Cellular senescence of granulosa cells in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated ß-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.

Potential drug interactions between pazopanib and proton pump inhibitors/potassium-competitive acid blockers in patients with soft tissue sarcoma.

Because absorption of the oral drug pazopanib depends on gastric pH, concomitant use of proton pump inhibitors (PPIs)/potassium-competitive acid blockers (P-CABs) may inhibit pazopanib absorption by elevating the gastric pH. This study investigated to what extent the concomitant use of PPIs/P-CABs affects treatment with pazopanib in patients with soft tissue sarcoma. We retrospectively reviewed the medical records of patients with soft tissue sarcoma who had received at least one dose of pazopanib at our institution, among which those who had received concomitant PPIs/P-CABs were included in this analysis. Using paired sample t tests, the frequency of dose reduction or interruption of pazopanib and the major adverse events (AEs) were compared in each patient between periods with and without PPIs/P-CABs. Between January 2018 and December 2022, eight patients were eligible. The median time to treatment failure (TTF) was 3.9 months (2.1-38.2 months). Two patients received concomitant PPIs/P-CABs throughout their treatment with pazopanib. Among the other six patients, dose reduction or interruption of pazopanib occurred less frequently (P = 0.021), and neutropenia tended to be milder (P = 0.155) with the concomitant use of PPIs/P-CABs. Although the concomitant use of PPIs/P-CABs had no apparent effect on TTF in patients undergoing pazopanib treatment, dose reduction or interruption of pazopanib occurred less frequently, and neutropenia was milder, suggesting that concomitant use of PPIs/P-CABs might decrease the pharmacological activity of pazopanib. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-023-00638-2.

The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency.

Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage.

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

Proteomic identification and quantification of Clostridium perfringens enterotoxin using a stable isotope-labelled peptide via liquid chromatography-tandem mass spectrometry.

PURPOSE: Detection of Clostridium perfringens enterotoxin (CPE) in human stool is critical evidence of food poisoning. However, processing patient-derived samples is difficult and very few methods exist to confirm the presence of CPE. In this study, a technique was developed using proteomic analysis to identify and quantify CPE in artificial gut fluid as an alternative. METHODS: The standard CPE was spiked into artificial gut fluids, and effective methods were developed by employing both a stable isotope-labelled internal standard peptide and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Proteotypic peptide EILDLAAATER formed by tryptic digestion was selected for quantitation of CPE. The peptide was identified using product ion spectra. Although the nontoxic peptides originating from CPE showed very low detectability in extraction and tryptic digestion, they could be detected with sufficient sensitivity using the method we developed. Based on a spiked recovery test at two concentrations (50 and 200 µg/kg), the recovery values were 85 and 78%, respectively. The relative standard deviations of repeatability and within-laboratory reproducibility were less than 8 and 11%, respectively. These standard deviations satisfied the criteria of the Japanese validation guidelines for residues (MHLW 2010, Director Notice, Syoku-An No. 1224-1). The limit of quantification (LOQ) was estimated to be 50 µg/kg. The combination of the product ion spectra and relative ion ratio supported CPE identification at the LOQ level. CONCLUSIONS: To the best of our knowledge, this is the first report of proteomic analysis of CPE using LC-MS/MS. The method would greatly help in assessing CPE reliably.

Clinical results of active surveillance for extra-abdominal desmoid-type fibromatosis.

BACKGROUND: The treatment of choice for desmoid-type fibromatosis (DF) has been changed to active surveillance (AS). However, few studies have reported clinical outcomes of AS modality in Asian countries. This study aimed to clarify the significance of AS as a DF treatment modality. METHODS: A total of 168 lesions from 162 patients with extra-abdominal DF were included. The mean age at diagnosis was 39 years (1-88 years), and the median maximum tumor diameter at the first visit was 64.1 mm (13.2-255.8 mm). The clinical outcomes of AS and the risk factors requiring active treatment (AT) (defined as an event) from AS modality were investigated. RESULTS: Of the 168 lesions, 94 (56%) were able to continue AS, with a 5-year event-free survival of 54.8%. Of the 68 lesions with PD, 21 (30.9%) lesions were able to continue AS. Neck location (p = 0.043) and CTNNB1 S45F mutation (p = 0.003) were significantly associated with the transition to AT, and S45F mutation was a significant factor associated with the transition to AT by multivariate analysis (hazard ratio: 1.96, p = 0.048). AT outcomes after AS were evaluable in 65 lesions, and 49 (75%) lesions did not require a transition to a second AT. CONCLUSIONS: AS was revealed as an effective treatment modality. The transition to AT needs to be considered for neck location and CTNNB1 S45F mutation DF. Good results can be obtained by selecting a treatment method that considers the tumor location even in cases that require intervention.

[A Resected Case of Intraperitoneal Foreign Body Granuloma Mimicking Peritoneal Dissemination].

Foreign body granuloma(FBG)is a granuloma that occurs due to chronic inflammation caused by various residual foreign objects. In the field of gastrointestinal surgery, intraperitoneal foreign body granulomas(IPFBGs)are often caused by sutures materials or residual gauzes, but those caused by food residue are extremely rare. We present an IPFBG case of food residue caused by anastomotic leakage, which was difficult to be distinguished from peritoneal dissemination. The patient is a 74- year-old male. Anastomotic leakage occurred following low anterior resection for rectal cancer, peritoneal drainage and ileostomy were performed. 1.5 years after rectal resection, liver metastasis was diagnosed by CT and peritoneal dissemination was diagnosed by PET-CT. Both lesions were resected at the same time. The pathological findings were liver metastasis and FBG. It was presumed to be an FBG formed by food residue left behind after anastomotic leakage. It has reported that FBG caused by residual gauzes were shown a ring-shaped uptake by PET-CT, but that was not observed in our case. In addition, since a nodule suspected of liver metastasis was observed simultaneously, we considered no differential diagnosis other than peritoneal dissemination. IPFBG resembling peritoneal dissemination, occurred after anastomotic leakage. A food residue can cause IPFBG, it is necessary to consider IPFBG in decision making treatment strategy for peritoneal nodule.

Surgical Treatment and Complications of Deep-Seated Nodular Plexiform Neurofibromas Associated with Neurofibromatosis Type 1.

BACKGROUND: Nodular plexiform neurofibromas in individuals with neurofibromatosis type 1 often cause significant symptoms and are treated with surgical excision despite the potential risk of complications. This study aimed to clarify the surgical outcomes of deep-seated nodular plexiform neurofibromas and identify the factors associated with postoperative complications. METHODS: We retrospectively reviewed patients with neurofibromatosis type 1 who underwent surgical excision for deep-seated nodular plexiform neurofibromas in our hospital from 2015 to 2021. Enucleation while preserving the nerve fascicles was attempted first, and en bloc resection, ligating the nerve origin in cases in which the parent nerve was entrapped by the tumor, making the tumor difficult to dissect, was performed. RESULTS: In 15 patients, 24 nodular plexiform neurofibromas received surgical excision. Sixteen tumors were enucleated, and eight were en bloc resected. The symptoms of all 10 patients with preoperative symptoms resolved after surgery. Four patients developed new neurological deficits immediately after surgery, two of whom had retained neurological symptoms at the last visit, but these symptoms were mild. CONCLUSIONS: The present study demonstrates that surgical treatment of nodular plexiform neurofibromas, even deep-seated neurofibromas, is safe with a low risk of severe complications and improvement in preoperative symptoms.

Notch Signaling Induced by Endoplasmic Reticulum Stress Regulates Cumulus-Oocyte Complex Expansion in Polycystic Ovary Syndrome.

Endoplasmic reticulum (ER) stress activated in granulosa cells contributes to the pathophysiology of polycystic ovary syndrome (PCOS). In addition, recent studies have demonstrated that Notch signaling plays multiple roles in the ovary via cell-to-cell interactions. We hypothesized that ER stress activated in granulosa cells of antral follicles in PCOS induces Notch signaling in these cells, and that activated Notch signaling induces aberrant cumulus-oocyte complex (COC) expansion. Expression of Notch2 and Notch-target transcription factors was increased in granulosa cells of PCOS patients and model mice. ER stress increased expression of Notch2 and Notch-target transcription factors in cultured human granulosa-lutein cells (GLCs). Inhibition of Notch signaling abrogated ER stress-induced expression of genes associated with COC expansion in cultured human GLCs, as well as ER stress-enhanced expansion of cumulus cells in cultured murine COCs. Furthermore, inhibition of Notch signaling reduced the areas of COCs in PCOS model mice with activated ER stress in the ovary, indicating that Notch signaling regulates COC expansion in vivo. Our findings suggest that Notch2 signaling is activated in granulosa cells in PCOS and regulates COC expansion. It remains to be elucidated whether aberrant COC expansion induced by the ER stress-Notch pathway is associated with ovulatory dysfunction in PCOS patients.

Efficacy of auranofin as an inhibitor of desmoid progression.

Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of ß-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of ß-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.

Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase.

KIAA1199 has a strong hyaluronidase activity in inflammatory arthritis. This study aimed to identify a drug that could reduce KIAA1199 activity and clarify its effects on inflammatory arthritis. Rat chondrosarcoma (RCS) cells were strongly stained with Alcian blue (AB). Its stainability was reduced in RCS cells, which were over-expressed with the KIAA1199 gene (RCS-KIAA). We screened the drugs that restore the AB stainability in RCS-KIAA. The effects of the drug were evaluated by particle exclusion assay, HA ELISA, RT-PCR, and Western blotting. We further evaluated the HA accumulation and the MMP1 and three expressions in fibroblast-like synoviocytes (FLS). In vivo, the effects of the drug on symptoms and serum concentration of HA in a collagen-induced arthritis mouse were evaluated. Ipriflavone was identified to restore AB stainability at 23%. Extracellular matrix formation was significantly increased in a dose-dependent manner (p = 0.006). Ipriflavone increased the HA accumulation and suppressed the MMP1 and MMP3 expression on TNF-α stimulated FLS. In vivo, Ipriflavone significantly improved the symptoms and reduced the serum concentrations of HA. Conclusions: We identified Ipriflavone, which has inhibitory effects on KIAA1199 activity. Ipriflavone may be a therapeutic candidate based on its reduction of KIAA1199 activity in inflammatory arthritis.

[Long-Term Relapse-Free Survival after Resection of Lung Metastasis in a Patient with Pancreatic Cancer-A Case Report].

The patient was a 71-year-old man with the pancreatic cancer. He underwent subtotal stomach-preserving pancreaticoduodenectomy and D2 lymphadenectomy. CT conducted 38 months after the surgery revealed the 10-mm mass at the lower lobe in the left lung. On PET-CT, the mass showed an abnormal uptake. We suspected that the mass was either a lung metastasis or a primary lung cancer. Partial resection of the left lung was performed, and pathological findings led to the diagnosis of lung metastasis originating from the primary pancreatic cancer. Currently at 9 years post-surgery, the patient has not had any recurrence of the metastasis. In this study, we report our case and discuss the literature.

Diffusion-Weighted Magnetic Resonance Imaging Improves the Accuracy of Differentiation of Benign from Malignant Peripheral Nerve Sheath Tumors.

OBJECTIVE: In patients with neurofibromatosis type 1 (NF1), it is important to accurately determine when plexiform neurofibroma (pNF) transforms to a malignant peripheral nerve sheath tumor (MPNST). The purpose of this study is to investigate the usefulness of diffusion-weighted imaging (DWI) in differentiating pNF and MPNST in NF1 patients. METHODS: Among the NF1 patients who were referred to our hospital between 1985 and 2015, 10 cases of MPNST and 19 cases of pNF were included. We evaluated features of standard magnetic resonance imaging according to the differentiation criteria of malignancy from benignancy as previously reported, apparent diffusion coefficient (ADC) value based on the DWI and the correlation between ADC value and benignancy/malignancy. ROC analysis was performed to determine the appropriate cutoff value of ADC. RESULTS: There were significant differences between MPNST and pNF in the size of the tumor (P = 0.009), peripheral enhancement pattern (P = 0.002), perilesional edema-like zone (P = 0.0008), and intratumoral cystic change (P = 0.02). The mean and minimum values of ADC were significantly lower in MPNST than those in pNF (P = 0.03 and P = 0.003, respectively). When we set a cutoff value of mean ADC as 1.85 × 10-3 mm2/s, the sensitivity and specificity were 80% and 74%, respectively. The area under the curve value improved by adding the Wasa score to the mean ADC evaluation. CONCLUSIONS: ADC values determined by DWI are useful in differentiating MPNST from pNF and adding ADC evaluation to standard MRI evaluation improved the diagnostic accuracy.

Clinical outcome in patients who underwent amputation due to extremity soft tissue sarcoma: Tokai Musculoskeletal Oncology Consortium study.

BACKGROUND: Soft tissue sarcomas are a diverse group of rare malignant tumours, mostly occurring in the lower extremities. Amputations are necessary for achieving local control when the soft tissue sarcomas are too large and/or have neurovascular involvement. Patients who require amputation have a poorer prognosis than those who undergo limb-salvage surgery. PATIENTS AND METHODS: We investigated the tumour characteristics and the clinical outcomes in 55 patients with primary soft tissue sarcomas, who underwent amputation. We excluded patients with amputation performed distal to the wrist or ankle joints and those with recurrent soft tissue sarcomas. RESULTS: The mean tumour size was 11.1 cm. Hip disarticulation was performed in 6 patients, 20 underwent above the knee amputation, 8 underwent knee disarticulation and 12 underwent below the knee amputation. Shoulder disarticulation was performed in three patients, five underwent above the elbow amputation, and one underwent below the elbow amputation. The 5-year disease-specific survival rate was 52.8%. The 5-year recurrence-free survival rate and 5-year metastasis-free survival rates were 90.1% and 38.5%, respectively. Larger tumour size, age and the distant metastases at first presentation were predictors of poor prognosis for survival in multivariate analysis. Twenty-eight patients could walk using artificial limbs. The level of amputation (above versus below the knee) showed a significant difference in achieving independent gait. CONCLUSION: Amputation is a useful treatment option for achieving local control in patients with large soft tissue sarcomas. Patients had an opportunity of walking, especially for those who underwent below the knee amputation.

[A Patient with Gastric Adenosquamous Cell Carcinoma].

A 73-year-old female was referred from a local clinic with abdominal pain. A diagnosis of gastric cancer(cT3, cN0, M0, cStage ⅡB)and acute cholecystitis was made. Distal gastrectomy, D2, and cholecystectomy were performed. Postoperative pathological examination led to a diagnosis of adenosquamous cell carcinoma(pT3, pN2, M0, pStage ⅢA). SOX therapy was administered as postoperative adjuvant chemotherapy. However, multiple liver metastases were detected. XP and DTX therapies were administered; however, there was a reduction in performance status. The patient died 10 months after surgery. Gastric adenosquamous cell carcinoma is classified as a specific type according to the Japanese Classification of Gastric Carcinoma(15th edition). This carcinoma accounts for 0.3 to 0.5% of patients undergoing gastric cancer surgery and is relatively rare. Its malignancy level is higher than that of gastric adenocarcinoma, and its prognosis is poorer.

Successful treatment with denosumab for pelvic fibrous dysplasia: A case report and review of the literature.

RATIONALE: Fibrous dysplasia is a rare disorder that results in fractures, pain, and disability and can affect any bone in the body. The treatment of symptomatic fibrous dysplasia is determined based on the affected bones. Although some lesions are often too extensive for surgical procedures, there are currently no effective or recommended medical treatments available for them. PATIENT CONCERNS: A 27-year-old woman developed right buttock pain and was diagnosed with a bone tumor in the right ilium. Clinical images revealed an expansive osteolytic lesion with thinning of the cortex and cystic change from the acetabulum to the sacroiliac joint. DIAGNOSIS: An incisional biopsy was performed, and the lesion was diagnosed as cystic fibrous dysplasia. Occasional osteoclast-like giant cells and woven bone were observed. The patient had no evidence of polyostotic lesions or findings of McCune-Albright syndrome. Biochemical blood test results showed no obvious abnormal values, except for an increase in serum tartrate-resistant acid phosphatase 5b to 459 mU/dL. INTERVENTIONS: Since surgical treatment appeared to be challenging, she was treated with denosumab with decreased dose-intensity schedules. OUTCOMES: The administration of denosumab caused osteosclerosis within the lesion, resulting in the elimination of bone pain. The patient received denosumab treatment for 18 months. Pain relief and lesion radiodensity were maintained for 9 months after denosumab discontinuation. The serum level of tartrate-resistant acid phosphatase 5b was measured to monitor the response to denosumab, which was suppressed during denosumab treatment. LESSONS: We described successful denosumab treatment in a patient with cystic fibrous dysplasia (FD) who maintained efficacy for 9 months after treatment. Although the use of denosumab in fibrous dysplasia is currently off-label, our experience with this patient supports the potential of denosumab therapy for patients for whom surgical treatment is challenging.

Clinical Outcome in Soft Tissue Sarcoma Patients with Lung Metastasis Who Received Metastasectomy and/or Radiofrequency Ablation: Tokai Musculoskeletal Oncology Consortium Study.

PURPOSE: Here, we investigated the oncological outcomes of lung metastasectomy and/or radiofrequency ablation (RFA) of 92 patients with soft tissue sarcoma (STS) at nine institutions. METHODS: The study cohort included 65 men and 27 women with a mean age of 59 years at the time of metastasis. The mean follow-up duration was 51 months. All patients underwent metastasectomy and/or RFA for lung metastasis. RESULTS: The mean maximum size of the initial lung metastasis was 14.6 mm. At the initial evaluation, 41 patients had a single metastasis, whereas 51 patients had multiple metastases. The mean number of metastasectomies and/or RFA was 2 per patient. A total of 70 patients underwent lung metastasectomy, whereas the other 13 underwent lung RFA. The remaining nine patients underwent both RFA and metastasectomy. The 5-year post-metastatic survival rate was 52%. The patients who underwent complete treatment for the initial metastasis had better post-metastatic survival rates than those who underwent incomplete treatment. A univariate analysis of all possible prognostic factors for complete treatment confirmed the predictive value of disease-free interval, metastasis at initial presentation, distribution, tumor size, and number of lung metastases. Of the 92 patients, 74 underwent complete treatment for initial metastasis; in these patients, univariate and multivariate analyses showed that a smaller tumor size and single-lung metastasis were prognostic factors for superior post-metastatic survival. The patients with a smaller (<11.5 mm) single metastasis had better post-metastasis survival. The 5-year post-metastatic survival rates were 89.9% for patients with a smaller (<11.5 mm) single metastasis versus 22.7% for patients with larger (>11.5 mm) and multiple metastases. DISCUSSION: We propose that complete treatment for lung metastasis in patients with STS may improve post-metastatic survival rates. Furthermore, tumor number and size are important variables for clinical decision-making.

Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome-like phenotypes in prenatally androgenized female mice.

It has been recently recognized that prenatal androgen exposure is involved in the development of polycystic ovary syndrome (PCOS) in adulthood. In addition, the gut microbiome in adult patients and rodents with PCOS differs from that of healthy individuals. Moreover, recent studies have suggested that the gut microbiome may play a causative role in the pathogenesis of PCOS. We wondered whether prenatal androgen exposure induces gut microbial dysbiosis early in life and is associated with the development of PCOS in later life. To test this hypothesis, we studied the development of PCOS-like phenotypes in prenatally androgenized (PNA) female mice and compared the gut microbiome of PNA and control offspring from 4 to 16 weeks of age. PNA offspring showed a reproductive phenotype from 6 weeks and a metabolic phenotype from 12 weeks of age. The α-diversity of the gut microbiome of the PNA group was higher at 8 weeks and lower at 12 and 16 weeks of age, and the ß-diversity differed from control at 8 weeks. However, a significant difference in the composition of gut microbiome between the PNA and control groups was already apparent at 4 weeks. Allobaculum and Roseburia were less abundant in PNA offspring, and may therefore be targets for future interventional studies. In conclusion, abnormalities in the gut microbiome appear as early as or even before PCOS-like phenotypes develop in PNA mice. Thus, the gut microbiome in early life is a potential target for the prevention of PCOS in later life.

Reconstruction of the extensor mechanism augmented with reverse transferred iliotibial band after proximal tibia tumor resection and mega-prosthetic replacement.

BACKGROUND: The optimal procedure for functional reconstruction of the extensor mechanism after proximal tibia mega-prosthetic replacement remains unclear. METHODS: Since 2006, 14 consecutive patients with aggressive bone tumors in the proximal tibia who underwent mega-prosthetic replacement were prospectively treated with reconstruction of the extensor mechanism using an ipsilateral iliotibial band. The surgical procedure consisted of wrapping the reversed iliotibial band around the tibia component, firmly suturing it to the remaining patellar tendon and tibialis anterior fascia, and covering it with a muscle flap. At the last follow up, the function was assessed based on extensor lag, active flexion of the knee, and Musculoskeletal Tumor Society score. Patellar height was measured with the Insall-Salvati ratio (ISR) preoperatively, postoperatively, and at the last follow up. RESULTS: At the last follow up, the extensor lag and active flexion in 14 patients averaged 2.5° and 86°, respectively. Musculoskeletal Tumor Society score could be obtained in nine surviving patients at the last follow up and was a mean of 20.7 points. The mean ISR preoperatively, postoperatively, and at the last follow up was 1.04, 0.75, and 0.89, respectively. The extensor lag was not associated with the ISR value at any points, while reduced active flexion significantly correlated with a low ISR at the last follow up (P = 0.015). Four patients underwent additional surgeries due to postoperative infection, but none required eventual revision or amputation. CONCLUSION: The extensor mechanism reconstruction with the reverse transferred iliotibial band for mega-prosthetic replacement after proximal tibia resection yielded reliable outcomes with functional benefit to stabilize active knee extension.

Less-invasive fascia-preserving surgery for abdominal wall desmoid.

The mainstay of treatment for desmoid has been shifted to active surveillance (AS). However, surgery is still being performed on abdominal wall desmoid with a wide surgical margin. The purposes of this study are to clarify the treatment results of less-invasive, fascia preserving surgery for patients with abdominal wall desmoid, and to propose a new treatment modality. Since 2009, 34 patients with abdominal desmoid have been treated in our institution. Among them, as a final treatment modality, 15 (44%) were successful with AS, 15 were subjected to less-invasive surgery, and 4 methotrexate and vinblastine treatment. The clinical results of less-invasive surgery were clarified. In the surgical group, although the surgical margin was all microscopic positive (R1), only one patient (6.7%), who has the S45F mutation type of CTNNB1, showed recurrence, at a mean follow-up of 45 months. There were no patients with familial adenomatous polyposis (FAP)-related desmoid in this cohort. Only two patients (13%) required fascia lata patch reconstruction after removal of the tumor. In patients with non FAP-related abdominal wall desmoid, less-invasive, fascia preserving surgery is recommended as a favorable option as active treatment. Based on the results of this study, multi-institutional further research is warranted with an increased number of patients.