Ligation of left gastric vein may cause delayed gastric emptying after pancreatoduodenectomy: a retrospective study.

BACKGROUND: This study aimed to determine which running pattern of the left gastric vein (LGV) is most frequently ligated in subtotal stomach-preserving pancreatoduodenectomy (SSPPD) and how LGV ligation affects delayed gastric emptying (DGE) after SSPPD. METHODS: We retrospectively analysed 105 patients who underwent SSPPD between January 2016 and September 2021. We classified the running pattern of LGV as follows: type 1 runs dorsal to the common hepatic artery (CHA) or splenic artery (SpA) to join the portal vein (PV), type 2 runs dorsal to the CHA or SpA and joins the splenic vein, type 3 runs ventral to the CHA or SpA and joins the PV, and type 4 runs ventral to the CHA or SpA and joins the SpV. Univariate and multivariate analyses were used to identify differences between patients with and without DGE after SSPPD. RESULTS: Type 1 LGV running pattern was observed in 47 cases (44.8%), type 2 in 23 (21.9%), type 3 in 12 (11.4%), and type 4 in 23 (21.9%). The ligation rate was significantly higher in type 3 (75.0%) LGVs (p < 0.0001). Preoperative obstructive jaundice (p = 0.0306), LGV ligation (p < 0.0001), grade B or C pancreatic fistula (p = 0.0116), and sepsis (p = 0.0123) were risk factors for DGE in the univariate analysis. Multivariate analysis showed that LGV ligation was an independent risk factor for DGE (odds ratio: 13.60, 95% confidence interval: 3.80-48.68, p < 0.0001). CONCLUSION: Type 3 LGVs are often ligated because they impede lymph node dissection; however, LGV preservation may reduce the occurrence of DGE after SSPPD.

The expression pattern of CD10 and CD31 identifies fine fibrovascular stroma of grade 1-endometrial endometrioid carcinomas in cytology.

INTRODUCTION: The objective of this study was to assess the diagnostic utility of CD10 in the differential diagnosis of grade 1-endometrial endometrioid carcinoma (G1-EEC) and the metaplastic changes associated with the endometrial glandular and stromal breakdown (EGBD) on liquid-based cytological (LBC) samples. METHODS: (1) The type and distribution of CD10-positive cells in EGBD and G1-EEC patients were evaluated. (2) Based on the results from (1), histological and cytological specimens were double-immunostained with CD31 and CD10 to confirm whether CD10-positive tubular-canalicular material found in (1) was represented by fine threads of endometrial-type fibrovascular stroma. (3) Based on the results from (2), additional immunostaining of histological specimens was performed for CD146 and αSMA as markers of perivascular cells. RESULTS: (1) CD10 positive cells showed two main patterns of expression: cytoplasmic immunoreactivity in the form of dense brown granules in EGBD and tubular-canalicular branching patterns in G1-EEC. (2) The tubular-canalicular material observed in cytological specimens of G1-EEC samples co-expressed CD10 and CD31, and was interpreted as representing fine threads of endometrial fibrovascular stroma in the corresponding histological samples. Conversely, metaplastic changes in EGBD cases, only a few CD31-positive signals were found inside the condensed stromal clusters with CD10-positive. (3) Cells surrounding the CD31-positive vascular endothelial cells expressed CD146 and αSMA; moreover, some of the thin CD10-positive fibrous stromal strands also co-expressed αSMA. CONCLUSIONS: CD10 is a very useful immunomarker for distinguishing between G1-EEC and the metaplastic changes of EGBD in LBC samples.

Effect of prior olaparib maintenance therapy for platinum sensitive recurrent ovarian cancer on response to subsequent platinum-based chemotherapy.

AIM: Several years have passed since olaparib maintenance therapy was approved in patients with platinum sensitive recurrent ovarian cancer (PSROC). We speculated that the response to platinum-based chemotherapy (PBC) would be impaired at the time of recurrence after olaparib maintenance therapy. We conducted a noninterventional retrospective study to clarify this clinical question in a single institution. METHODS: We included all patients with PSROC who received olaparib after second or later line of PBC between April 18, 2018, and August 31, 2021. We evaluated the effect of olaparib maintenance therapy on PBC after progression. RESULTS: We identified 42 patients who received olaparib maintenance therapy after second or later line of PBC. Twenty-four patients relapsed after olaparib maintenance therapy, and 17 patients received PBC again. Four of 17 patients (complete response 2, partial response 2) responded to the PBC. The median progression-free survival was longer in patients with platinum-free interval ≥12 months than platinum-free interval of 6-12 months (9.7 vs 2.6 months, hazard ratio, 0.20: 95% confidence interval, 0.04-0.90; p = 0.04). CONCLUSIONS: In the patients with PSROC who experienced disease progression after olaparib maintenance therapy, especially in those with platinum-free interval of 6-12 months, the response to subsequent PBC was extremely poor. The efficiency of re-administration of PBC for PSROC patients with a short-term recurrence after olaparib treatment may need to be reconsidered.

Rhabdomyolysis with Multiple Electrolyte Imbalances under Proton Pump Inhibitor Treatment after Total Thyroidectomy.

A 90-year-old man presented with muscle weakness, difficulty concentrating, and dysphagia. About eighteen months prior to presentation, lansoprazole had been initiated to prevent stress ulcers; he also had a history of total thyroidectomy due to papillary thyroid cancer ten years prior. Laboratory findings were as follows: K 2.4 mEq/L, Ca 3.7 mg/dL, Mg 1.3 mg/dL, CK 5386 U/L, and intact PTH (iPTH) 14 pg/mL. Rhabdomyolysis with multiple electrolyte imbalances under proton pump inhibitor (PPI) treatment was diagnosed. We initiated intravenous hydration and electrolyte supplementation with discontinuation of PPI. After discontinuing PPI, the patient's serum magnesium, potassium, and calcium levels normalised with oral vitamin D and calcium supplementation. PPIs can cause hypocalcaemia and hypokalaemia via hypomagnesemia; hypocalcaemia is also a common postoperative complication of thyroidectomy. Careful monitoring of electrolyte levels is required in patients with long-term PPI treatment, especially in post-thyroidectomy cases.

Survival impact of adjuvant concurrent chemoradiotherapy after radical hysterectomy in FIGO stage IIIC1 cervical adenocarcinoma.

BACKGROUND: We evaluated the survival effect of adjuvant concurrent chemoradiotherapy after radical hysterectomy in patients with clinical pelvic node-positive cervical adenocarcinoma. METHODS: Patients with pelvic node-positive cervical adenocarcinoma diagnosed between 2000 and 2016 at our institution were identified. Survival was compared between patients who underwent radical hysterectomy alone and those who received concurrent chemoradiotherapy as an adjuvant treatment. Survival analysis using log-rank test and Cox proportional hazards model was performed. RESULTS: We identified 80 patients who underwent radical hysterectomy for clinical pelvic node-positive cervical adenocarcinoma; of these, four with pathological pelvic node-negative adenocarcinoma were excluded. Of the 76 patients, 27 underwent radical hysterectomy alone and 49 received radical hysterectomy followed by concurrent chemoradiotherapy. With a median follow-up of 53 months, the 5-year overall survival rate was 51.0% in patients who underwent radical hysterectomy alone versus 53.0% in patients who received additional concurrent chemoradiotherapy (log-rank p = 0.455). CONCLUSION: The addition of concurrent chemoradiotherapy after radical hysterectomy did not significantly improve survival among patients with pelvic node-positive cervical adenocarcinoma. More appropriate treatment strategies are needed to improve the survival outcomes of these patients.

Treatment strategy for locally advanced squamous cell cervical cancer with clinically positive pelvic lymph nodes metastasis.

AIM: To determine the optimal treatment for locally advanced squamous cell cervical cancer with clinical positive pelvic lymph nodes metastasis (cN1). METHODS: We enrolled patients with squamous cell cervical cancer with 2008 FIGO stages IB, IIA, or IIB diagnosed with cN1, who were treated at Hyogo Cancer Center between April 2010 and December 2016. Patients with para-aortic lymph nodes metastasis were excluded. RESULTS: Of the 69 eligible patients, 24 underwent concurrent chemoradiotherapy (CCRT), 11 underwent radical hysterectomy with pelvic lymphadenectomy (RH) with or without adjuvant RT, and 34 underwent neoadjuvant chemotherapy (NAC) followed by RH as initial treatment. The regimens of NAC included dose-dense TC (paclitaxel 80 mg/m2 , days 1, 8, 15; and carboplatin at an area under the curve = 6 on day 1, every 3 weeks) and dose-dense TP (paclitaxel 80 mg/m2 on days 1, 8, 15; and cisplatin 75 mg/m2 on day 1, every 3 weeks). The median observation period was 57 (12-107) months. The 5-year disease-free survival rates of the CCRT, RH, and NAC groups were 78.7%, 63.6%, and 88.2%, respectively (p = 0.14). The 5-year overall survival rates of the CCRT, RH, and NAC groups were 78.6%, 70.1%, and 94.1%, respectively (p = 0.11). CONCLUSIONS: We recommend avoiding RH as primary treatment for cN1 with locally advanced squamous cell cervical cancer. Although CCRT should be considered for cN1, further studies are required to determine if NAC followed by RH will serve as an effective option.

Quality of life assessment of cell-free and concentrated ascites reinfusion therapy during initial treatment for advanced ovarian cancer: A prospective cohort study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) is applied to relieve symptoms in patients with malignant ascites. We performed a prospective cohort study to evaluate the efficacy and safety of CART performed on patients with advanced ovarian and peritoneal cancers with massive ascites during the initial treatment. METHODS: From April 2018 to July 2020, CART was performed during the initial treatment of 31 patients with advanced ovarian and peritoneal cancers with cancerous ascites. Patient characteristics and clinical information before and after CART were collected. We performed quality of life assessment using the Japanese version of the M.D. Anderson Symptom Inventory (MDASI-J) 24 h before and after CART. RESULTS: CART was performed 38 times in 24 patients before or during neoadjuvant chemotherapy and 11 times in 11 patients prior to surgery. Four patients underwent CART before primary surgery and before and/or during chemotherapy. Grade 1-2 fever was observed in 18 of 31 cases (58%), and all were controllable by nonsteroidal anti-inflammatory drugs. CART did not adversely affect the main treatment, chemotherapy, or surgery. CART significantly improved the MDASI-J symptom and interference scores within 24 h after the procedure. The symptom and interference scores decreased from 2.4 to 1.8 and from 4.8 to 3.0, respectively. CONCLUSIONS: CART can be safely performed and is useful for symptom relief and improvement of general condition prior to initial surgery and during initial chemotherapy in ovarian and peritoneal cancers. Performing CART at the time of initial treatment may facilitate initiation of the main treatment.

Leptomeningeal metastases arising from gynecological cancers.

BACKGROUND: Most cases of leptomeningeal metastasis (LM) arise from solid tumors, such as breast cancer, lung cancer, or malignant melanoma. LM arising from gynecological cancers are extremely rare. Longer survival owing to recent advances in chemotherapy and other treatments has contributed to the increased frequency of gynecological cancers metastasizing to the central nervous system (CNS). Detailed information regarding LM is scarce; therefore, we conducted a study concerning LM arising from primary gynecological cancers. METHODS: Among 24 patients with CNS metastases from gynecological cancer treated at our hospital between January 2011 and August 2018, those who were eventually diagnosed with LM were included in this retrospective study. RESULTS: Among 24 patients with CNS metastases, five patients (20.8%) were diagnosed with LM. The primary cancer was endometrial in two, cervical in one, and peritoneal in two patients. Of these five patients, three developed LM as a complication 1-11 months after the treatment of brain metastases; one patient had multiple brain metastases diagnosed at the same time as LM, and one had LM alone, without accompanying brain metastases. The median survival after the diagnosis of LM was 23 (12-69) days, while the median survival of 24 patients after the initial diagnosis of CNS metastases was 106 (13-959) days. CONCLUSION: Although LM arising from gynecological cancers is considered rare, identification of LM may be important to predict prognosis and develop new therapeutic strategies.

Suppressive effect upon carboplatin hypersensitivity reaction via pegylated liposomal doxorubicin combination therapy.

BACKGROUND: Occurrence of hypersensitivity reaction (HSR) in patients having received multiple doses of carboplatin has been reported. Several studies demonstrated reduction of carboplatin-associated HSR with in combination with pegylated liposomal doxorubicin (PLD). The objective of this study was to determine the suppressive effect on carboplatin-induced HSR via combined treatment with PLD within clinical practice. METHODS: We reviewed the medical records of women with primary or recurrent ovarian, fallopian tube, or peritoneal cancer treated with carboplatin containing regimen at our hospital between January 2009 and March 2019. We compared the incidence of carboplatin-induced HSR among patients who received more than one cycle of PLD plus carboplatin (PLD-C) therapy (i.e., PLD-C group) versus patients who never received PLD-C therapy (non-PLD-C group). RESULTS: A total of 414 women were included in this study (48: PLD-C group, 366: non-PLD-C group). Carboplatin-induced HSR occurred in 34 total patients (8.2%) [1/48 (2.1%) in the PLD-C group and 33/366 (9.0%) in the non-PLD-C group], with a median cycle number of carboplatin administration at onset of HSR being 9. Incidences of carboplatin-induced HSR within the PLD-C versus non-PLD-C group at the 8th, 12th, and 16th cycles of carboplatin administration were 2.2% vs 11.2%, 2.2% vs 28.6%, and 2.2% vs 39.1%, respectively [hazard ratio: 19.2 (95% confidence interval: 9.82-39.4), p < 0.0001]. CONCLUSION: Based on the data analyzed here, a suppressive effect on carboplatin-induced HSR via combination therapy with PLD was confirmed within clinical practice.

Dose-dense paclitaxel and carboplatin vs. conventional paclitaxel and carboplatin as neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: a retrospective study.

BACKGROUND: The purpose of this study was to determine the optimal regimen of neoadjuvant chemotherapy (NAC) for advanced epithelial ovarian, fallopian tube, and peritoneal cancers. METHODS: A clinical information survey involving 171 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer was conducted. These patients underwent NAC followed by interval debulking surgery at the Hyogo Cancer Center (Hyogo, Japan) between January 2006 and December 2015. RESULTS: The median observation period was 41 (range 4-138) months. Dose-dense paclitaxel and carboplatin (TC) was administered in 101 patients (59%); tri-weekly TC was administered 70 patients (41%). Median progression-free survival was 21 [95% confidence interval (CI) 18-23] months and 15 (95% CI 13-17) months in the dose-dense TC and conventional-TC group [hazard ratio (HR) = 0.69, 95% CI 0.46-0.96; p = 0.02], respectively. The median overall survival was 59 (95% CI 46-72) and 40 (95% CI 32-57) months in the dose-dense TC group and conventional-TC group (HR = 0.72, 95% CI 0.48-1.06; p = 0.09). Multivariate analysis for progression-free survival demonstrated that dose-dense TC represented an independent prognostic factor (HR = 0.70, 95% CI 0.50-0.99; p = 0.04). CONCLUSIONS: Dose-dense TC is a promising regimen of NAC for advanced epithelial ovarian cancer.

The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt-expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt-expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (Bdnf), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt-induced DNA hypermethylation at the Bdnf regulatory region and reactivate Bdnf expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt-induced neuronal death and may in part operate through epigenetic mechanisms.

Phase II trial of paclitaxel, carboplatin, and bevacizumab for advanced or recurrent cervical cancer.

OBJECTIVE: We evaluated the efficacy and safety of the combination of paclitaxel, carboplatin, and bevacizumab in patients with advanced or recurrent cervical cancer. METHODS: Subjects included patients with advanced or recurrent cervical cancer not amenable to curative treatment with surgery or radiation therapy. Treatment consisted of paclitaxel 175 mg/m2, carboplatin area under the curve 6 mg/mL/min, and bevacizumab 15 mg/kg every 21 days until disease progression, complete remission, or limiting toxicity. The primary endpoint was the objective response. RESULTS: In total, 34 patients received a median of 6 treatment cycles (range 2-25). The median follow-up period was 18.5 months (range 2-29). The objective response was 88% (95% confidence interval: 72.5%-96.7%). Seventeen patients (50%) experienced complete response, whereas 13 patients experienced (38%) partial response with a median duration of 6 months. Grades 3 and 4 hematologic toxicities manifested as neutropenia in 14 (41.2%), leukopenia in 14 (41.2%), anemia in 11 (32.4%), and thrombocytopenia in 9 (26.5%) patients. One patient who underwent prior pelvic irradiation developed grade 2 rectovaginal fistula. CONCLUSION: The combination of paclitaxel, carboplatin, and bevacizumab is effective and safe in patients with advanced or recurrent cervical cancer.

Correlation between pre-operative and final histological diagnosis on endometrial cancer.

OBJECTIVE: We conducted a retrospective study to evaluate the correlation between pre-operative and post-operative histological diagnoses on endometrial cancer, and to describe the treatments and outcomes when post-operative diagnoses are downgraded from pre-operative histology. METHODS: Patients who underwent surgery for endometrial cancer in our facility between 2010 and 2013 were enrolled in the study. The definition of downgrade discordance is in accordance with the following criteria: 1) the pre-operative and post-operative histological diagnoses were both endometrioid and the final pathology was a lower grade than the pre-operative pathology and 2) the pre-operative diagnosis was not endometrioid, whereas the post-operative diagnosis was endometrioid grade 2 or less. RESULTS: A total of 250 patients were enrolled, and the concordance rates were 56% for endometrioid adenocarcinoma grade 1 (EMG1), 67% for EMG2, 67% for EMG3, 82% for carcinosarcoma, 71% for serous carcinoma, and 67% for clear cell carcinoma. Eighteen cases (6.6%) were identified as downgrade discordancy. Of the 18 patients, the triage for adjuvant therapy remained the same for 15 cases (83%), all of whom had no evidence of disease at their last visit. Three cases had discordances with respect to triage for adjuvant therapy; the therapies were triaged based on post-operative diagnosis. Of these patients one had a recurrence. CONCLUSIONS: Good correlation was observed between pre-operative and final histological diagnoses of endometrioid carcinoma (56%-67%) and type 2 carcinoma (67%-82%). Approximately 7% (18/250) of patients had downgrade discordancy; however, triage for adjuvant therapy did not change for approximately 80% (15/18) of the patients with downgrade discordancy. Further studies are needed to evaluate the effectiveness of triages that are based on post-operative diagnoses.

An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma.

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD+). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD+ synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD+ levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD+-dependent network. Accordingly, we demonstrate E2F2 is required for GSC self-renewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD+ metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.

Pelvic fractures after definitive and postoperative radiotherapy for cervical cancer: A retrospective analysis of risk factors.

OBJECTIVES: This study clarified the incidence of and identified the risk factors for post-radiation pelvic insufficiency fractures (PIFs) in women who received postoperative definitive or adjuvant radiotherapy (RT) for cervical cancer. PATIENTS AND METHODS: The medical records and data of imaging studies, including computed tomography scan and magnetic resonance imaging, of women with cervical cancer who received external-beam RT for the entire pelvic area between January 2003 and December 2012 at our institution were reviewed. RESULTS: A total of 533 patients with histologically diagnosed cervical cancer who received RT (298: definitive RT, 235: adjuvant RT) were included in this study. Eighty-four patients (15.8%) developed PIF in the irradiated field. Median age at onset of PIF was 72.5years (range: 54-95years), and 82 of them (98%) were postmenopausal women. Sixty-nine patients (80%) developed PIF within 3years from the completion of RT. The median time for the development of PIF was 14months (range: 1-81months). The most commonly involved fracture site was the sacral bone. Postmenopausal state, coexistence of rheumatoid arthritis, and high-dose-rate intracavitary brachytherapy (HDR-ICBT) use were significant predisposing factors for the development of PIF, according to multivariate analysis. CONCLUSIONS: The incidence rate of PIF among patients who received RT for locally advanced cervical cancer was 15.8%. The principal predisposing factors for post-radiation PIF were postmenopausal state, rheumatoid arthritis, and HDR-ICBT use. Active interventions, including bone density screening followed by medication, should be considered during the early stage of RT for women with high-risk factors of PIF.

The inhibitory effect of soybean and soybean isoflavone diets on 2,4-dinitrofluorobenzene-induced contact hypersensitivity in mice.

Murine contact hypersensitivity (CHS) is one of the most frequently used animal models of human allergic contact dermatitis. We investigated the inhibitory effects of soybean and soy isoflavone (SI) diets on 2,4-dinitrofluorobenzene- (DNFB) induced CHS in mice. The DNFB-induced ear swelling was inhibited in the soy- and SI-treated groups. Histopathological investigations revealed that oral feeding of soybean and SI attenuated ear tissue edema and reduced the number of Gr-1(+) cell infiltrations into ear tissues. DNA microarray analysis showed that the expression of Ccl24, Xcl1, Ifng, and Ccl17 in the ear tissues was lower in the soy-treated mice than in the positive controls. In addition, CCL24 mRNA and protein expression in the ear tissues were more highly suppressed in the soy- and SI-treated groups. These results suggest that soybean and SI consumption downregulated the gene and protein expression of CCL24, thereby affording protection against CHS in mice.

Correlation between acute conjunctivitis and Asian dust on ocular surfaces.

The aim of this study was to determine the presence of Asian dust particles (ADP) in patients suffering from conjunctivitis and its correlation with clinical scores for conjunctivitis. Forty-five patients from the Fukuoka area who were newly diagnosed acute conjunctivitis were selected. The degrees of inflammatory reaction, itchy sensation, hyperemia, eye discharge, and foreign body sensation were clinically recorded and scored. Eyes were washed with physiological solution. Solid particles collected from the washing solution were observed using a scanning electron microscope. Of the 45 samples, 44 were positive for the elements silicon (Si) and aluminum (Al), which are components of ambient Asian dust. Higher conjunctivitis scores were found in the subgroup in which the Asian dust/whole particle ratio was greater than average. This is the first apparent report on the correlation between amount of ADP exposure at the ocular surface and severity of ocular symptoms.

Incidence of spontaneous twin anemia-polycythemia sequence in monochorionic-diamniotic twin pregnancies: Single-center prospective study.

AIM: The purpose of this study was to prospectively estimate the incidence of spontaneous twin anemia-polycythemia sequence (TAPS) in monochorionic-diamniotic twin pregnancies. METHODS: We prospectively examined umbilical cord hemoglobin (Hb) and reticulocyte count of consecutive monochorionic-diamniotic twin pregnancies delivered at Seirei Hamamatsu General Hospital from December 2006 to September 2013. We excluded cases of twin-twin transfusion syndrome, intrauterine fetal demise, and missing data (Hb and reticulocyte count missing from the medical record). TAPS was diagnosed using the postnatal criteria of intertwin Hb difference >8.0 g/dL and reticulocyte count ratio >1.7. Acute feto-fetal hemorrhage was defined as Hb difference >7 g/dL and reticulocyte count ratio <1.7. RESULTS: A total of 185 monochorionic-diamniotic twin pregnancies were included in this study. Three fulfilled the diagnostic criteria for postnatal TAPS, and one fulfilled the diagnostic criteria for acute feto-fetal hemorrhage. CONCLUSION: The incidence of spontaneous TAPS in monochorionic-diamniotic twin pregnancies was 1.6% (3/185) at Seirei Hamamatsu General Hospital.

Standardization of the Japanese National Standard, Equine Botulinum Antitoxin Type A, and Factors Affecting Standardization.

Equine botulinum antitoxin is one of the most popular countermeasures for human botulism. The unitage of the antitoxin product is defined according to national minimum requirement or pharmacopoeia in each country by referring to national standard antitoxins for four types (A, B, E, and F). With the expected depletion of the national standard antitoxins, replacement national standard antitoxins are produced and standardized through collaboration of the National Control Laboratory and other participants, including manufacturer(s). Therefore, Japanese National Standard Botulinum Antitoxin Type A, Equine, was replaced according to the results of a collaborative study involving the National Institute of Infectious Diseases and KM Biologics Co., Ltd. The unitage of the replacement material was determined through mouse neutralization tests, which involved toxin-antitoxin mixture injection at pH 7.0. Potency value of 440 units/vial was obtained. However, the Japanese Minimum Requirement for Biological Products was revised, and the neutralization reactions were repeated at pH 6.0, for which considerably different potency value (656 units/vial) and survival profile of mice were obtained. In September 2021, the replacement material, Japanese National Standard Botulinum Antitoxin Type A, Equine, lot 2, was established with potency value of 656 Units/vial. The impact of pH-dependent change in potency on antitoxin quality control is discussed.

The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway.

Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.