DPPA3 facilitates genome-wide DNA demethylation in mouse primordial germ cells.

BACKGROUND: Genome-wide DNA demethylation occurs in mammalian primordial germ cells (PGCs) as part of the epigenetic reprogramming important for gametogenesis and resetting the epigenetic information for totipotency. Dppa3 (also known as Stella or Pgc7) is highly expressed in mouse PGCs and oocytes and encodes a factor essential for female fertility. It prevents excessive DNA methylation in oocytes and ensures proper gene expression in preimplantation embryos: however, its role in PGCs is largely unexplored. In the present study, we investigated whether or not DPPA3 has an impact on CG methylation/demethylation in mouse PGCs. RESULTS: We show that DPPA3 plays a role in genome-wide demethylation in PGCs even before sex differentiation. Dppa3 knockout female PGCs show aberrant hypermethylation, most predominantly at H3K9me3-marked retrotransposons, which persists up to the fully-grown oocyte stage. DPPA3 works downstream of PRDM14, a master regulator of epigenetic reprogramming in embryonic stem cells and PGCs, and independently of TET1, an enzyme that hydroxylates 5-methylcytosine. CONCLUSIONS: The results suggest that DPPA3 facilitates DNA demethylation through a replication-coupled passive mechanism in PGCs. Our study identifies DPPA3 as a novel epigenetic reprogramming factor in mouse PGCs.

Conversion surgery for initially unresectable locally advanced pancreatic ductal adenocarcinoma after chemotherapy followed by carbon-ion radiotherapy: a case report.

BACKGROUND: Recent advances in chemotherapy and chemoradiotherapy have enabled conversion surgery (CS) to be performed for selected patients with initially unresectable locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Many studies indicate CS might extend the survival of patients with initially unresectable LA PDAC. However, several clinical questions concerning CS remain, such as the optimal preoperative treatment. Carbon-ion radiotherapy (CIRT) is a unique radiotherapy that offers higher biological effectiveness than conventional radiotherapy. Here, we report a long-term survival case with initially unresectable LA PDAC who underwent CS after chemotherapy followed by CIRT. CASE PRESENTATION: The patient was a 72-year-old Japanese woman with unresectable LA pancreatic head cancer with tumor contact to the superior mesenteric artery (SMA). She underwent four courses of chemotherapy (gemcitabine plus nanoparticle albumin-bound paclitaxel). However, the lesion did not shrink and tumor contact with the SMA did not improve after chemotherapy. Because the probability of achieving curative resection was judged to be low, she underwent radical dose CIRT, and chemotherapy was continued. She complained of vomiting 2 months after CIRT. Although imaging studies showed no tumor growth or metastasis, a duodenal obstruction which was speculated to be an adverse effect of CIRT was observed. She could not eat solid food and a trans-nasal feeding tube was inserted. Therapeutic intervention was required to enable enteral nutrition. We proposed several treatment options. She chose resection with the expectation of an anti-tumor effect of chemotherapy and CIRT rather than course observation with tube feeding or bypass surgery. Therefore, subtotal-stomach-preserving pancreatoduodenectomy with portal vein resection was performed as CS. Pathological examination of the resected specimen revealed an R0 resection with a histological response of Evans grade IIA. Postoperatively, she recovered uneventfully. Adjuvant chemotherapy with tegafur/gimeracil/oteracil (S1) was administrated. At the time of this report, 5 years have passed since the initial consultation and she has experienced no tumor recurrence. CONCLUSIONS: The present case suggests that multidisciplinary treatment consisting of a combination of recent chemotherapy and CIRT may be beneficial for unresectable LA PDAC. However, further studies are required to assess the true efficacy of this treatment strategy.

[Perioperative Nutritional and Rehabilitation Therapy for Esophagectomy Cancer Patients].

The combination of nutritional therapy and rehabilitation in the perioperative period is expected to have synergistic effects on nutrition, muscle mass, inflammation, and other systemic conditions. It is important to form a perioperative team composed of members from other professions in order to implement a nutritional rehabilitation program efficiently and explain it in an easy-to-understand manner to patients. Nutritional guidance by a dietitian is provided from the preoperative outpatient visit, and a target daily nutritional intake is established. A feeding tube or percutaneous endoscopic gastrostomy (PEG) may be considered for patients with inadequate oral intake. Products containing branched-chain amino acids should be administered after exercise. Preoperative upper and lower limb muscle strengthening training is provided by physical and occupational therapists, and postoperative coughing and standing exercises are performed at the same time to facilitate the introduction of postoperative training. Postoperative nutritional management is primarily enteral nutrition through a tube enterostomy tube. Oral intake is resumed after fluoroscopy on day 7. The patient will be trained in bed for joint mobility, sitting on the edge of the bed, and standing on day 1. Gait training is started on day 2. After the third day, gait training is performed in the ward, and stretching, strength training, bicycle ergometer, and other exercises are performed in the training room. It is important to provide seamless nutritional rehabilitation therapy from preoperative to postoperative outpatient.

Anaplastic lymphoma kinase-positive inflammatory myofibroblastic tumor of the breast: a case report and review of the literature.

BACKGROUND: Few reports of inflammatory myofibroblastic tumor (IMT) of the breast have been published worldwide. Furthermore, primary anaplastic lymphoma kinase (ALK)-positive IMT of the breast is extremely rare. To date, only six patients with ALK-positive IMT have been reported in the literature. CASE PRESENTATION: A 52-year-old woman underwent a medical examination, and a left breast mass was detected. She did not feel a mass in her chest. Mammography showed a focal asymmetric density at the lower outer portion of the left breast. Breast ultrasonography showed a 1.2-cm hypoechoic lesion with relatively clear boundaries and poor blood flow. Magnetic resonance imaging and computed tomography revealed a solitary heterogeneous mass in the left breast. Pathologic examination revealed a fibrosing lesion with proliferation of fibroblastic cells arranged in a storiform pattern and admixed inflammatory cells. Immunohistochemical examination showed that the tumor cells were positive for ALK. Under the preoperative diagnosis of IMT, we performed partial mastectomy with adequate margins. The postoperative diagnosis was pathologically confirmed as IMT. Immunohistochemical staining also showed overexpression of ALK-1 in the tumor. The patient had a good clinical course for 24 months postoperatively, without recurrence or metastasis. CONCLUSIONS: IMT of the breast shows nonspecific imaging findings, making preoperative diagnosis difficult. Nevertheless, IMT has the characteristics of low-grade neoplasms with recurrence, invasion, and metastatic potential. Our report emphasizes the importance of determining a treatment plan as soon as possible based on an accurate diagnosis to improve the prognosis of this disease.

Mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater: a case report.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms of the ampulla of Vater are rare and heterogenous, making it difficult to achieve a definitive preoperative diagnosis. Herein, we describe a patient in whom a provisional diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater was made preoperatively. CASE PRESENTATION: Computed tomography revealed an enhancing periampullary tumor in a 69-year-old man with obstructive jaundice. Subsequent duodenoscopy revealed an ulcerated lesion in the swollen ampulla of Vater, from which six biopsies were collected. Pathological examination revealed adenocarcinoma in five of them. The remaining one was a neuroendocrine neoplasm according to immunohistochemical analysis. With a provisional diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy with modified Child's reconstruction and was discharged without complications. Pathological examination revealed both adenocarcinoma and neuroendocrine carcinomas, each accounting for ≥ 30% of the tumor, resulting in a definitive diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater. Lymph node metastases with neuroendocrine components were also observed. Adjuvant chemotherapy was not administered because of the patient's renal dysfunction. Liver and lymph node metastases were detected 2 months after surgery, the neuroendocrine component being considered responsible for that relapse. The patient underwent platinum-based chemotherapy at 50% dosage, which initially resulted in significant tumor shrinkage; however, he died 6 months after surgery. CONCLUSIONS: While these tumors' heterogeneity make definitive preoperative diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater difficult, the possibility of this disease can be considered by careful examination. Further study is needed to establish the optimal diagnostic criteria and treatment strategy.

Relationship between prognostic impact of N3 lymph node metastasis at the root of the feeding artery and location of colon cancer.

PURPOSE: To determine whether N3 nodal involvement predicts outcomes and whether its prognostic implications vary with tumor location in patients with Stage III colon cancer (CC). METHODS: We defined N3 as lymph node metastases near the bases of the major feeding arteries. We retrospectively examined recurrence rates and patterns by tumor location and sites of lymph node metastases in 57 patients with N3 CC who had undergone curative resections between January 2000 and March 2019. Survival analysis was performed to compare the prognoses of patients with and without N3 lymph node metastasis. RESULTS: Most N3 patients had large tumors (T ≥ 3); five had T2 disease. Recurrence occurred quickly in one patient with T2N3M0 disease. Multivariate survival analysis demonstrated that N3 lymph node metastasis is an independent predictor of poor prognosis in Stage III CC patients (P < 0.001). Categorizing N3 patients according to UICC-TNM staging system does not stratify risk of recurrence (P = 0.970). To investigate the impact of tumor location on recurrence risk, we classified N3 CC into two subtypes according to tumor location: metastasis at the base of the superior mesenteric artery in right-sided CC and inferior mesenteric artery in left-sided CC. The former was found to have a statistically significant poorer prognosis than the latter (P = 0.091). CONCLUSION: N3 is a robust prognostic marker in CC patients. Recurrence risk varies by tumor location. N3 right-sided CCs with lymph node metastasis at the base of the superior mesenteric artery have poorer prognoses than do N3 left-sided CCs.

A region-dependent allele-biased expression of Dopa decarboxylase in mouse brain.

Genomic imprinting is an epigenetic event in which genes are expressed only from either the paternal or maternal allele. Dopa decarboxylase (Ddc), is an imprinted gene that encodes an enzyme which catalyzes the conversion of L-dopa to dopamine. Although Ddc has been reported to be paternally expressed in embryonic and neonatal hearts, its expression pattern in the brain has been controversial. To visualize Ddc-expressing neurons, we established a knock-in mouse carrying a humanized Kusabira orange 1 (hKO1) reporter cassette at the Ddc locus (Ddc-hKO1). The expression of Ddc-hKO1 was detected in all known Ddc-positive cells in the brains of embryonic, neonatal, adult, and aged mice. We further developed an efficient purification method for Ddc-hKO1-positive neurons using a cell sorter. RNA sequencing analysis confirmed the enrichment of dopaminergic, serotonergic and cholinergic neurons in Ddc-hKO1-positive cell population recovered using this method. A detailed analysis of Ddc-hKO1 paternally and maternally derived heterozygous mice combined with immunostaining revealed that Ddc was preferentially expressed from the maternal allele in ventral tegmented area (VTA), substantia nigra pars compacta (SNc), and retrorubral field (RRF); while it was expressed from both alleles in dorsal raphe nucleus (DR). These results indicate that Ddc exhibit an allele-specific expression pattern in different brain regions, presumably reflecting the diverse regulatory mechanisms of imprinting.

Piezo Actuator-Driven Pulsed Water Jet for Neurosurgery: Laboratory Evaluation with the Swine Model and Implications of Mechanical Properties.

Object Pulsed water jet is an emerging surgical instrumentation intended to achieve both maximal lesion resection and functional maintenance through preservation of fine vessels and minimal damage to the surrounding tissue. The piezo actuator-driven pulsed water jet (ADPJ) is a new technology that can deliver a precisely controlled uniform and efficient pulsed water jet with minimum water flow. The present study evaluated the ADPJ system in preclinical animal studies in the swine brain, and investigated breaking strength, one of the parameters for mechanical properties, to elucidate the mechanism of tissue selectivity for tissue dissection by the water jet. Methods This system consisted of a pump chamber driven by a piezo actuator, a stainless steel tube, and a nozzle (internal diameter: 0.15 mm). The water was supplied at 6 ml/min. The relationship between input voltage (3-25 V at 400 Hz) and peak pressure was measured using a pressure sensor through a sensing hole. Temporal profile of dissection depth during moving application was evaluated using gelatin brain phantom and swine brain. The dissected specimens were evaluated histologically. The mechanical property (breaking strength) of swine brain was measured by a compact table-top universal tester. Results Peak pressure increased linearly with increase in the input voltage, which reflected dissection depth in both the gelatin brain phantom and swine brain. Small arteries were preserved, and minimum damage to surrounding tissues occurred. The breaking strength of arachnoid membrane (0.12 ± 0.014 MPa) was significantly higher compared to gray matter (0.030 ± 0.010 MPa) and white matter (0.056 ± 0.009 MPa) (p < 0.05). The breaking strength of gray matter corresponded to that of 3 wt% gelatin, and that of white matter corresponded to a value between those of 3.5 and 4 wt% gelatin, and the dissection depth seemed to be estimated by 3-4 wt% gelatin. Conclusion The present study suggests that the ADPJ system has the potential to achieve accurate tissue dissection with preservation of blood vessels in neurosurgery. The difference in breaking strength may explain the tissue selectivity between brain parenchyma and tissue protected by the arachnoid membrane.

[Idiopathic and Iatrogenic Esophageal Rupture].

One of the most common indications for emergency surgery is full-layer rupture of the esophagus. Iatrogenic injury to the esophagus is the most frequent cause of esophageal rupture, followed by spontaneous rupture. If the patient is not treated promptly, mediastinitis can develop into a serious and life-threatening condition. Diagnosis and treatment must be initiated as soon as possible. Spontaneous esophageal rupture often requires emergency surgical intervention. Various surgical techniques for esophageal rupture have been reported, including transabdominal or transthoracic, open or thoracoscopic surgery, drain placement, and surgical position. There have been reports of thoracoscopic primary closure of esophageal tear and thoracic drainage in the prone or lateral decubitus position. On the other hand, iatrogenic esophageal rupture is often treated conservatively, those patients require fasting, administration of antibiotics and proton pump inhibitors, suctioning and decompression using nasogastric tube, and chest drainage if necessary. In addition, close follow-up should be maintained so that the opportunity for surgery is not missed when necessary. Although esophageal rupture is relatively rare and is not an everyday occurrence, it is an urgent condition that requires prompt diagnosis and treatment, so it is necessary to have prior knowledge and to respond promptly.

Comparison of CEA and CA19-9 as a predictive factor for recurrence after curative gastrectomy in gastric cancer.

BACKGROUND: Our aim of was to compare importance of the tumor markers (TMs) serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 in prediction of recurrence after curative gastrectomy for gastric cancer. METHODS: We reviewed retrospectively the clinical records of 149 patients who underwent curative gastrectomy for stage I-III gastric cancer and whose CEA and CA19-9 levels were determined once preoperatively and for more than 3 years postoperatively. We investigated whether the clinicopathological characteristics of patients including age, sex, pathological disease stage, operative approach, type of gastrectomy, and degree of lymph node dissection as well as preoperative positivity of CEA and CA19-9 were risk factors for recurrence in univariate and multivariate analyses. Rate of recurrence was compared between patients positive and negative for postoperative CEA or CA19-9. We also calculated sensitivity, specificity, positive and negative predictable values of postoperative positivity of CEA and CA19-9 for recurrence. The lead time was compared between CEA and CA19-9 that was defined as the time of the first detection of increases in tumor markers and confirmation of recurrence on imaging modalities. RESULTS: The number of patients positive for preoperative CEA was 25 (17%) and for CA19-9 was 11 (7%). Recurrence was confirmed in 29 (19%) patients. Stage III disease, preoperative positivity for CA19-9 but not CEA, and total gastrectomy were risk factors for recurrence in univariate analysis, but stage III disease was the only risk factor for recurrence in multivariate analysis. Forty and 15 patients were positive for postoperative CEA and CA19-9, respectively. The recurrence rate of 47% (7/15) in patients positive for postoperative CA19-9 was greater than that in negative patients (22/134 = 16%), but it did not differ between patients who were positive or negative for postoperative CEA. Specificity for CA19-9 was greater than that for CEA (P < 0.05). The lead time of CEA (3.9 ± 4.7 months) was not different from that of CA19-9 (6.1 ± 7.1 months). CONCLUSIONS: These results indicate that CA19-9 rather than CEA is likely to be more useful for the detection of recurrence after curative gastrectomy for gastric cancer.

Perioperative Administration of Cystine and Theanine Suppresses Inflammation and Facilitates Early Rehabilitation and Recovery after Esophagectomy: A Randomized, Double-Blind, Controlled Clinical Trial.

Oral administration of cystine and theanine (CT) increases glutathione levels to modulate the inflammatory response, which has yet to be sufficiently explored for patients' recovery and early rehabilitation. We planned a randomized, double-blind, placebo-controlled trial to determine whether perioperative oral administration of CT promotes recovery after esophagectomy. Patients were randomized into either CT or placebo groups, who received preoperative and postoperative treatments for 4 and 13 days, respectively. The main outcome measures were triaxial accelerometer readings, inflammation indicators, a 6 min walk test (6MWT), and a quality of life questionnaire (QoR-40). The study involved 32 patients. Although the CT group (n = 16) showed better patient activity across the investigated period, there was no significant difference between the two groups. However, white blood cell count on postoperative days (POD) 2 and 10, neutrophil count (POD 2, 7, and 10), and C-reactive protein level (POD 13) in the CT group were significantly lower than in the placebo group. Furthermore, 6MWT on POD 7 and QoR-40 on POD 13 were significantly higher in the CT group than those in the placebo group. This study suggests that perioperative administration of CT may contribute to early recovery and rehabilitation after esophagectomy via suppression of inflammatory response.

Cross-sectional area of psoas muscle as a predictive marker of anastomotic failure in male rectal cancer patients: Japanese single institutional retrospective observational study.

PURPOSE: Preoperative sarcopenia worsens postoperative outcomes in various cancer types including colorectal cancer. However, we often experienced postoperative anastomotic leakage in muscular male patients such as Judo players, especially in rectal cancer surgery with lower anastomosis. It is controversial whether the whole skeletal muscle mass impacts the potential for anastomotic failure in male rectal cancer patients. Thus, the purpose of this study was to clarify whether skeletal muscle mass impacts anastomotic leakage in rectal cancer in men. METHODS: We reviewed the medical charts of male patients suffering from rectal cancer who underwent colo-procto anastomosis below the peritoneal reflection without a protective diverting stoma. We measured the psoas muscle area and calculated the psoas muscle index. RESULTS: One hundred ninety-seven male rectal cancer patients were enrolled in this study. The psoas muscle index was significantly higher in patients with anastomotic leakage (P<0.001). Receiver operating characteristic curve determined the optimal cut-off value of the psoas muscle index for predicting anastomotic leakage as 812.67 cm2/m2 (sensitivity of 60% and specificity of 74.3%). Multivariate analysis revealed that high psoas muscle index (risk ratio [RR], 3.933; P<0.001; 95% confidence interval [CI], 1.917-8.070) and super low anastomosis (RR, 2.792; P=0.015; 95% CI, 1.221-6.384) were independent predictive factors of anastomotic leakage. CONCLUSION: This study showed that male rectal cancer patients with a large psoas muscle mass who underwent lower anastomosis had a higher rate of postoperative anastomotic leakage.

Effects of transgene insertion loci and copy number on Dnmt3L gene silencing through antisense transgene-derived PIWI-interacting RNAs.

PIWI-interacting RNAs (piRNAs), which are germ cell-specific small RNAs, are essential for spermatogenesis. In fetal mouse germ cells, piRNAs are synthesized from sense and antisense RNAs of transposable element sequences for retrotransposon silencing. In a previous study, we reported that transgenic mice expressing antisense-Dnmt3L under the control of the Miwi2 promoter (Tg-Miwi2P-asDnmt3L) exhibited piRNA-mediated DNMT3L down-regulation. In this study, two transgene integration loci (B3 and E1) were identified on chromosome 18 of the Tg-Miwi2P-asDnmt3L mice; these loci were weak piRNA clusters. Crossbreeding was performed to obtain mice with the transgene cassette inserted into a single locus. DNMT3L was silenced and spermatogenesis was severely impaired in mice with the transgene cassette inserted at the B3 locus (Tg-B mice). In contrast, spermatogenesis in mice bearing the transgene at the E1 locus (Tg-E mice) was normal. The number of piRNAs for Dnmt3L in Tg-B mice was eightfold higher than that in Tg-E mice. Therefore, both gene silencing and impaired spermatogenesis depended on the transgene copy number rather than on the insertion loci. Additionally, the endogenous Dnmt3L promoter was not methylated in Tg mice, suggesting that Dnmt3L silencing was caused by post-transcriptional gene silencing. Based on these data, we discuss a piRNA-dependent gene silencing mechanism against novel gene insertions.

Gallbladder Ciliated Foregut Cyst Suspected of Malignancy Preoperatively.

BACKGROUND: Gallbladder ciliated foregut cysts (CFCs) of the lower diaphragm are extremely rare. Furthermore, they are rarely suspected of malignancy preoperatively. Case Presentation. A 50-year-old woman was referred to our hospital for further examination and treatment of a gallbladder tumor that was detected using abdominal ultrasonography (US). After a close inspection, she was diagnosed with a gallbladder tumor that was possibly malignant. Accordingly, open whole layer cholecystectomy was performed because intraoperative US revealed a tumor located on the intraperitoneal side of the gallbladder, and a rapid intraoperative pathological diagnosis identified no malignancy. A postoperative pathological examination revealed a cystic lesion with thin walls covered with ciliated epithelium, which laid on a connective tissue with smooth muscle fibers. Based on the above results, the final pathological diagnosis was CFC of the gallbladder without malignancy. CONCLUSIONS: Cases of gallbladder CFC can be considered as cysts requiring treatment owing to CFCs' potential for malignant transformation and high-frequency symptoms.

Ribosomal stress induces 2-cell embryo-like state transition of the mouse ESCs through p53 activation.

Embryonic stem cells (ESCs) maintain a pluripotent state and genome integrity in long-term culture. A rare population of ESCs showing 2-cell embryo-specific gene expression is believed to play critical roles in sustainable pluripotency and genome stability. However, the molecular mechanism controlling this transition to a 2-cell embryo-like (2CL) state remains unclear. We carried out screening to search for the factors involved in 2CL state induction and found a ribosomal RNA processing factor, Pum3 to be a candidate. Increased 2CL state population accompanied with an accumulation of pre-ribosomal RNA and activated p53 in the Pum3-KO ESC. Furthermore, the increase of 2CL state cells in the Pum3-KO ESCs was completely abrogated by the deletion of p53. The DNA damage induced by the Ultraviolet light (UV) irradiation and Zeocin promoted the transition to a 2CL state in a p53-dependent manner. Thus, our study provides new insights into a 2CL state transition mechanism through stress-dependent p53 activation of ESCs.

MORC3, a novel MIWI2 association partner, as an epigenetic regulator of piRNA dependent transposon silencing in male germ cells.

The PIWI (P-element-induced wimpy testis)-interacting-RNA (piRNA) pathway plays a crucial role in the repression of TE (transposable element) expression via de novo DNA methylation in mouse embryonic male germ cells. Various proteins, including MIWI2 are involved in the process. TE silencing is ensured by piRNA-guided MIWI2 that recruits some effector proteins of the DNA methylation machinery to TE regions. However, the molecular mechanism underlying the methylation is complex and has not been fully elucidated. Here, we identified MORC3 as a novel associating partner of MIWI2 and also a nuclear effector of retrotransposon silencing via piRNA-dependent de novo DNA methylation in embryonic testis. Moreover, we show that MORC3 is important for transcription of piRNA precursors and subsequently affects piRNA production. Thus, we provide the first mechanistic insights into the role of this effector protein in the first stage of piRNA biogenesis in embryonic TE silencing mechanism.

Tet1 regulates epigenetic remodeling of the pericentromeric heterochromatin and chromocenter organization in DNA hypomethylated cells.

Pericentromeric heterochromatin (PCH), the constitutive heterochromatin of pericentromeric regions, plays crucial roles in various cellular events, such as cell division and DNA replication. PCH forms chromocenters in the interphase nucleus, and chromocenters cluster at the prophase of meiosis. Chromocenter clustering has been reported to be critical for the appropriate progression of meiosis. However, the molecular mechanisms underlying chromocenter clustering remain elusive. In this study, we found that global DNA hypomethylation, 5hmC enrichment in PCH, and chromocenter clustering of Dnmt1-KO ESCs were similar to those of the female meiotic germ cells. Tet1 is essential for the deposition of 5hmC and facultative histone marks of H3K27me3 and H2AK119ub at PCH, as well as chromocenter clustering. RING1B, one of the core components of PRC1, is recruited to PCH by TET1, and PRC1 plays a critical role in chromocenter clustering. In addition, the rearrangement of the chromocenter under DNA hypomethylated condition was mediated by liquid-liquid phase separation. Thus, we demonstrated a novel role of Tet1 in chromocenter rearrangement in DNA hypomethylated cells.

High frequency of bone recurrence as an initial recurrence site after radical surgery in T1N3 gastric cancer: a propensity score matching analysis.

PURPOSE: T1 gastric cancer (GC) with seven or more metastatic lymph nodes is extremely rare, and very few clinical studies have been conducted to evaluate the clinicopathological features of their recurrence. METHODS: We retrospectively analyzed the outcomes of T1 GC and T2-4 GC patients who had multiple nodal metastases after radical surgery from 2006 to 2020. Propensity score matching was performed to compare the two groups of patients. RESULTS: After propensity score matching, 18 of 22 patients in the T1 group and 36 of 144 patients in the T2-4 group were selected. Recurrence occurred in six patients (33.3%) in the T1 group. In the T1 group, the most common site of initial recurrence was bone (15.0%). The prevalence of bone recurrence was significantly higher in the T1 group than in the T2-4 group (P = 0.02). The median interval time between radical surgery and bone recurrence was 24 months, and the median survival time after bone recurrence was 14 months. CONCLUSION: Bone recurrence was more frequently identified as an initial recurrence site in T1 GC cases with multiple metastases after radical surgery compared with that in T2-4 GC cases. Careful attention should be paid to postoperative bone recurrence in the long-term postoperative course of these patients.

Predictive factors associated with relapse of stage II/III colon cancer treated with peroral anti-cancer agents in the adjuvant setting.

Postoperative adjuvant chemotherapy for patients with stage III colon cancer (CC) is regarded as the standard treatment worldwide for outcome improvement and relapse prevention. Similarly, high-risk stage II CC requires adjuvant chemotherapy because of its high recurrence rate. Previous randomized controlled trials showed that oxaliplatin (OX), in addition to fluorinated pyrimidine-based therapy for patients with stage II/III CC, significantly improves cancer survival but it remains controversial as to which patient groups should receive OX-containing regimens. Among 1,150 consecutive patients who underwent curative resection for stage II/III CC between 2009 and 2016 at two tertiary hospitals, 349 patients treated with only peroral (PO) fluorinated pyrimidine-based chemotherapy and 149 patients who received fluorinated pyrimidine-based chemotherapy with OX as adjuvant chemotherapy were retrospectively reviewed. The primary outcome was recurrence-free survival (RFS). Clinicopathological factors were more advanced in patients treated with OX than in patients treated only with PO fluorinated pyrimidine agents. Multivariate analysis for 5-year RFS showed that T4 [hazard ratio (HR), 2.947; P=0.0001], N2 (HR, 2.704; P=0.0075), vessel or lymphatic invasion (HR, 1.675; P=0.0437) and high cancer antigen (CA)19-9 (HR 3.367, P=0.0002) levels were independent risk factors of cancer relapse. Propensity score matching analysis was performed to match clinicopathological differences between the PO and OX groups. After matching, subgroup analysis of the patients showed that greater effects of OX on cancer survival were observed in patients in the OX group with high CA19-9 levels and tended to be associated with T4 and N2 compared with the PO group. Thus, OX-containing regimens should be recommended for patients with CC with these factors in an adjuvant setting.