cases divided by the corresponding total person years. RESULTS: The NCR data yielded 8,239 patients with rare HBP tumors between 2016 and 2017. The ratios of rare tumors to all cancer types were 0.5%, 0.7%, 3.9%, 1.6%, 0.8%, and 7.2% in the liver, intrahepatic bile duct, gallbladder, extrahepatic bile duct, ampulla of Vater, and pancreas, respectively. Rare tumors occurred more frequently in men, except for gallbladder tumors. The main tumor stage was localized in liver cells (42.4%) and the intrahepatic bile duct (51.6%); more patients were diagnosed in advanced stage with gallbladder (84.1%) and extrahepatic bile duct (74.4%) tumors. Approximately equal percentage of patients were diagnosed at designated cancer care hospitals (DCCHs) and non-DCCHs, whereas 60% to 70% patients received treatment at DCCHs. CONCLUSION: This is the first report to provide comprehensive information on the epidemiological status of rare HBP tumors in Japan by utilizing population-based NCR data.

The influence of UGT1A1 polymorphisms on modified FOLFIRINOX dose in double-variant-type patients with advanced pancreatic cancer.

BACKGROUND: UGT1A1 polymorphisms should be considered when using irinotecan-containing regimens, especially in patients with a double-variant-type (DV), including homozygous for UGT1A1*28 and UGT1A1*6 and heterozygous for both UGT1A1*28 and UGT1A1*6. We investigated the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) (irinotecan 80 mg/m2) in patients having DV. METHODS: Patients with advanced pancreatic cancer who had received FOLFIRINOX between January 2015 and December 2019 were included in this study. Non-DV patients received the standard mFOLFIRINOX (irinotecan 150 mg/m2) as first-line (non-DV1) or second-line therapy (non-DV2); however, DV patients received mFOLFIRINOX (irinotecan 80 mg/m2) as the second-line therapy (DV2). We retrospectively evaluated the safety and efficacy of the lowered irinotecan dose in the DV2 group relative to the non-DV1 (safety) or non-DV2 (safety and efficacy) groups. RESULTS: A total of 235 patients were eligible for this study with 118 patients in the non-DV1, 106 in the non-DV2, and 11 in the DV2 groups. Major grade 3-4 adverse events were neutropenia (33.9, 31.1, and 18.2%) and febrile neutropenia (6.8, 3.8, and 9.1%) in the non-DV1, non-DV2, and DV2 groups, respectively. The median progression-free survival was 3.4 months in the non-DV2 group, and 4.4 months in the DV2 group. The overall survival from the date of starting second-line chemotherapy was 8.8 months in the non-DV2 group and 11.5 months in the DV2 group. CONCLUSIONS: Based on our findings, the safety and efficacy of mFOLFIRINOX (irinotecan 80 mg/m2) in DV patients were comparable with the standard mFOLFIRINOX (irinotecan 150 mg/m2) in non-DV patients.

Endoscopic ultrasound-guided choledochoduodenostomy without fistula dilation using a stent with a 5.9-Fr delivery system: Comparison to a conventional procedure with fistula dilation.

Objectives: To evaluate the feasibility and safety of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) without fistula dilation using a novel self-expandable metal stent (SEMS). Methods: This retrospective study examined patients who underwent EUS-CDS for malignant distal biliary obstruction between October 2017 and May 2021 at the National Cancer Center, Japan. The primary outcome was a technical success without fistula dilation. Secondary outcomes were the overall technical success, clinical success, adverse events (AEs), procedure time, recurrent biliary obstruction (RBO), and time to RBO (TRBO). Results: Forty-one patients were enrolled; 31 patients underwent EUS-CDS with fistula dilation using a conventional SEMS with 7.5-8.5-Fr delivery system (conventional SEMS group), and 10 patients underwent EUS-CDS without fistula dilation using the novel SEMS with a 5.9-Fr delivery system (novel SEMS group). In the novel SEMS group, the rate of technical success without fistula dilation was 90%. There were no differences in overall technical success (100% vs. 97%, p = 1.00), clinical success (80% vs. 90%, p = 0.58), and overall AEs (10% vs. 23%, p = 0.65) rates between the novel and conventional SEMS groups. In the novel SEMS group, no early AEs were observed and no bile leakage into the abdominal cavity was observed on the computed tomography scan after the procedure. The median procedure time was significantly shorter in the novel SEMS group (17 min vs. 24 min, p = 0.03). RBO and median TRBO did not differ between the 2 groups. Conclusions: EUS-CDS without fistula dilation using the novel SEMS with a 5.9-Fr delivery system is technically feasible, straightforward, quick, and safe.

Atezolizumab-induced Encephalitis in a Patient with Hepatocellular Carcinoma: A Case Report and Literature Review.

We herein report a case of encephalitis in a 42-year-old woman with hepatocellular carcinoma following atezolizumab plus bevacizumab therapy. After two weeks of treatment, she was admitted for a high fever, impaired consciousness, and convulsive seizure refractory to diazepam. Magnetic resonance imaging revealed a hyperintense splenial lesion. A cerebrospinal fluid test excluded malignancy and infection. These findings were highly suggestive of a diagnosis of encephalitis due to atezolizumab, an immune-related adverse event. Steroid pulse therapy improved the fever and seizure. However, her incomplete right-sided paralysis and aphasia persisted. This is the first case report of encephalitis caused by atezolizumab plus bevacizumab therapy for hepatocellular carcinoma.

Exosome Transfer Between Pancreatic-cancer Cells Is Associated With Metastasis in a Nude-mouse Model.

BACKGROUND/AIM: Cancer-derived exosomes play an important role in metastasis. In the present study, we determined whether exosome transfer between cancer cells is associated with metastasis in a mouse model. MATERIALS AND METHODS: AsPC-1 human pancreatic-cancer cells expressing red fluorescent protein (RFP) and AsPC-1 human pancreatic-cancer cells transduced by exosome-specific pCT-CD63-green fluorescent protein (GFP), were co-injected into the spleen of nude mice. RESULTS: Both pancreatic-cancer cell lines grew in the spleen and metastasized to the liver, peritoneum, and lungs, as shown by color-coded imaging. The ratio of GFP-expressing exosomes incorporated in RFP-labeled AsPC-1 cells was statistically-significantly higher in the liver, lung, and peritoneal metastases than in the spleen. CONCLUSION: Exosome transfer between cancer cells is associated with metastasis. Exosome transfer may play a role in increasing the metastatic capability of the recipient cells.

Color-coded Imaging of the Fate of Cancer-cell-derived Exosomes During Pancreatic Cancer Metastases in a Nude-mouse Model.

BACKGROUND/AIM: Tumor-derived exosomes play important roles in tumor metastases. In this report, we observed the fate of tumor-derived exosomes in pancreatic cancer metastatic nude-mouse models using color-coded imaging. MATERIALS AND METHODS: Mia-PaCa-2 human pancreatic cancer cells expressing red fluorescent protein (RFP) were transduced by exosome-specific pCT-CD63-green fluorescent protein (GFP) and injected in the spleen of nude mice. RESULTS: Four weeks after injection of these cells into the spleen, liver metastases developed and tumor-derived exosomes were observed within the metastatic cancer cells and in Kupffer cells. Furthermore, tumor-derived exosomes diffused to bone marrow and lung cells, especially macrophages, without any metastases present. CONCLUSION: In the present study, we visualized the distribution of cancer-derived exosomes for the first time at the cellular level, in a pancreatic-cancer metastatic model.

Choline-deficient-diet Decreases Fibroblasts in the Circulating Tumor Cell (CTC) Microenvironment.

BACKGROUND/AIM: Circulating tumor cells (CTCs) may have an important role in metastasis. CTC clusters, which contain fibroblasts, indicate poor prognosis. In the present study, we used our malignant lymphoma metastatic mouse model to compare the effect of a choline-deficient-diet (CDD) and the control diet (CD) on fibroblasts in CTCs. MATERIALS AND METHODS: We compared the number and morphology of CTCs in CDD and CD mice using color-coded imaging with fluorescent proteins. Malignant lymphoma EL4 cells expressing RFP were injected in the spleen of transgenic C57B/6-GFP mice, which were fed a CDD or CD. Two weeks later, we harvested and observed the number of CTCs and fibroblast-like cells both in heart blood and portal blood. Imaging of CTC morphology was performed with smeared glass slides and in culture. RESULTS AND CONCLUSION: There was no significant difference in the number of CTCs between CDD and CD mice. The number of fibroblast-like cells in the CTC microenvironment in CD mouse portal blood was significantly larger than in CDD mouse portal blood. These differences may be caused by deficiency in choline that leads to less metastasis in choline-deficient-diet-induced fatty liver.

Color-coded Imaging of the Circulating Tumor Cell Microenvironment.

BACKGROUND/AIM: Circulating tumor cells (CTCs) may initiate metastasis. Some studies show that the number of CTCs and existence of CTC clusters can be prognostic. In the present study, our color-coded imaging nude mouse model of metastatic lymphoma was utilized to investigate the microenvironment of CTC clusters using fluorescent-protein imaging. MATERIALS AND METHODS: EL-4 mouse lymphoma cells expressing red fluorescent protein (RFP) were injected into the spleen of transgenic C57B/6-green fluorescent protein (GFP) mice. Three weeks later, the number of CTCs and CTC clusters both in heart blood and portal blood were quantified and characterized using confocal microscopy for color-coded imaging. RESULTS: There was no significant difference in the number of CTCs between heart and portal blood. CTC clusters comprised 8.8% of CTCs, determined by color-coded imaging. Heterotypic CTC clusters containing other types of cells were distinguishable from homotypic CTCs. Heterotypic CTC clusters comprising cancer cells and fibroblasts were more rare than homotypic ones. Heterotypic CTC clusters with fibroblasts were observed only in portal blood, not in heart blood. CONCLUSION: CTCs can have variable properties depending on the blood source. CTCs can form clusters, which may contain fibroblast that may play a role in promoting CTC metastasis. Our results demonstrate the concept of the CTC microenvironment (CME), which may play a critical role in CTC behavior, including of metastasis.

Color-coded Imaging Distinguishes Cancer Cells, Stromal Cells, and Recombinant Cancer-stromal Cells in the Tumor Microenvironment During Metastasis.

BACKGROUND/AIM: Our laboratory pioneered color-coded imaging of the tumor microenvironment (TME). We observed recruitment of cancer and stromal cells to the TME and recombination between cancer and stromal cells. The aim of the present study was to observe the dynamics of the TME by color-coded imaging during metastasis and in the formation of a pre-metastatic niche. MATERIALS AND METHODS: Red-fluorescent protein (RFP-expressing) mouse colon-cancer 26 cells were initially injected subcutaneously in green-fluorescent protein (GFP) nude mice. The resulting subcutaneous tumors were harvested and cultured. The cultured subcutaneous tumors contained RFP colon cancer cells, GFP stromal cells and recombinant cancer-stromal cells expressing yellow fluorescence. After 14 days culture, the cells were injected into the spleen. RESULTS: After splenic injection, colon-cancer 26 metastases were observed in the liver, ascites, and bone marrow. Using the Olympus FV1000 confocal microscope, the cells cultured from tumors and metastasis in each site were visualized. RFP colon-cancer cells, GFP stromal cells derived from host GFP nude mice, and recombinant yellow-fluorescent cells were observed in each organ. In addition, in the liver, areas with only GFP stromal cells were observed and assumed to be a pre-metastatic niche. CONCLUSION: Color-coded imaging demonstrated the dynamics of colon cancer and stromal cells at different metastatic sites including the formation of recombinant cancer-stromal cells.

Differential Organ-targeting and Cellular Characteristics of Metastatic Human Pancreatic Cancer Cell Lines in Mouse Models.

BACKGROUND/AIM: The lethal characteristic of pancreatic cancer is metastasis which is recalcitrant to currently-used chemotherapy. Our aim was to understand metastasis at the cellular level. We previously reported that multi-nucleate cells or spindle cells were more prominent in pancreatic cancer metastasis than in the primary tumor. In the present report, we investigated four representative human pancreatic cell lines for differences in cell morphology between the primary tumor and various metastatic organ targets for each cell line. MATERIALS AND METHODS: Human pancreatic cancer cell lines AsPC-1, Panc-1, KP2 and KP3 were used. Pancreatic cancer cells were injected into spleen of nude mice resulting in experimental metastasis to various organs which were observed at the cellular level when the organs were placed into culture. RESULTS: AsPC-1 and KP2 pancreatic cells formed many experimental liver metastases, in contrast to Panc-1 and KP3. Lung metastasis was only observed for AsPC-1. In the cultures established from the primary and metastatic tumors, multi-nucleate cells were found to be more prominent in the metastasis of the pancreatic cell lines with frequent metastasis, AsPC-1 and KP2. Spindle-like cells were observed prominently in AsPC-1 lung metastasis. CONCLUSION: Human pancreatic cancer cell lines have differential metastatic characteristics with regard to target organs and cell-morphology changes. Multi-nucleate and spindle cells may play an important role in pancreatic cancer metastasis to the liver and lung, respectively.