Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History.

Introduction: Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with polycystic kidneys who have a positive family history, >90% have pathogenic variants in PKD1 or PKD2, whereas only 1% have IFT140. However, approximately 40% of patients with polycystic kidneys without a family history do not have any pathogenic variants in PKD1 and PKD2. Methods: We conducted a comprehensive genetic analysis of 157 adult patients with polycystic kidneys whose parents did not have evident polycystic kidneys. We sequenced up to 92 genes associated with inherited cystic kidney disease, including IFT140. Results: Of the 157 patients, 7 (4.5%) presented with monoallelic loss-of-function variants in the IFT140 gene, 51 (32.5%) with pathogenic variants in the PKD1 or PKD2 gene, and 7 (4.5%) with pathogenic variants in other genes related to inherited kidney cystic disease. The proportion of monoallelic loss-of-function IFT140 variants in this cohort was higher than that in previously reported cohorts with polycystic kidneys who had a positive family history. None of the patients with monoallelic loss-of-function IFT140 variants had polycystic liver disease (PLD). Furthermore, patients with IFT140 pathogenic variants had a significantly smaller kidney volume and a remarkably higher estimated glomerular filtration rate (eGFR) than those with PKD1 pathogenic variants (P = 0.01 and 0.03, respectively). Conclusion: Because the phenotype of polycystic kidneys caused by the IFT140 gene is mild, parental kidney disease may be overlooked. Therefore, patients without a positive family history are more likely to carry pathogenic variants in IFT140.

Outcome of intradiscal condoliase injection therapy for patients with recurrent lumbar disc herniation.

STUDY DESIGN: Retrospective cohort study. PURPOSE: This study aimed to compare data from patients who received intradiscal condoliase (chondroitin sulfate ABC endolyase) injection for primary lumbar disc herniation (LDH) and recurrent LDH. OVERVIEW OF LITERATURE: Chemonucleolysis with condoliase for LDH is a treatment with relatively good results and a high safety profile; however, few studies have reported recurrence after LDH surgery. METHODS: The study participants were 249 patients who underwent intradiscal condoliase injection for LDH at nine participating institutions, including 241 patients with initial LDH (group C) and eight with recurrent LDH (group R). Patient characteristics including age, sex, body mass index, disease duration, intervertebral LDH level, smoking history, and diabetes history were evaluated. Low back pain/leg pain Numerical Rating Scale (NRS) scores and the Oswestry Disability Index (ODI) were used to evaluate clinical symptoms before treatment and at 6 months and 1 year after treatment. RESULTS: Low back pain NRS scores (before treatment and at 6 months and 1 year after treatment, respectively) in group C (4.9 → 2.6 → 1.8) showed significant improvement until 1 year after treatment. Although a tendency for improvement was observed in group R (3.5 → 2.8 → 2.2), no significant difference was noted. Groups C (6.6 → 2.4 → 1.4) and R (7.0 → 3.1 → 3.2) showed significant improvement in the leg pain NRS scores after treatment. Group C (41.4 → 19.5 → 13.7) demonstrated significant improvement in the ODI up to 1 year after treatment; however, no significant difference was found in group R (35.7 → 31.7 → 26.4). CONCLUSIONS: Although intradiscal condoliase injection is less effective for LDH recurrence than for initial cases, it is useful for improving leg pain and can be considered a minimally invasive and safe treatment method.

Prognostic Impact and Genomic Backgrounds of Renal Parenchymal Infiltration or Micronodular Spread in Nonmetastatic Clear Cell Renal Cell Carcinoma.

A subset of clear cell renal cell carcinomas (ccRCCs) exhibits various growth patterns that infiltrate the normal renal parenchyma; however, our understanding of its association with cancer aggressiveness is incomplete. Here, we show that the morphology of the tumor interface with normal renal parenchyma is robustly associated with cancer recurrence after surgery, even when compared with the TNM staging system or the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in nonmetastatic ccRCC. Hematoxylin and eosin-stained slides of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with nonmetastatic ccRCC treated with radical nephrectomy. The patients were classified into 10 subgroups based on our classification algorithms for assessing the tumor interface with normal renal parenchyma. Among the 10 subgroups, 4 subgroups consisting of 40 patients (12%) were identified to have aggressive forms of nonmetastatic ccRCC associated with poor prognosis and unified as renal parenchymal infiltration or micronodular spread (RPI/MNS) phenotypes. Multivariable analyses showed that RPI/MNS phenotypes were robustly associated with shorter disease-free survival, independently of existing pathological factors including the TNM staging system and WHO/ISUP nuclear grade. The hazard ratio was highest for RPI/MNS (4.62), followed by WHO/ISUP grades 3 to 4 (2.11) and ≥pT3a stage (2.05). In addition, we conducted genomic analyses using next-generation sequencing of infiltrative lesions in 18 patients with RPI/MNS and tumor lesions in 33 patients without RPI/MNS. Results showed that alterations in SETD2 and TSC1 might be associated with RPI/MNS phenotypes, whereas alterations in PBRM1 might be associated with non-RPI/MNS phenotypes. These data suggest that RPI/MNS may be associated with aggressive genomic backgrounds of ccRCC, although more comprehensive analyses with a larger sample size are required. Future studies may further elucidate the clinical implications of RPI/MNS, particularly for deciding the indication of adjuvant treatment after nephrectomy.

Surgical Treatment of Heterotopic Ossification of the Bilateral Shoulder and Elbow Joints Caused by Burn Injury: A Case Report.

CASE: A 27-year-old man sustained chemical burns affecting 54% of his body caused by steam and acetic acid at a dyeing factory. He developed restricted bilateral elbow and shoulder motion because of heterotopic ossification (HO) beginning 3 months after the incident. The skin healed within 1 year, but ankylosis developed because of progressing ossification. We performed HO surgical excision in 4 stages. Two years after the final surgery, the function of both upper extremities had recovered. CONCLUSION: For HO caused by severe burns, improvement in upper extremity function can be achieved even if surgery is performed after skin healing.

Long-term Outcome After Surgical Resection of Paraaortic Lymph Node Metastasis of Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND: The significance of resection of paraaortic lymph node metastasis in colorectal cancer is controversial. OBJECTIVE: To clarify the prognosis of colorectal cancer after paraaortic lymph node metastasis resection. DESIGN: Multicenter retrospective study. SETTINGS: Thirty-six institutions in Japan participated in this study. PATIENTS: Patients with resected and pathologically proven paraaortic lymph node metastasis of CRC between 2010 and 2015. DATA SOURCES: Database and medical records at each institution. MAIN OUTCOME MEASURES: Overall survival after paraaortic lymph node metastasis resection, recurrence-free survival, and recurrence patterns after R0 resection of paraaortic lymph node metastasis. RESULTS: A total of 133 patients were included in the primary analysis population in this study. The 5-year overall survival rate (95% confidence interval [CI]) was 41.0% (32.0, 49.8), and the median survival (95% CI) was 4.1 (3.4, 4.7) years. Independent prognostic factors for overall survival were the pathological T stage (pT4 vs. pT1- 3, adjusted hazard ratio [aHR]: 1.91, p = 0.006), other organ metastasis (present vs. absent, aHR: 1.98, p = 0.005), time to metastases (synchronous vs. metachronous, aHR: 2.02, p = 0.02), and number of paraaortic lymph node metastasis (≥3 vs. <3, aHR: 2.13, p = 0.001). The 5-year recurrence-free survival rate (95% CI) was 21.1% (13.5, 29.7), with a median (95% CI) of 1.2 (0.9, 1.4) years. The primary tumor location (left- vs. right-sided colon, aHR: 4.77, p = 0.01; rectum vs. right-sided colon, aHR: 5.27, p = 0.006), other organ metastasis (present vs. absent, aHR: 1.90, p = 0.03), number of paraaortic lymph node metastasis (≥3 vs. <3, aHR: 2.20, p = 0.001), and hospital volume (<10 vs. ≥10, aHR: 2.18, p = 0.02) were identified as independent prognostic factors for recurrence-free survival. Paraaortic lymph node recurrence was the most common at 33.3%. LIMITATIONS: Selection bias cannot be ruled out because of the retrospective nature of the study. CONCLUSIONS: Less than three paraaortic lymph node metastasis was a favorable prognostic factor for both overall survival and recurrence-free survival. However, paraaortic lymph node metastases were considered to be a systemic disease and the significance of resection was limited. See Video Abstract.

Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/NCCH1510).

BACKGROUND: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune-checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. METHODS: The number of patients expected to be enrolled was 15-25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7-8.6 months) and the median OS was 15.8 months (95% CI, 8.2-not reached). CONCLUSIONS: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS.

Robotic versus open and laparoscopic pelvic exenterations for pelvic cancer: a multicenter propensity-matched analysis in Japan.

BACKGROUND: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors. METHODS: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias. RESULTS: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002). CONCLUSION: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors.

Optimization of Endoscopic Ultrasound Characteristics in the Diagnosis of Malignant Intraductal Papillary Mucinous Neoplasm.

OBJECTIVES: Endoscopic ultrasound (EUS) is an excellent diagnostic tool that provides high-resolution images of pancreatic cystic lesions. However, its role in the diagnosis of malignant intraductal papillary mucinous neoplasm (IPMN) remains limited and unclear. We aimed to determine the usefulness of this modality for such diagnosis. METHODS: Overall, 246 patients who underwent EUS for IPMN after computed tomography (CT)/magnetic resonance imaging (MRI) from April 2018 to June 2021 were followed up until March 2022. We assessed the added value of performing EUS after CT or MRI for diagnosing malignant IPMN, using receiver operating characteristic curve analysis. Walls as thick as 2 mm were considered thickened in this study if they were highly uneven. RESULTS: EUS clearly enhanced accuracy in identifying enhancing nodules and thickened walls. The areas under the receiver operating characteristic curve and corresponding 95% confidence intervals were 0.655 (0.549-0.760) and 0.566 (0.478-0.654) upon CT/MRI but 0.853 (0.763-0.942) and 0.725 (0.634-0.817) when observed using EUS. The combination of nodule size, thickened wall, and main duct size yielded the highest area under the receiver operating characteristic curve (0.944 [0.915-0.973]). CONCLUSIONS: EUS more accurately detects malignant IPMN, as uneven wall thickening and certain nodules cannot be identified with CT/MRI.

Validation study on the 2 mm diameter cutoff in lymph node-positive cases following radical prostatectomy in accordance with the AJCC/UICC TNM 8th edition: Real-world data analysis from a Japanese cohort.

OBJECTIVES: The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition has proposed micrometastasis as a lymph node metastasis (LN+) of diameter ≤2 mm in prostate cancer. However, supporting evidence has not described. We evaluated LN+ patients' survival after radical prostatectomy (RP) based on the LN maximum tumor diameter (MTD). METHODS: Data from 561 LN+ patients after RP and pelvic LN dissection (PLND) treated between 2006 and 2019 at 33 institutions were retrospectively investigated. Patients were stratified by a LN+ MTD cutoff of 2 mm. Outcomes included castration resistance-free survival (CRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: In total, 282 patients were divided into two groups (LN+ MTD >2 mm [n = 206] and ≤2 mm [n = 76]). Patients of LN+ status >2 mm exhibited significantly decreased CRFS and MFS, and poorer CSS and OS. No patients developed CRPC in the LN+ status ≤2 mm group when the PLND number was ≥14. Multivariate analysis showed the number of LN removed, RP Gleason pattern 5, and MTD in LN+ significantly predicted CRFS. CONCLUSIONS: Patients of LN+ status ≤2 mm showed better prognoses after RP. In all the patients in the ≤2-mm group, the progression to CRPC could be prevented with appropriate interventions, particularly when PLND is performed accurately. Our findings support the utility of the pN substaging proposed by the AJCC/UICC 8th edition; this will facilitate precision medicine for patients with advanced prostate cancer.

Minimally invasive arthroscopy-assisted arthrodesis for thumb carpometacarpal osteoarthritis.

INTRODUCTION: Arthrodesis is a reliable surgical procedure for treatment of thumb carpometacarpal (CMC) osteoarthritis that provides hand strength and pain relief. Locking plate fixation is a common technique that provides rigid fixation and a high rate of bone union; however, it requires extensive surgical exploration of the first metacarpal and trapezium. Here, we report the surgical outcome of minimally invasive arthroscopy-assisted thumb CMC arthrodesis that preserves soft tissue supplying the blood flow to the bones. MATERIALS AND METHODS: Nine thumbs of nine patients who underwent arthroscopy-assisted thumb CMC arthrodesis were retrospectively analysed (mean postoperative follow-up, 19.7 months). We investigated the time from surgery to bone union, grip strength, pinch strength (pulp and key), range of motion (ROM) of the thumb, visual analogue scale (VAS) score for pain, Disabilities of Arm, Shoulder, and Hand (DASH) score, and Hand20 questionnaire score preoperatively and at the final follow-up. RESULTS: Bone union was observed in eight of the nine patients. The mean time to bone union was 2.9 months (range 8 weeks-9 months). Although grip strength changed from 24.0 kg preoperatively to 25.8 kg at the final follow-up (not significant), the pulp pinch strength and key pinch strength significantly increased from 2.3 kg and 3.7 kg preoperatively to 3.8 kg and 5.6 kg at the final follow-up, respectively. No significant change occurred in the thumb ROM. The DASH score, Hand20 questionnaire score, and VAS score for pain significantly improved from 29.8, 42.2, and 78.4 preoperatively to 12.4, 11.2, and 13.2 at the final follow-up, respectively. Non-union was observed in one patient. No other complications were observed. CONCLUSIONS: Arthroscopy-assisted arthrodesis is a valuable procedure for thumb CMC osteoarthritis. However, the learning curve for this procedure must be overcome before the operative time can be shortened and successful bone union and satisfactory outcomes achieved.

Phase II Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 and Cisplatin for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin. PATIENTS AND METHODS: Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity. RESULTS: Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5-83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1-24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6-62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death. CONCLUSIONS: Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Two-stage reconstruction using a vancomycin-impregnated cement spacer for finger osteomyelitis with bone and joint destruction.

OBJECTIVES: Septic arthritis and osteomyelitis are serious infections. Several treatment methods for the small joints and bones of the hands have been reported. We hypothesized that antibiotic-impregnated cement spacers could be useful for purulent finger osteomyelitis with bone and joint destruction. PATIENTS AND METHODS: Seven patients with finger osteomyelitis with bone and joint destruction were treated using vancomycin (VCM)-impregnated cement spacers. During the first surgery, a cement spacer was placed in the space created after debridement, maintaining finger length. Intraoperative specimens were tested for bacterial growth. Systemic antibiotic treatment was administered. A second surgery was performed 6-8 weeks after the first. After spacer removal, reconstruction surgeries were performed: arthrodesis using the Masquelet technique (n = 5), vascularized bone grafting (n = 1), and silicone implant arthroplasty (n = 1). We assessed the pathogenic bacteria, duration of antibiotic treatment, infection control, time to bone union, pain on visual analogue scale (VAS) (0 - 100), total active motion (TAM) of the affected fingers, and grip strength. RESULTS: The pathogenic bacteria were methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and unknown in 3, 3, and 1 patients, respectively. Mean duration of antibiotic treatment was 6.4 weeks. In all patients, infection resolved without recurrence. One patient underwent joint arthroplasty; otherwise, bone union was achieved in 6 patients. Mean VAS score for pain was 0.9. Mean TAM was 147° for the index and middle fingers and 50° for the thumb. Mean grip strength was 86.4% of that of the unaffected side. CONCLUSION: VCM-impregnated cement spacers could be useful for finger osteomyelitis, facilitating effective infection control and the maintenance of finger length, even in severe conditions.

Characteristics of two different cryoballoon systems for treatment of paroxysmal atrial fibrillation: study protocol for a multicenter randomized controlled trial (CONTRAST-CRYO Trial).

BACKGROUND: Single-shot pulmonary vein isolation (PVI) utilizing cryothermal energy is an effective and safe treatment for atrial fibrillation (AF) patients. A novel cryoballoon system, POLARx™, has been recently introduced. The aim of this study was to compare the efficacy, safety, and biophysical parameters of PVI between the novel cryoballoon system, POLARx™, and the standard cryoballoon system, Arctic Front Advance Pro™ (AFA-Pro), in patients with paroxysmal AF. METHODS: The CONTRAST-CRYO trial is a prospective, multicenter, open-label, randomized controlled study performed at seven large cardiac centers. This study was approved by the central ethics committee or the local ethics committee of each participating hospital and has been registered at UMIN Clinical Trials Registry (UMIN000049948). The trial will assign 200 patients with paroxysmal AF undergoing PVI to POLARx™ and AFA-Pro in a 1:1 randomization. The primary endpoint is the one-shot acute success rate of the right inferior pulmonary vein. Second endpoints include freedom from documented atrial fibrillation, atrial flutter, or atrial tachycardia without antiarrhythmic drugs at 12 months after the procedure, freedom from re-do procedures, the incidence of procedure-related adverse events, freezing duration, and the biophysical parameters during applications for each PV, total procedure and fluoroscopy time, and PVI durability during re-do procedures. CONCLUSION: The CONTRAST-CRYO trial is a prospective, multicenter, randomized study designed to elucidate the difference in the efficacy, safety, and biophysical parameters between POLARx™ and AFA-Pro in paroxysmal AF patients undergoing PVI. The findings from this trial may provide a valuable indication for selecting the optimal cryoballoon system. CLINICAL TRIAL REGISTRATION:  UMIN000049948.

Role of Common Antihypertensives in the Growth of Abdominal Aortic Aneurysm at the Presurgical Stage.

Background: Whether drug therapy slows the growth of abdominal aortic aneurysms (AAAs) in the Japanese population remains unknown. Methods and Results: In a multicenter prospective open-label study, patients with AAA at the presurgical stage (mean [±SD] AAA diameter 3.27±0.58 cm) were randomly assigned to treatment with candesartan (CAN; n=67) or amlodipine (AML; n=64) considering confounding factors (statin use, smoking, age, sex, renal function), with effects of blood pressure control minimized setting a target control level. The primary endpoint was percentage change in AAA diameter over 24 months. Secondary endpoints were changes in circulating biomarkers (high-sensitivity C-reactive protein [hs-CRP], malondialdehyde-low-density lipoprotein, tissue-specific inhibitor of metalloproteinase-1, matrix metalloproteinase [MMP] 2, MMP9, transforming growth factor-ß1, plasma renin activity [PRA], angiotensin II, aldosterone). At 24 months, percentage changes in AAA diameter were comparable between the CAN and AML groups (8.4% [95% CI 6.23-10.59%] and 6.5% [95% CI 3.65-9.43%], respectively; P=0.23]. In subanalyses, AML attenuated AAA growth in patients with comorbid chronic kidney disease (CKD; P=0.04) or systolic blood pressure (SBP) <130 mmHg (P=0.003). AML exhibited a definite trend for slowing AAA growth exclusively in never-smokers (P=0.06). Among circulating surrogate candidates for AAA growth, PRA (P=0.02) and hs-CRP (P=0.001) were lower in the AML group. Conclusions: AML may prevent AAA growth in patients with CKD or lower SBP, associated with a decline in PRA and circulating hs-CRP.

C-X-C domain ligand 14-mediated stromal cell-macrophage interaction as a therapeutic target for hand dermal fibrosis.

Dupuytren's contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren's contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren's contractures, we demonstrate that the activation of Wnt/ß-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/ß-catenin signalling are closely related to stromal cell-macrophage interactions, and Wnt/ß-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-ß-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell-macrophage interaction is a promising therapeutic target for Wnt/ß-catenin-induced fibrosis.

Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial).

PURPOSE: Mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) are positive predictive markers for immune checkpoint inhibitors. However, data on the activity of nivolumab in advanced dMMR/MSI-H rare cancers and more accurate biomarkers are worth exploring. PATIENTS AND METHODS: We conducted a multicenter phase II, open-label, single-arm clinical trial to explore the effectiveness and safety of nivolumab monotherapy in patients with advanced rare cancers with dMMR/MSI-H, in parallel with immune phenotype analysis, to explore new biomarkers. A Bayesian adaptive design was applied. Characterization of peripheral blood mononuclear cells (PBMC) was characterized by multicolor flow cytometric analysis and CyTOF using samples collected before and after the intervention. The dMMR was identified by the complete loss of MLH1/MSH2/MSH6/PMS2. RESULTS: From May 2018 to March 2021, 242 patients were screened, and 11 patients were enrolled, of whom 10 were included in the full analysis. Median follow-up was 24.7 months (interquartile range, 12.4-31.5). Objective response rate was 60% [95% confidence interval (CI), 26.2-87.8] by central assessment and 70% (95% CI, 34.8-93.3) by local investigators. Median progression-free survival was 10.1 months (95% CI, 0.9-11.1). No treatment-related adverse events of grade 3 or higher were observed. Patients with a tumor mutation burden of ≥10/Mb showed a 100% response rate (95% CI, 47.8-100). Responders had increased T-bet+ PD-1+ CD4+ T cells in PBMC compared with nonresponders (P < 0.05). CONCLUSIONS: The trial met its primary endpoint with nivolumab, demonstrating clinical benefit in advanced dMMR/MSI-H rare solid cancers. Besides, the proportion of T-bet+ PD-1+ CD4+ T-cells may serve as a novel predictive biomarker.

The Incidence of Heterotopic Ossification in Surgically and Non-surgically Treated Elbow Fractures at a Municipal Hospital in Japan.

Background: Heterotopic ossification (HO) is a well-recognised complication of after elbow trauma. The prevalence and risk factors of HO have been previously reported. However, these reports were based on elbow trauma that had undergone surgical treatment and most of them were from Western countries. This study aimed to assess the incidence of HO in patients with elbow fractures who were treated surgically and non-surgically in Japan. Methods: We retrospectively identified consecutive patients who were treated of elbow fractures and fracture-dislocations at our institution in recent consecutive 3-year periods. We extracted patient demographics, injury mechanisms and treatment details from the medical records. Furthermore, we reviewed radiographs to classify the fracture pattern and identify the presence or absence of HO. Results: HO was identified in 6/97 (6%) patients. Fracture-dislocation was noted in 4/6 patients. The fracture types with HO included terrible triad injury (n = 2), isolated coronoid process fractures (n = 2), distal humerus A-type fractures (n = 1) and radial head fracture (n = 1). According to the Hastings and Graham classification, HO was classified as Class I in five patients and Class II B in one patient who underwent additional surgery for HO resection. Conclusions: The incidence of HO was relatively low in our patients. However, of the 20 conservatively treated elbows, one patient developed clinically relevant HO and required excision of HO. Even patients with elbow fractures treated conservatively should be informed of the potential risk of developing severe HO requiring surgical excision. In addition, surgeons in this region could use these data to inform patients about the risk of HO development after an elbow injury. Level of Evidence: Level IV (Therapeutic).

Racial differences in longitudinal toxicities of anticancer agents in early phase cancer clinical trials.

BACKGROUND: Racial differences have been reported in toxicity outcomes for anticancer drug treatments. However, these observations were often from studies with small sample sizes, and many only reported the maximum grade of toxicity and no longitudinal information. This current analysis aims to investigate racial differences in longitudinal toxicities using a large-scale clinical trials database. METHODS: Early-phase clinical trials sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute, USA, that evaluated cytotoxic drugs and molecularly targeted agents between March 2000 and December 2012 were studied. Race was categorized as White, Black or African-American, and Asian. Each toxicity's grade prevalence, mean grade at each cycle, and time to develop grade 2 or higher toxicity was evaluated. RESULTS: In total, 25,442 patients from 697 trials were included in this study. The number of patients categorized as White, Black, and Asian designations was 22,756 (89%), 1874 (7%), and 812 (3%), respectively. Notable findings include the rate of any grade of diarrhea in Black people was 26% and 21% lower than that of White and Asian people. The median time to the first grade 2 or higher event was 6 cycles in White people, 8 in Black people, and 6 in Asian people. The rate of any grade hyperglycemia was significantly higher in Asian people. CONCLUSIONS: Although we identified several racial differences in longitudinal toxicities, most were of generally lower grade. Further study is needed to clarify the cause of racial differences in treatment-associated toxicities.

Prognostic impact of the radiological infiltrative feature of primary renal tumor in metastatic renal cell carcinoma.

OBJECTIVES: Recent studies suggest that the radiological infiltrative feature (r-IF) of renal tumors is strongly correlated with poor oncologic outcomes in locally advanced renal cell carcinoma (RCC). This study investigated the prognostic impact of r-IF of primary renal tumors in metastatic RCC (mRCC) in comparison with International Metastatic RCC Database Consortium (IMDC) risk model. METHODS: We retrospectively analyzed 91 patients with previously untreated mRCC. Dynamic computed tomography of the primary renal tumor was reviewed to assess r-IF, defined as a focally/extensively ill-defined tumor interface with normal renal parenchyma. RESULTS: The median age was 67 years, and 69 patients (76%) were men. Prior nephrectomy was performed in 47 patients (52%). The median size of the primary renal tumor was 6.7 cm, and 50 patients (55%) presented with cT3-4 stage. Overall, 25 (28%)/52 (57%)/14 (15%) patients were classified into IMDC favorable/intermediate/poor-risk groups, respectively. An image review identified r-IFs in the primary renal tumor in 40 patients (44%). The incidences of r-IFs were 28%/46%/64% in IMDC favorable/intermediate/poor-risk groups, respectively. During a median follow-up of 2.6 years, 31 patients (34%) died of RCC. On multivariable analysis, r-IF and IMDC intermediate-poor risks were independently associated with poor cancer-specific survival (CSS). Two-year CSS were 64%/87% in patients with/without r-IF, respectively. C-index was improved from 0.73 to 0.81 by adding r-IF to the IMDC risk factors. CONCLUSIONS: R-IF of the primary renal tumor was an independent risk factor for poor CSS in patients with mRCC, which may improve the prognostic accuracy when combined with the IMDC risk model.