Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner.

BACKGROUND: Cancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear. METHODS: Here, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynamics and cellular motility, as a responsible factor and elucidated its mechanism of action using molecular and cellular biology techniques. RESULTS: HMHA1 expression was found to be induced at the transcription initiation level in a HIF-dependent manner under hypoxia. Boyden chamber invasion assay revealed that the induction of HMHA1 expression is required for the increase in invasion of hypoxic cancer cells. Reoxygenation treatment after ionising radiation in vitro that mimics dynamic changes of a microenvironment in hypoxic regions of tumour tissues after radiation therapy further enhanced HMHA1 expression and invasive potential of HMHA1 wildtype cancer cells in ROS- and HIF-dependent manners, but not of HMHA1 knockout cells. CONCLUSION: These results together provide insights into a potential molecular mechanism of the acquisition of invasiveness by hypoxic cancer cells after radiotherapy via the activation of the ROS/HIF/HMHA1 axis.

Prediction of response to promising first-line chemotherapy in ovarian cancer patients with residual peritoneal tumors: practical biomarkers and robust multiplex models.

BACKGROUND: Platinum/taxane (TC) chemotherapy with debulking surgery stays the mainstay of the treatment in ovarian cancer patients with peritoneal metastasis, and recently its novel modality, intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip), was shown to have greater therapeutic impact. Nevertheless, the response varies among patients and consequent recurrence, or relapse often occurs. Discovery of therapeutic response predictor to ddTCip and/or TC therapy is eagerly awaited to improve the treatment outcome. METHODS: Using datasets in 76 participants in our ddTCip study and published databases on patients received TC therapy, we first validated a total of 75 previously suggested markers, sought out more active biomarkers through the association analyses of genome-wide transcriptome and genotyping data with progression-free survival (PFS) and adverse events, and then developed multiplex statistical prediction models for PFS and toxicity by mainly using multiple regression analysis and the classification and regression tree (CART) algorithm. RESULTS: The association analyses revealed that SPINK1 could be a possible biomarker of ddTCip efficacy, while ABCB1 rs1045642 and ERCC1 rs11615 would be a predictor of hematologic toxicity and peripheral neuropathy, respectively. Multiple regression analyses and CART algorithm finally provided a potent efficacy prediction model using 5 gene expression data and robust multiplex toxicity prediction models-CART models using a total of 4 genotype combinations and multiple regression models using 15 polymorphisms on 12 genes. CONCLUSION: Biomarkers and multiplex models composed here could work well in the response prediction of ddTCip and/or TC therapy, which might contribute to realize optimal selection of the key therapy.

Prognostic impact of heart failure admission in survivors of acute myocardial infarction.

AIMS: The incidence and prognosis of symptomatic heart failure following acute myocardial infarction (AMI) in the primary percutaneous coronary intervention era have rarely been reported in the literature. This study aimed to (i) determine the incidence of heart failure admission among AMI survivors, (ii) compare 1 year outcomes between patients with heart failure admission and those without, and (iii) identify the independent risk factors associated with heart failure admission. METHODS AND RESULTS: The Japan Acute Myocardial Infarction Registry is a prospective multicentre registry from which data on consecutively enrolled patients with AMI from 50 institutions between 2015 and 2017 were obtained. Among the 3411 patients enrolled, 3226 who survived until discharge were included in this study. The primary endpoint was all-cause mortality. The secondary endpoints were major adverse cardiovascular events (defined as cardiovascular mortality, non-fatal myocardial infarction, or non-fatal cerebral infarction) and major bleeding events corresponding to Bleeding Academic Research Consortium Type 3 or 5. Clinical outcomes were compared between the patients who were and were not admitted for heart failure. Over a median follow-up of 12 months, 124 patients (3.8%) were admitted due to heart failure. Independent risk factors for heart failure admission included older age, female sex, Killip class ≥2 on admission, left ventricular ejection fraction <40%, estimated glomerular filtration rate ≤30 mL/min/1.73 m2, a history of malignancy, and non-use of angiotensin-converting enzyme inhibitors at discharge. The cumulative incidence of all-cause mortality was significantly higher in the heart failure admission group than in the no heart failure admission group (11.3% vs. 2.5%, P < 0.001). The rates of major adverse cardiovascular events (16.9% vs. 2.7%, P < 0.001) and major bleeding (6.5% vs. 1.6%, P < 0.001) were significantly higher in the heart failure admission group. Heart failure admission was associated with a higher risk of all-cause mortality, even after adjusting for potential confounders (adjusted hazard ratio: 2.41, 95% confidence interval: 1.33-4.39, P = 0.004). CONCLUSIONS: Utilizing real-world data of the contemporary percutaneous coronary intervention era from the Japan Acute Myocardial Infarction Registry database, this study demonstrates that the heart failure admission of AMI survivors was significantly associated with higher all-cause mortality rates.

A Dynamic Elbow Testing Apparatus for Simulating Elbow Joint Motion in Varying Shoulder Positions.

Purpose: To develop and evaluate the capabilities of a dynamic elbow testing apparatus that simulates unconstrained elbow motion throughout the range of humerothoracic (HTA) abduction. Methods: Elbow flexion was generated by six computer-controlled electromechanical actuators that simulated muscle action, while six degree-of-freedom joint motion was measured using an optical tracking device. Repeatability of joint kinematics was assessed at four HTA angles (0°, 45°, 90°, 135°) and with two muscle force combinations (A1-biceps brachialis, brachioradialis and A2-biceps, brachioradialis). Repeatability was determined by comparing kinematics at every 10° of flexion over five flexion-extension cycles (0° to 100°). Results: Multiple muscle force combinations can be used at each HTA angle to generate elbow flexion. Trials showed that the testing apparatus produced highly repeatable joint motion at each HTA angle and with varying muscle force combinations. The intraclass correlation coefficient was greater than 0.95 for all conditions. Conclusions: Repeatable smooth cadaveric elbow motion was created that mimicked the in vivo situation. Clinical relevance: These results suggest that the dynamic elbow testing apparatus can be used to characterize elbow biomechanics in cadaver upper extremities.

Predictive factors of early FDG-PET response to [131I] MIBG treatment for unresectable or metastatic pheochromocytomas and paragangliomas (PPGLs).

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that produce catecholamines. [131I] MIBG-avid unresectable or metastatic PPGLs are treated with [131I] MIBG therapy. A high metabolic tumour volume (MTV) and total lesion glycolysis (TLG) can be poor prognostic factors. Therefore, we evaluated the metabolic responses to [131I] MIBG therapy with respect to other clinical factors.A retrospective study was performed on a series of 20 patients who underwent FDG-PET before and after [131I] MIBG therapy. We administered a single dose comprising 5.5 GBq of [131I] MIBG. Semi-quantitative parameters (SUVmax, MTV, and TLG) were calculated using the liver SUV (mean + 3SD) as a threshold on Metavol software. The semi-quantitative FDG-PET parameters for determining response were complete response , partial remission, stable disease, and progressive disease (PD). We divided our study participants into the PD and non-PD groups and compared the overall survival between the two groups. Subsequently, we evaluated the relationships between metabolic response and age, sex, tumour type, metastatic site, chemotherapy or external radiation history, and 24-hour urine catecholamine levels by univariate logistic regression analyses. Both MTV-based and TLG-based criteria for PD vs. non-PD were significant prognostic factors (p = 0.014). However, treatment response as evaluated based on the SUVmax was not a significant predictor. Higher urinary dopamine levels were associated with poor metabolic response as assessed by MTV and TLG. The other clinical parameters were non-significant. Poor metabolic response (measured with MTV and TLG) to [131I] MIBG therapy in unresectable or metastatic PPGLs was related to shorter OS. The poor metabolic response can be predicted using the urinary dopamine level.

The Effect of Elbow Flexion On Valgus Carrying Angle.

PURPOSE: This study aimed to examine the effect of flexion on valgus carrying angle in the human elbow using a dynamic elbow testing apparatus. METHODS: Active elbow motion was simulated in seven cadaveric upper extremities. Six electromechanical actuators simulated muscle action, while 6 degrees-of-freedom joint motion was measured with an optical tracking system to quantify the kinematics of the ulna with respect to the humerus as the elbow was flexed at the side position. Repeatability of the testing apparatus was assessed in a single elbow over five flexion-extension cycles. The varus angle change of each elbow was compared at different flexion angles with the arm at 0° of humerothoracic abduction or dependent arm position. RESULTS: The testing apparatus achieved excellent kinematic repeatability (intraclass correlation coefficient, >0.95) throughout flexion and extension. All elbows decreased their valgus carrying angle during flexion from 0° to 90° when the arm was maintained at 0° of humerothoracic abduction. Elbows underwent significant total varus angle change from full extension of 3.9° ± 3.4° (P = .007), 7.3° ± 5.2° (P = .01), and 8.9° ± 7.1° (P = .02) at 60°, 90°, and 120° of flexion, respectively. No significant varus angle change was observed between 0° and 30° of flexion (P = .66), 60° and 120° of flexion (P = .06), and 90° and 120° of flexion (P = .19). CONCLUSIONS: The dynamic elbow testing apparatus characterized a decrease of valgus carrying angle during elbow flexion and found that most varus angle changes occurred between 30° and 90° of flexion. All specimens underwent varus angle change until at least 90° of flexion. CLINICAL RELEVANCE: Our model establishes the anatomic decrease in valgus angle by flexion angle in vitro and can serve as a baseline for testing motion profiles of arthroplasty designs and ligamentous reconstruction in the dependent arm position. Future investigations should focus on characterizing motion profile change as the arm is abducted away from the body.

Harvest location has a minimal impact on differences in cross-sectional area of quadriceps tendon in anterior cruciate ligament reconstruction.

PURPOSE: Anterior cruciate ligament (ACL) reconstruction with quadriceps tendon (QT) has been gaining popularity. However, it is unknown how differences in harvest location of the QT affect its thickness and cross-sectional area (CSA). The present study aimed to clarify the differences in thickness and CSA of the QT based on location of tendon harvesting. METHODS: Patients scheduled for, or who underwent, ACL reconstruction were prospectively included in the study. The short-axis images on ultrasound were used to assess the CSA of the QT at 30 and 60 mm proximal to the superior pole of the patella. QT autografts with CSAs greater than or equal to 10 mm of width were included and measured at three different locations, namely the center, medial one-third, and lateral one-third at the widest diameter of the QT. Patients with less than 10-mm width of the QT at 60 mm proximal to the superior pole of the patella were excluded. The thickness and CSA were compared based on the location of tendon harvest. RESULTS: Thirty-seven patients were recruited for the study. The mean thickness and CSA were larger in the center of the QT compared to the lateral one-third at 30 mm proximal to the superior pole of the patella (thickness, 6.7 ± 1.3 mm vs. 5.9 ± 1.3 mm; P = 0.009; CSA, 65.6 ± 11.4 mm2 vs. 58.8 ± 11.9 mm2; P = 0.036). There were no significant differences in thickness and CSA of the QT among the three assessment locations at 60 mm proximal to the superior pole of the patella (n.s.). CONCLUSION: The thickness and CSA of QT was greater in the center compared to the lateral one-third at 30 mm proximal to the QT insertion point. However, the difference in value was clinically non-significant, and therefore, harvest location of the QT autograft may not meaningfully impact intraoperative graft diameter. As a result, surgeons may choose the harvest location without concern for resultant graft diameter as long as the enough length of QT is secured. LEVEL OF EVIDENCE: III.

Early prediction of treatment outcome for lenvatinib using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma refractory to radioiodine treatment: a prospective, multicentre, non-randomised study.

BACKGROUND: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes. RESULTS: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078). CONCLUSIONS: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016.

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Ultrasonographic Assessment of Glenohumeral Joint Stability Immediately After Arthroscopic Bankart-Bristow Procedure.

Background: The changes in glenohumeral joint stability after surgery in a clinical setting are yet unknown. Purpose/Hypothesis: This study aimed to compare the anterior humeral head translation between pre- and postsurgical conditions using ultrasonography. It was hypothesized that ultrasonographic assessment would reveal decreased anterior translation. Study Design: Case series; Level of evidence, 4. Methods: A total of 27 patients (24 male, 3 female; mean age, 24.1 ± 9.7 years) with anterior shoulder instability were studied prospectively. All the patients underwent the arthroscopic Bankart-Bristow procedure under general anesthesia, and ultrasonographic evaluation was performed before and immediately after surgery. The forearm was fixed with an arm positioner in the beach-chair position, and the ultrasonographic transducer was located at the posterior part of the shoulder to visualize the humeral head and glenoid rim at the level of interval between the infraspinatus tendon and teres minor tendon. The upper arm was drawn anteriorly with a 40-N force at 0°, 45°, and 90° of shoulder abduction with neutral rotation. The distance from the posterior edge of the glenoid to that of the humeral head was measured using ultrasonography with and without anterior force. Anterior translation was defined by subtracting the distance with anterior force from the distance without anterior force. Results: The humeral head position was translated posteriorly immediately after surgery in all patients. Anterior translation decreased significantly after surgery at 45° (7.7 ± 4.3 vs 5.8 ± 2.0 mm; P = .031) and 90° (8.9 ± 3.4 vs 6.1 ± 2.2 mm; P < .001) of abduction, whereas there was no difference between pre- and postsurgical translation at 0° of abduction (4.9 ± 2.3 vs 4.0 ± 2.1 mm, P = .089). Conclusion: Ultrasonographic assessment immediately after a Bankart-Bristow procedure showed the humeral head was translated posteriorly relative to the glenoid at 0°, 45°, and 90° of abduction. The surgery also decreased anterior translation in response to an anteriorly directed force at 45° and 90° of abduction.

Expression of Karyopherin Alpha 2 and Karyopherin Beta 1 Correlate with Poor Prognosis in Gastric Cancer.

INTRODUCTION: Karyopherin alpha 2 (KPNA2) and karyopherin beta 1 (KPNB1) constitute nuclear transport protein complexes involved in nuclear import and are significant in tumor progression. Although high KPNA2 expression was associated with poor prognosis in solid tumors, the relationship between KPNA2 and KPNB1 expression and their prognostic role in gastric cancer (GC) remains unclear. METHODS: Immunohistochemistry was used to correlate the expression of KPNA2 and KPNB1 with various features, including clinicopathological characteristics in 130 patients with GC and survival in 94 patients with invasive lesions extending to the submucosa or deeper. RESULTS: High expression of KPNA2 and KPNB1 was found in 25% and 36% of the patients, respectively. Both were significantly related to tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and Ki-67 expression. KPNA2 expression was significantly related to that of KPNB1 (p < 0.001). Patients with high KPNB1 expression had poorer prognosis than those with low expression (p = 0.027), as was also observed in case of KPNA2 (p < 0.001). Patients with high expression of both KPNA2 and KPNB1 accounted for 18% and had a poorer prognosis than those with high expression of either and those with low expression of both (p = 0.001). Multivariate analysis revealed that high expression of both KPNA2 and KPNB1 was an independent prognostic factor in patients with GC (hazard ratio, 3.46; 95% confidence interval, 1.64-2.73, p = 0.001). CONCLUSION: KPNA2 expression was correlated with KPNB1 expression, and high co-expression of KPNA2 and KPNB1 may represent a strong prognostic biomarker in GC.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.

BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. PATIENTS AND METHODS: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. RESULTS: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. CONCLUSION: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Ultrasound Assessment of Anterior Humeral Head Translation in Patients With Anterior Shoulder Instability: Correlation With Demographic, Radiographic, and Clinical Data.

Background: Ultrasonography can be used to quantitatively assess anterior humeral head translation (AHHT) at different degrees of shoulder abduction. Risk factors for recurrent shoulder instability have been identified. Hypothesis: It was hypothesized that the number of dislocations or glenoid or humeral bone loss would be associated with more AHHT as measured using ultrasound. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 39 patients who underwent surgery for anterior shoulder instability were prospectively studied. Ultrasound assessment of AHHT was performed immediately after general anesthesia was induced. The upper arm was placed at 0°, 45°, and 90° of abduction, and a 40-N anterior force was applied to the proximal third of the arm. The distance from the posterior edge of the glenoid to that of the humeral head was measured at each abduction angle using ultrasound with and without a 40-N anterior force, and the AHHT was calculated. The differences in translation at each shoulder angle were compared. Additionally, the authors investigated the association between AHHT and demographic, radiographic, and clinical data. Results: Compared with the AHHT at 0° of abduction (5.29 mm), translation was significantly larger at 45° of abduction (8.90 mm; P < .01) and 90° of abduction (9.46 mm; P < .01). The mean translation was significantly larger in female patients than in male patients at all degrees of abduction (P ≤ .036 for all). There was no correlation between AHHT at any abduction angle and number of dislocations, clinical data, or radiographic data (including bone loss). Conclusion: Ultrasound assessment of AHHT showed larger amounts of laxity at 45° and 90° than at 0° of abduction. Anterior glenohumeral laxity was greater in female than male patients. Glenoid or humeral bone loss did not correlate with AHHT, thereby clarifying that bone loss has no direct effect on measurements of capsular laxity in neutral rotation.

Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.

BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Superb microvascular imaging (SMI) detects increased vascularity of the torn anterior cruciate ligament.

PURPOSE: Ultrasound with superb microvascular imaging (SMI) is a novel microvascular imaging technology which may be useful to assess the vascularity of the torn anterior cruciate ligament (ACL) as a potential measure of healing potential following surgery. This study aimed to quantify the vascularity of the torn and intact ACL using ultrasound with SMI. METHODS: 23 patients (mean age ± standard deviation, 27.1 ± 12.8 years), who were diagnosed with an ACL tear with an intact contralateral ACL were enrolled (ACL injury group). Ten healthy volunteers (36.1 ± 4.9 years) who had intact ACLs in both knees were also recruited (ACL healthy controls). The vascularity of the ACL was assessed using SMI within 15 mm from the tibial insertion in both knees. The amount of the vascular signal was assessed using a semi-quantitative grading scale (vascularity grade: grade 0-3) and a quantified ratio of vascularized area with respect to total area of the region of interest (vascularity ratio). RESULTS: In the ACL injury group, a significantly higher vascularity grade and ratio were observed in the torn ACL (vascularity grade 0-3: 1, 8, 7, and 7 patients, respectively; vascularity ratio: 1.3 ± 1.4%) than the contralateral intact ACL (vascularity grade 0-3: 21, 1, 1, and 0 patients, respectively; vascularity ratio: 0.1 ± 0.5%) (P < 0.001), whereas no significant difference was observed between both ACLs in the ACL healthy control group. CONCLUSIONS: SMI was useful to assess the increased vascularity in torn ACL, which may reflect the potential for, or state of, ACL maturation following reconstruction or repair. LEVEL OF EVIDENCE: Level III.

Preoperative ultrasound predicts the intraoperative diameter of the quadriceps tendon autograft more accurately than preoperative magnetic resonance imaging for anterior cruciate ligament reconstruction.

PURPOSE: Sizing of potential autografts is essential to match the native anterior cruciate ligament (ACL) dimensions when performing ACL reconstruction (ACLR). We aimed to investigate the accuracy and reliability of the thickness and cross-sectional area (CSA) assessments for the prediction of the intraoperative diameter of the QT autograft using preoperative ultrasound and MRI. METHODS: Thirty patients (mean age ± standard deviation, 19.9 ± 5.0 years), who underwent ACLR using QT autograft, were included. The maximum thickness of the QT was assessed at 15 and 30 mm proximal using ultrasound with a long axis image, and at 15 mm proximal to the superior pole of the patella using MRI with a sagittal image. The CSA was assessed at the central 10 mm of the medial-lateral QT width at 30 mm proximal using ultrasound with a short axis image, and at 15 mm proximal to the superior pole of the patella using MRI with an axial image. Intraoperatively, QT autograft was harvested with a 10 mm width and the diameter was measured using a graft sizing device. RESULTS: Intra- and inter-observer reliabilities of all measurements using ultrasound and MRI were good (Intra-class correlation coefficient, 0.720-0.941). Correlation coefficient with the intraoperative diameter of the QT autograft was higher in ultrasound (R = 0.738-0.791, P < 0.001) than MRI (R = 0.449-0.543, P = 0.002-0.013). CONCLUSIONS: Preoperative ultrasound predicted the intraoperative diameter of the QT autograft more accurately than MRI. Ultrasound may be used clinically to assure a sufficiently large QT autograft diameter to match the diameter of the patient's native ACL. LEVEL OF EVIDENCE: Level III.

Long-term survival after repetitive lymphadenectomy for nodal recurrence of pancreatic neuroendocrine neoplasms: a report of two cases.

Pancreatic neuroendocrine neoplasms (PNENs) are rare, but their incidence has increased in recent years. Curative surgery is recommended in several global guidelines for resectable PNENs. Lymph node recurrence after R0 resection for PNENs is infrequent, and global guidelines recommend surgical resection for recurrence, if resectable. However, data on the prognosis after surgical resection for nodal recurrence of PNENs are limited. We herein report two cases in which long-term survival was achieved after repetitive lymphadenectomy for nodal recurrence of PNENs. In both cases, the pathological findings for primary PNEN showed well-differentiated neuroendocrine neoplasms and R0 resection was successfully performed. The Ki-67 index increased with each resection in both cases. Both patients showed long-term survival (10 and 14 years, respectively). Repetitive lymphadenectomy for nodal recurrence of PNENs may improve patient prognosis.

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA).

PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Hepatectomy and immune checkpoint inhibitor treatment for liver metastasis originating from non-cutaneous melanoma: a report of three cases.

The outcomes of hepatectomy alone for liver metastasis derived from non-cutaneous melanoma are insufficient, and the outcomes of systemic therapy alone are also insufficient, even since the development of immune checkpoint inhibitors (ICIs). We report the cases of three patients, in whom liver metastasis derived from non-cutaneous melanoma was treated with hepatectomy combined with ICI therapy, which was administered in various settings. One patient received ICI treatment for recurrent melanoma and survived 107 months after the first hepatectomy, one patient received both preoperative and adjuvant ICI treatment and has been disease-free for 27 months, and another patient received postoperative ICI treatment after reduction hepatectomy and has been alive with disease for 47 months. Since long-term survival is possible, hepatectomy combined with ICI therapy should be considered for the treatment of liver metastasis derived from non-cutaneous melanoma.

Bilateral suprascapular notches are asymmetrically shaped in a third of the Asian population.

PURPOSE: The side-to-side differences within an individual's suprascapular notch (SSN) and the clinical characteristics of an ossified superior transverse scapular ligament are unclear. Therefore, the morphological asymmetry of the SSN was investigated, and the factors associated with the ossification of the superior transverse scapular ligament were analyzed. METHODS: Two hundred and seventy-six computed tomography images were retrospectively analyzed, which included those of both scapulae of Asian patients (mean age, 62.1 ± 19.1 years; males, 197) with high-energy injuries or respiratory diseases. Variations in the SSN were classified into six types based on Rengachary's classification using reconstructed three-dimensional computed tomography. The group with a type VI SSN (completely ossified superior transverse scapular ligament) in at least one scapula was compared with the other group for age, sex, and chronic comorbidities. RESULTS: Among 276 patients, 95 (34.4%) had asymmetric SSNs and 15 (5.4%) had type VI SSNs. There were no significant differences in age, sex, or comorbidities between both the groups. However, on comparing age groups, the prevalence of type VI SSN was higher in patients aged > 70 years than in those aged < 70 years. Fifteen patients had type VI SSNs, which were unilateral in 10 patients. CONCLUSION: Asymmetric SSNs were observed in a third of the Asian patients. There were variations in SSNs between individuals and also within an individual. In the cases with suprascapular nerve paralysis, the difference in SSN morphology compared to a healthy side should be considered. LEVEL OF EVIDENCE: III.