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.

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.

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.

Spectroscopic mapping of the gold complex oligomers (dimer, trimer, tetramer, and pentamer) by excited-state coherent nuclear wavepacket motion in aqueous solutions.

We investigate the excited-state dynamics of the [Au(CN)2-] oligomers following photo-initiated intermolecular Au-Au bond formation by carrying out femtosecond time-resolved absorption and emission measurements at various concentrations (0.080-0.6 mol dm-3) with different photoexcitation wavelengths (290-340 nm). The temporal profiles of the time-resolved absorption signals exhibit clear oscillations arising from the Au-Au stretch coherent wavepacket motion of the excited-state oligomers, which is initiated with the photo-induced Au-Au bond formation. The frequency of the observed oscillation is changed with the change of the concentration, excitation wavelength, and wavelength of the excited-state absorption monitored, reflecting the change in the size of the oligomers detected. Fourier transforms (FTs) of the oscillations provide 2D plots of the FT amplitude against the oscillation frequency versus the detected wavelengths. Because the FT amplitude exhibits a node at the peak wavelength of the absorption of the species that gives rise to the oscillation, the 2D plots enabled us to determine the peak wavelength of the excited-state absorption of the dimer, trimer, tetramer, and pentamer. We also performed femtosecond time-resolved absorption measurements for the 0.3 mol dm-3 solution with 260 nm photoexcitation, which is the condition employed in previous time-resolved X-ray studies (e.g., K. H. Kim et al. Nature, 2015, 518 (7539), 385-389). It was found that various excited-state oligomers, including the dimer, were simultaneously generated under this condition, although the analysis of the previous time-resolved X-ray studies was made by assuming that only the excited-state trimer was generated. The obtained results show that the excited-state dynamics of the trimer claimed based on the time-resolved X-ray data is questionable and that re-analysis and re-examining of its data are necessary.

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.

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.

Stand-up test could be a helpful adjunct for screening elbow disorders in Little League baseball players.

BACKGROUND: The purpose of this study is to justify the result of the modified Stand-Up test (MSUT) in Little League baseball players and to clarify the association with sports related disorders in the elbow. METHODS: A total of 245 (240 boys and 5 girls) Little League baseball players aged 9 to 12 underwent physical examination, elbow ultrasonography and questionnaires during a routine medical checkup. In addition, the MSUT, based on the Japanese Orthopaedic Association (JOA)'s original Stand-Up test to evaluate the risk of Locomotive syndrome, was performed. RESULTS: Seventeen osteochondritis dissecans (OCD) of capitellum and 4 medial epicondylar fragmentation (MEF) cases were diagnosed with ultrasonography in 242 players. Based on the MSUT, five boys could not stand up from 40 cm platform with the single leg stance, two of whom complained of current elbow pain, three of whom diagnosed with a positive finding with ultrasonography. Odds ratio (95% confidence limits) of risk factors for failing to the 40 cm-MSUT with the single leg stance were: incidence of current elbow pain 5.7 (0.9-35.5); OCD (Grade 1b and 2) 8.2 (0.8-83); and MEF 19.5 (1.7-230). CONCLUSION: Two percent of Little League baseball players were unable to stand up from a 40 cm high platform/stool with the single leg stance by the MSUT and it was associated with an increase in MEF or OCD diagnosis by ultrasonography and presence of elbow pain. These results suggest that players who failed to the 40 cm-MSUT with the single leg stance are at risk of elbow disorders. Also, these results are consistent with previous research on throwing injuries that have associated poor control in the legs or trunk with pain and injury involving the upper extremities. MSUT, a relatively simple procedure, may be a helpful adjunct for screening to estimate readiness for resuming general physical activity in Little League baseball players.

General Design Strategy to Precisely Control the Emission of Fluorophores via a Twisted Intramolecular Charge Transfer (TICT) Process.

Fluorogenic probes for bioimaging have become essential tools for life science and medicine, and the key to their development is a precise understanding of the mechanisms available for fluorescence off/on control, such as photoinduced electron transfer (PeT) and Förster resonance energy transfer (FRET). Here we establish a new molecular design strategy to rationally develop activatable fluorescent probes, which exhibit a fluorescence off/on change in response to target biomolecules, by controlling the twisted intramolecular charge transfer (TICT) process. This approach was developed on the basis of a thorough investigation of the fluorescence quenching mechanism of N-phenyl rhodamine dyes (commercially available as the QSY series) by means of time-dependent density functional theory (TD-DFT) calculations and photophysical evaluation of their derivatives. To illustrate and validate this TICT-based design strategy, we employed it to develop practical fluorogenic probes for HaloTag and SNAP-tag. We further show that the TICT-controlled fluorescence off/on mechanism is generalizable by synthesizing a Si-rhodamine-based fluorogenic probe for HaloTag, thus providing a palette of chemical dyes that spans the visible and near-infrared range.

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.

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.

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.

Severe hypertriglyceridemia induced by S-1: Subsequent case series of four patients and further review of the literature.

OBJECTIVE: We previously reported a case where S-1, containing tegafur, gimeracil, and oteracil potassium, induced severe hypertriglyceridemia. After the case, we regularly monitored serum lipid levels and surprisingly observed an additional 4 cases within 1.5 years. We here report the treatment process. CASE REPORT: At least 3 patients exhibited hyperlipidemia at baseline; in 2 of them, this was caused by previous fluoropyrimidine treatment. One patient experienced grade 4 hypertriglyceridemia, and the other 3 grade 3 hypertriglyceridemia. One patient developed temporary serum triglyceride elevation during the S-1 administration period, and the 3 experienced persistent elevation. The severity of serum triglyceride level worsened with increasing administration and peaked in cycles 2 - 6. Fenofibrate 80 - 160 mg/day and S-1 dose reduction were effective, with some significantly and others gradually decreasing to grade 0 - 1. DISCUSSION: The summarized clinical features are as follows: (1) Severe hypertriglyceridemia tends to appear after several treatment cycles and worsens with increasing administration. (2) It tends to occur in patients with hyperlipidemia at baseline. (3) Patients previously affected with fluoropyrimidines-induced hypertriglyceridemia can experience S-1 symptoms. (4) In some cases, it might decrease after the S-1 suspension period. (5) Fibrates and S-1 dose reductions were effective. As the final fluoropyrimidine product is fluorouracil, its presence or that of its metabolizing enzymes and the genetic background of the patients might have affected the results. We should be aware of the risk of temporal and asymptomatic occurrence of S-1-induced hypertriglyceridemia for early detection with appropriate treatment.

Phase II trial of combination treatment with S-1/cetuximab in patients with platinum-ineligible recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab. METHODS: Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m2/day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). RESULTS: Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49-82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22-66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0-18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1-8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%). CONCLUSIONS: Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123.

In situ cross-sectional area of the quadriceps tendon using preoperative magnetic resonance imaging significantly correlates with the intraoperative diameter of the quadriceps tendon autograft.

PURPOSE: Preoperative assessment to determine the sizes of potential autografts is necessary for individualized anterior cruciate ligament reconstruction (ACLR). However, no study has investigated the prediction of the intraoperative diameter of the quadriceps tendon (QT) autograft based upon preoperative imaging. This study investigated the correlation between the intraoperative diameter of a QT autograft and in situ thickness or cross-sectional area (CSA) measured using preoperative MRI. METHODS: Thirty-one knees of 31 patients (mean age 20.9 ± 5.0 years) who underwent individualized anatomic ACLR using all soft tissue QT autograft were included retrospectively. At 15 mm proximal to the superior pole of the patella, the maximum QT thickness was assessed in the sagittal plane and the CSA was assessed at the central 10 mm of the QT in the axial plane. The angle between the axial plane and a line perpendicular to the QT longitudinal axis was used to calculate an adjusted CSA using a cosine function. Intraoperatively, each QT autograft was harvested with 10 mm width and the diameter was measured using a graft sizing device. RESULTS: Intra- and inter-observer reliabilities of all measurements using preoperative MRI were excellent (intra-class correlation coefficient, 0.833-0.970). Significant correlations were observed between the thickness, CSA, or adjusted CSA, and the intraoperative diameter (R = 0.434, 0.607, and 0.540, respectively; P < 0.05). CONCLUSIONS: The CSA correlated most strongly with the QT autograft diameter. For individualized anatomic ACLR, measuring in situ CSA can be useful for preoperative planning of appropriate graft choices prior to surgery. LEVEL OF EVIDENCE: III.

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.

An improved quantitative ultrasonographic technique could assess anterior translation of the glenohumeral joint accurately and reliably.

PURPOSE: Since poor repeatability of the load and shift test using a grading scale has been reported, an objective and quantitative method to assess anterior translation should be established to assess glenohumeral joint function. The purpose of this study was to assess the accuracy and repeatability of the ultrasonographic techniques to quantify anterior translation of the glenohumeral joint. METHODS: Eight fresh-frozen cadaveric shoulders were used. For the standard technique, the ultrasound transducer was positioned on the anterolateral aspect of the shoulder viewing the coracoid process, glenoid, and humeral head. For the revised technique, the transducer was positioned on the anterior aspect of the shoulder, perpendicular to the scapular plane, viewing the conjoint tendon, glenoid, and humeral head. During the load and shift test, the distance between anterior edges of the glenoid and the humeral head was measured. The difference between distances before and after applying an anterior load was calculated as an anterior translation and compared with the anterior translation assessed using a motion tracking system. The repeatability and accuracy of both techniques were analyzed statistically. RESULTS: Intra- and inter-observer repeatability was good-excellent for both ultrasonographic techniques (ICC, 0.889-0.998). The revised technique achieved a stronger correlation to the anterior translations obtained using the motion tracking system (R = 0.810-0.913, p < 0.001) than the standard technique (R = 0.619-0.806, p < 0.001). CONCLUSION: Better accuracy and repeatability was found in the revised technique than the standard technique. The revised technique will be useful to determine the individual laxity and modify the treatment plan and return-to-sports protocol. LEVEL OF EVIDENCE: III.

Mode-Specific Vibrational Analysis of Exciton Delocalization and Structural Dynamics in Conjugated Oligomers.

Exciton delocalization in organic semiconducting polymers, affected by structures at a molecular level, plays a crucial role in modulating relaxation pathways, such as charge generation and singlet fission, which can boost device efficiency. However, the structural diversity of polymers and broad signals from typical electronic spectroscopy have their limits when it comes to revealing the interplay between local structures and exciton delocalization. To tackle these problems, we apply femtosecond stimulated Raman spectroscopy in archetypical conjugated oligothiophenes with different chain lengths. We observed Raman frequency dispersions of symmetric bond stretching modes and mode-specific kinetics in the S1 Raman spectra, which underpins the subtle and complex interplay between exciton delocalization and bond length alternation along the conjugation coordinate. Our results provide a more general picture of exciton delocalization in the context of molecular structures for conjugated materials.

A phase 2 study of intraperitoneal carboplatin plus intravenous dose-dense paclitaxel in front-line treatment of suboptimal residual ovarian cancer.

BACKGROUND: We evaluated the efficacy of intraperitoneal (IP) carboplatin in combination with dose-dense paclitaxel (ddTCip) for suboptimal residual ovarian cancer. METHODS: This was a phase 2 study to evaluate ddTCip. Patients with stage II-IV ovarian carcinoma, who underwent primary cytoreductive surgery and had radiologically evaluable disease after surgery, were eligible to participate in this study. IP carboplatin (AUC = 6) was administered on day 1, and intravenous paclitaxel (80 mg/m2) was administered on days 1, 8 and 15. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Interval- debulking surgery followed by the same regimen was allowed when indicated. RESULTS: A total of 117 patients were considered eligible for this study prior to surgery and temporarily registered. Of the 117 patients, 76 patients met the inclusion criteria and were enrolled in this study. Fifty-nine (83.1%) patients had objective clinical responses. Median PFS and OS were 18.3 and 55.5 months, respectively. Sixty-four (84.2%) patients had grade 3/4 neutropenia, 43 (56.5%) patients had anaemia and 17 (22.4%) patients had thrombocytopenia. Port-related adverse events occurred in nine (11.8%) patients. CONCLUSIONS: Front-line chemotherapy with ddTCip therapy appears safe and effective, even for patients with suboptimal residual ovarian cancer. TRIAL REGISTRATION: UMIN Clinical Trials Registry (ID: UMIN000001713) on February 16th, 2009.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.

BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.