English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology.

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

Bleeding From a Ruptured, Extraluminally Growing Gastric Gastrointestinal Stromal Tumor Treated by Transcatheter Arterial Embolization: A Case Report.

A 49-year-old man with abdominal pain was referred to our hospital. Abdominal computed tomography showed an extraluminal tumor near the gastric anterior wall and intra-abdominal fluid collection. A ruptured intra-abdominal tumor was suspected, and emergency abdominal angiography was performed. Hemorrhage into the abdominal cavity was seen, and transcatheter arterial embolization (TAE) was performed, which stopped the bleeding. The tumor was surgically resected, and a diagnosis of an extraluminally growing gastric gastrointestinal stromal tumor was made. TAE should be considered for rare cases of extraluminally growing tumors with intra-abdominal hemorrhage.

Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.

Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

A case of non-Hodgkin lymphoma of the upper gingiva with minimal residual disease detected in cryopreserved ovarian tissue: A case report.

Recently, more than 200 live births following ovarian tissue cryopreservation (OTC) and transplantation in cancer survivors have been reported worldwide. However, cancer survivors with minimal residual disease (MRD) in cryopreserved ovarian tissue are at the risk of relapse through the graft. Here, we report a rare case of a 19-year-old female patient with non-Hodgkin lymphoma who had MRD in the ovary harvested for OTC. The patient was diagnosed with aggressive B-cell lymphoma after gingival biopsy. The 18F-fluoro-2-deoxy-D-glucose positron emission tomography scan performed before OTC showed no viable lesions in either ovary. However, on histological evaluation, we detected infiltration of lymphoma cells in the ovary. Informed consent about MRD is required even if there is no evidence of MRD in the ovary before OTC. Patients whose cryopreserved ovaries have MRD may require the development of alternative assisted reproductive technologies such as in vitro growth or artificial ovary.

Involvement of YKL-40-positive macrophages commonly identified in polymyositis and dermatomyositis in the pathogenesis of myositis: a retrospective study.

YKL-40 is implicated in inflammation and tissue repair, but no reports have investigated its involvement in myositis in polymyositis (PM) and dermatomyositis (DM). Therefore, we aimed to investigate the relationship between YKL-40 and PM/DM. We retrospectively enrolled 35 patients diagnosed with PM/DM along with 26 healthy controls (HCs). Both PM and DM were diagnosed according to Bohan and Peter's criteria. Serum YKL-40 levels were measured, age-corrected to YKL-40 percentile values, and compared to HCs. Patients with myositis without interstitial lung disease were also enrolled and compared to HCs. Immunofluorescence staining was performed to identify YKL-40-positive inflammatory cells in muscle biopsy samples from two patients each with PM and DM. Age-corrected serum YKL-40 levels were significantly higher in patients with PM/DM compared to HCs with and without lung disease; however, these levels decreased significantly after treatment. Immunohistochemical analysis showed infiltration of YKL-40-positive inflammatory cells into the intramuscular sheath and perimuscular membrane. Immunofluorescence staining showed CD68 expression in YKL-40-positive inflammatory cells, suggesting that these cells were macrophages. To the best of our knowledge, this is the first study to demonstrate that YKL-40-positive macrophages are present in PM and DM, indicating that YKL-40 may be involved in PM/DM.

The impact of contour maps on estimating the risk of gastrointestinal stromal tumor recurrence: indications for adjuvant therapy: an analysis of the Kinki GIST registry.

INTRODUCTION: Contour maps enable risk classification of GIST recurrence in individual patients within 10 postoperative years. Although contour maps have been referred to in Japanese guidelines, their usefulness and role in determining indications for adjuvant therapy is still unclear in Japanese patients. The aims of this study are to investigate the validity of contour maps in Japanese patients with GIST and explore the new strategy for adjuvant therapy. MATERIALS AND METHODS: A total of 1426 Japanese GIST patients who were registered to the registry by the Kinki GIST Study Group between 2003 and 2012 were analyzed. Patients who had R0 surgery without perioperative therapy were included in this study. The accuracy of contour maps was validated. RESULTS: Overall, 994 patients have concluded this study. Using contour maps, we validated the patients. The 5-year recurrence-free survival rates of patients within the GIST classification groups of 0-10%, 10-20%, 20-40%, 40-60%, 60-80%, 80-90%, and 90-100% were 98.1%, 96.6%, 92.3%, 48.0%, 37.3%, 41.0% and 42.4%, respectively. We confirmed that this classification by contour maps was well reflected recurrence prediction. Further, in the high-risk group stratified by the modified National Institutes of Health consensus criteria (m-NIHC), the 10-year RFS rate was remarkably changed at a cutoff of 40% (0-40% group vs. 40-100% group: 88.7% vs. 50.3%, p < 0.001). CONCLUSION: Contour maps are effective in predicting individual recurrence rates. And it may be useful for the decision of individual strategy for high-risk patients combined with m-NIHC.

Treatment strategy for successful conversion surgery in clinical stage IVB gastric cancer.

INTRODUCTION: Recent advances in chemotherapy have resulted in successful conversion surgery (CS) for clinical stage (cStage) IVB gastric cancer (GC). This study aimed to evaluate the success rate of CS in clinical practice and determine optimal treatment strategies. METHODS: Totally, 166 patients with cStage IVB gastric and gastroesophageal junction adenocarcinoma, who underwent chemotherapy at Hyogo Medical University Hospital between January 2017 and June 2022, were included. CS was performed after confirming tumor to be M0 based on imaging and/or staging laparoscopy, except for resectable liver metastases. Preoperative chemotherapy was continued for at least 6 months provided that adverse events were manageable. RESULTS: Of 125 eligible patients, 23 were treated with CS, achieving a conversion rate of 18.4% and an R0 resection rate of 91.3%. The median duration of preoperative chemotherapy was 8.5 months; the median number of cycles was eight. The highest conversion rate was observed in patients receiving first-line treatment (14.4%), followed by those receiving second and third lines (5.8% and 2.3%, respectively). The median survival time in patients who received CS was significantly longer than that in patients who continued chemotherapy alone (56.7 versus 16 months, respectively, P < 0.0001). There was no significant difference in the 3-year overall survival between the patients who achieved CS after first-line treatment (63.2%, n = 18) and those who achieved CS after second- or third-line treatment (66.7%, n = 5). CONCLUSION: Consistent chemotherapy strategies could lead to successful CS and improved prognosis in a greater number of patients with cStage IVB GC, regardless of line of treatment.

Frequency and Distribution of Sheet and Nodular Calcification in Coronary Arteries in Japanese Patients.

Whether a nodular calcification (NC), which is the precursor to intracoronary thrombosis, is focally or diffusely distributed in the coronary tree has major implications for ongoing efforts to identify. This study aimed to investigate the frequency and spatial distribution patterns of sheet calcification (SC) and NC in a 3-vessel examination of autopsied human hearts.A total of 323 coronary artery specimens from 110 cadavers were obtained from autopsy cases. After fixation and decalcification, the coronary artery trees were cut every 5 mm into 4-µm transverse cross-sections for histological assessment. An SC was defined as a plate-like calcification of > 1 quadrant of the vessel or > 3 mm in diameter, and NC as nodular calcium deposits separated by fibrin, and a deposit size > 1 mm in diameter.Of the 6,306 histological cross-sections, SCs and NCs were identified in 1,627 (26%) and 233 (4%) cross-sections, respectively. SCs and NCs had a similar distribution pattern in all 3 coronary arteries. In the left anterior descending artery (LAD), NCs were predominantly located in the proximal segment: the first 45 mm from the LAD ostium (72%) and the first 60 mm from the LAD ostium (84%), respectively. However, NCs were evenly distributed throughout the length of the coronary artery in the right coronary artery (RCA) and left circumflex artery (LCX).NCs coexisted with SCs, and tended to cluster in predictable parts within the proximal segments of the LAD, but were evenly distributed throughout the RCA and LCX in coronary arteries from cadavers.

Surgery for multiple gastric gastrointestinal stromal tumors and large esophageal diverticulum related to germline mutation of the KIT gene: a case report.

BACKGROUND: Familial gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract caused by germline gain-of-function mutations in the KIT gene or platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations cause not only multiple GISTs but also diffuse hyperplasia of interstitial cells of Cajal (ICCs), which is related to esophageal motility disorder. CASE PRESENTATION: A 53-year-old man was referred to our hospital because of anemia and dysphagia. Fifteen years earlier, he had undergone a laparoscopic partial gastrectomy for multiple gastric GISTs with a germline mutation in exon 17 of the KIT gene. An upper gastrointestinal endoscopy revealed that the patient had multiple gastric GISTs and a large esophageal diverticulum directly above the esophagogastric junction. The largest gastric tumor was 7 cm, with a delle that might cause bleeding. Because the patient presented with dysphagia, we performed video-assisted thoracic esophagectomy and laparoscopic-assisted proximal gastrectomy simultaneously. The patient had survived without metastasis for 4 years after surgery and dysphagia had improved. CONCLUSIONS: This is the first report of successful laparoscopic-thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.

[Port Site Recurrence After Laparoscopic Nephrectomy for Renal Cell Carcinoma --Report of Two Cases and Literature review-].

CASE 1: A male in his 60s underwent a right transperitoneal laparoscopic partial nephrectomy procedure for a right renal tumor. Rupture of a renal cyst located close to the tumor occurred intraoperatively. The histopathological diagnosis was clear cell renal cell carcinoma (CCRCC), pT1aN0M0, G2, v0, with negative resection margins. At 84 months after surgery, computed tomography (CT) revealed a 10 mm mass in the rectus abdominis muscle at the camera port site used for the partial nephrectomy. An open lumpectomy was then performed and the histopathological diagnosis was CCRCC. One year later, a 40 mm sized mass was detected in the mesentery of the small intestine by CT, which was removed laparoscopically with part of the mesentery and diagnosed as CCRCC. Since that surgery, the patient has been free from recurrence for 8 years. CASE 2: A male in his 60s underwent a left retroperitoneal laparoscopic nephrectomy procedure for a left renal tumor. The histopathological diagnosis was CCRCC, pT1aN0M0, G1, v0, with negative resection margins. At 31 months after surgery, CT revealed a 32 mm mass in the retroperitoneal cavity at the right hand port site used for the laparoscopic nephrectomy. The mass was removed with part of the twelfth rib and erector spinae muscles in a lump, and the histopathological diagnosis was CCRCC. Since that surgery, the patient has been free from recurrence for 19 months. For the treatment of solitary port site recurrence of renal cell carcinoma after a laparoscopic radical/partial nephrectomy, we recommend surgical resection for a good prognosis.

Clinical Significance of Early Venous Filling Detected via Preoperative Angiography in Glioblastoma.

Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between 1 April 2013 and 31 March 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of the 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angiography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, p = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.

Detection of Abdominal Lymph Node Metastasis from Pancreatic Neuroendocrine Tumor by Somatostatin Receptor Scintigraphy: Comparison with Somatostatin Receptor Type 2 Immunostaining.

We report a 58-year-old male with a histopathologically proven grade 2 (G2) pancreatic neuroendocrine neoplasm and multiple abdominal node metastases by use of a laparoscopic pancreatic body and tail resection procedure, plus abdominal lymph node dissection. A primary pancreatic tail neuroendocrine tumor sized 20 × 25 mm was detected by contrast-enhanced computed tomography, somatostatin receptor scintigraphy (SRS), and fluorodeoxyglucose positron emission tomography (FDG-PET) examinations and pathologically diagnosed as a pancreatic neuroendocrine tumor (PNET, G2) based on positive immunostaining for somatostatin receptor (SSTR) type 2. Of three metastatic histopathological lymph nodes, two measured 18 × 21 and 10 × 12 mm, respectively, with whole strong SSTR immunostaining showing moderate uptake in SRS findings, whereas the other node, sized 8 × 10 mm, had strong SSTR immunostaining only in a small 6 × 6-mm-sized portion and showed no uptake in SRS findings, likely because of the limited spatial resolution of scintigraphy. On the other hand, only the largest node (18 × 21 mm) was visualized by FDG-PET. SRS may be useful for metastatic lymph node diagnosis based on SSTR immunostaining, though a disadvantage is the spatial resolution limitation.

Prognostic role of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography with an image-based harmonization technique: A multicenter retrospective study.

Objectives: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography-based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non-small cell lung cancer. Methods: We retrospectively examined 495 patients with clinical stage I non-small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Results: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Conclusions: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non-small cell lung cancers.

Medroxyprogesterone as the Initial Systemic Treatment of Recurrent Endometrial Cancer: A Single Institutional Study.

BACKGROUND/AIM: Hormonal treatment is the preferred initial systemic therapy for patients with advanced or recurrent G1 or G2 endometrial cancer (EC) in terms of efficacy, toxicity, and economy. Few reports are available on the topic and we, therefore, conducted a retrospective study. PATIENTS AND METHODS: Patients with EC who received high-dose medroxyprogesterone (MPA) at our Hospital between January 2010 and December 2022 were reviewed. Patients who were treated for fertility preservation or had a history of systemic chemotherapy other than adjuvant therapy were excluded. RESULTS: Sixteen patients who were eligible for study inclusion had recurrent G1 or G2 EC. Their median age was 65 years (range=51-82 years), median body mass index was 22.6 kg/m2 (range=15.3-43.2 kg/m2), and all patients had an ECOG Performance Status of 0. All patients received 200 mg/day of MPA, and eight patients concomitantly received 100 mg/day of aspirin. None of the patients experienced severe adverse events. One patient had grade 2 deep vein thrombosis. Two patients discontinued MPA treatment because of adverse events. The response rate was 44% [95% confidence interval (CI)=20-68%] and median progression-free survival (PFS) was 6.9 months (95% CI=7.5-26 months). Four of 16 patients had PFS longer than 12 months, all of whom had positive tissue estrogen receptor (ER) and progesterone receptor (PR), and PFS at 2 years was 35% (95% CI=10.2-59.8%). CONCLUSION: Hormone therapy is effective long-term in ER- and PR-positive EC and can be recommended as initial systemic therapy. Toxicity is mild and manageable.

Primordial follicles remaining in young cancer survivors who received chemotherapy.

AIM: Ovarian tissue cryopreservation (OTC) is performed for fertility preservation in cancer patients undergoing chemotherapy. Although anti-Müllerian hormone is used as a marker for ovarian reserve, serum levels do not always correlate with the number of follicles. Additionally, the follicle development stage most affected by chemotherapy is unclear. We examined the association between serum anti-Müllerian hormone levels and the number of remaining primordial follicles after chemotherapy, as well as which follicle stage is most affected by chemotherapy before ovarian cryopreservation. METHODS: Thirty-three patients who underwent OTC were divided into the chemotherapy (n = 22) and non-chemotherapy (n = 11) groups; their ovarian tissues underwent histological examination. Pathological ovarian damage induced by chemotherapy was assessed. Ovarian volumes were estimated from weights. We compared the number of follicles at each developmental stage as a percentage of primordial follicles between the groups. The relationship between serum anti-Müllerian hormone level and primordial follicle density was analyzed. RESULTS: The chemotherapy group had a significantly lower serum anti-Müllerian hormone level, ovarian volume, and density of developing follicles than the non-chemotherapy group. Serum anti-Müllerian hormone levels correlated with primordial follicle density only in the non-chemotherapy group. The chemotherapy group had significantly lower numbers of primary and secondary follicles. CONCLUSIONS: Chemotherapy induces ovarian damage and follicle loss. However, serum anti-Müllerian hormone level does not always reflect the number of primordial follicles after chemotherapy, and chemotherapy more significantly affects primary and secondary follicles than primordial follicles. Many primordial follicles remain in the ovary after chemotherapy, supporting OTC for fertility preservation.

Long-term outcomes of a phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumors of the stomach.

BACKGROUND: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking. METHODS: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6-9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years. RESULTS: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more. CONCLUSIONS: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence.

An increase in tumor-infiltrating lymphocytes after treatment is significantly associated with a poor response to neoadjuvant endocrine therapy for estrogen receptor-positive/HER2-negative breast cancers.

BACKGROUND: The reason for the poor prognosis of estrogen receptor (ER) + /human epidermal growth factor receptor 2 (HER2)- breast cancer patients with high levels of tumor-infiltrating lymphocytes (TILs) is poorly understood. The association between TILs and response to neoadjuvant endocrine therapy (NET) was examined. METHODS: We recruited 170 patients with ER + /HER2- breast cancer who were treated with preoperative endocrine monotherapy. TILs were evaluated before and after NET, and their changes were noted. Furthermore, T cell subtypes were examined using CD8 and FOXP3 immunohistochemical analyses. Neutrophil and lymphocyte counts in the peripheral blood were analyzed with reference to TIL levels or changes. Responders were defined as Ki67 expression levels ≤ 2.7% after treatment. RESULTS: Post-treatment (p = 0.016), but not pre-treatment (p = 0.464), TIL levels were significantly associated with the response to NET. TIL levels increased significantly after treatment among non-responders (p = 0.001). FOXP3 + T cell counts increased significantly after treatment in patients with increased TILs (p = 0.035), but not in those without increased TILs (p = 0.281). Neutrophil counts decreased significantly after treatment in patients without increased TILs (p = 0.026), but not in patients with increased TILs (p = 0.312). CONCLUSION: An increase in TILs after NET was significantly associated with a poor response to NET. Given that FOXP3 + T-cell counts increased, and neutrophil counts did not decrease in patients with increased TILs after NET, the induction of an immunosuppressive microenvironment was speculated to play a role in the inferior efficacy. These data might partially indicate the involvement of the immune response in the efficacy of endocrine therapy.