An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case-control study.

The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors. PURPOSE: To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA). METHODS: In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), - 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period. RESULTS: The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P = 0.013) and total hip (2.4% vs. 4.8%; P = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group (n = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD. CONCLUSIONS: The efficacy of ROMO may be attenuated by RA-related factors.

The Phase II Study of Panitumumab in Chemotherapy-Naïve Frail or Elderly Patients with RAS Wild-type Colorectal Cancer: OGSG 1602 Final Results.

BACKGROUND: We previously reported the response rate of a phase II OGSG1602 study on panitumumab in chemotherapy-naive frail or elderly patients with RAS wild-type unresectable colorectal cancer (CRC) [Terazawa T, Kato T, Goto M, et al. Oncologist. 2021;26(1):17]. Herein, we report a survival analysis. METHODS: Patients aged ≥65 years and considered unsuitable for intensive chemotherapy or aged ≥76 years were enrolled. Primary tumors located from the cecum to the transverse colon were considered right-sided tumors (RSTs); those located from the splenic flexure to the rectum were considered left-sided tumors (LSTs). RESULTS: Among the 36 enrolled patients, 34 were included in the efficacy analysis, with 26 and 8 having LSTs and RSTs, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.0 [95% CI, 5.4-10.0] and 17.5 months (95% CI, 13.8-24.3), respectively. Although no significant differences existed in PFS between patients with LST and RST {6.6 (95% CI, 5.4-11.5) vs. 4.9 months [95% CI, 1.9-not available (NA), P = .120]}, there were significant differences in OS [19.3 (95% CI, 14.2-NA) vs.12.3 months (95% CI, 9.9-NA), P = .043]. CONCLUSION: Panitumumab showed favorable OS in frail or elderly patients with RAS wild-type CRC and no prior exposure to chemotherapy. Panitumumab may be optimal for patients with LSTs (UMIN Clinical Trials Registry Number UMIN000024528).

Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6-CXCR2 pathway.

OBJECTIVE: To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. METHODS: Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. RESULTS: Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. CONCLUSION: SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.

Comparative effectiveness of early initiation of oral nonsteroidal anti-inflammatory drug and oral acetaminophen therapies on the time to knee replacement in patients with knee osteoarthritis in Japan.

BACKGROUND: Although disease-modifying properties of nonsteroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis (OA) have been reported, the effects of NSAIDs on OA progression remain controversial. The purpose of this study was to investigate the effect of early initiation of oral NSAID therapy on the progression of knee OA. METHODS: In this retrospective cohort study, we extracted data of patients newly diagnosed with knee OA between November 2007 and October 2018 from a Japanese claims database. The primary outcome was the time to knee replacement (KR), and the secondary outcome was the time to composite event including joint lavage and debridement, osteotomy, or arthrodesis in addition to KR. Weighted Cox regression analysis with standardized mortality/morbidity ratio (SMR) weight was performed to compare the outcomes between patients prescribed oral NSAID (NSAID group) and those prescribed oral acetaminophen (APAP) (APAP group) early after a diagnosis of knee OA. Propensity scores were calculated using logistic regression conditioned on potential confounding factors, and SMR weights were calculated using the propensity scores. RESULTS: The study population comprised 14,261 patients, who were divided into two groups as follows: 13,994 in the NSAID group and 267 in the APAP group. The mean ages of patients in the NSAID and APAP groups were 56.9 and 56.1 years, respectively. Furthermore, 62.01% and 68.16% patients in the NSAID and APAP groups, respectively, were female. The NSAID group had a reduced risk of KR compared with the APAP group in the analysis using SMR weighting (SMR-weighted hazard ratio, 0.19; 95% confidence interval, 0.05-0.78). While no statistically significant difference was found for the risk of composite event between the two groups (SMR-weighted hazard ratio, 0.56; 95% confidence interval, 0.16-1.91). CONCLUSIONS: The risk of KR in the NSAID group was significantly lower than that in the APAP group after accounting for residual confounding using SMR weighting. This finding suggests that oral NSAID therapy early after the initial diagnosis is associated with a reduced risk of KR in patients with symptomatic knee OA.

Add-on effectiveness of methotrexate or iguratimod in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors: The ANSWER cohort study.

OBJECTIVES: This multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKis). METHODS: Forty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients' background is as follows: age, 59.2 years; disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index, 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; and JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months. RESULTS: Thirty-five patients continued the combination therapy for 6 months without a significant change in concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, p < 0.05; IGU, 3.3 to 2.1, p < 0.001) and clinical disease activity index (MTX, 16.7 to 8.8, p < 0.05; IGU, 14.6 to 6.5, p < 0.01) improved significantly from baseline. Using the 2019 European League Against Rheumatism criteria, 45.4% (MTX) and 39.1% (IGU) achieved moderate or good response and 40.9% (MTX) and 39.1% (IGU) achieved American College of Rheumatology 20% improvement criteria. CONCLUSIONS: Adding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.

[Providing Opportunities for Close Examination of Lynch Syndrome after Microsatellite Instability Testing in a Hospital Setting].

Microsatellite instability(MSI)testing is performed in cancer patients to determine the indication for chemotherapy with immune checkpoint inhibitors. We report on our scheme to ensure that Lynch syndrome patients are offered the opportunity for genetic counseling and genetic testing. Two hundred and eight cancer patients(107 males and 101 females, 20- 87 years, mean 63.3 years)underwent MSI testing at our hospital between February 2019 and November 2021. From February 2019 to December 2020, the MSI testing was performed with a consent document that included a commentary on Lynch syndrome, and the results were explained only by the attending cancer doctors. Eleven(8.6%)of the 136 cases had MSI-high, but none of them led to a visit to the genetic medicine department. The Genome Center in our hospital, which was operational from April 2020, undertook information sharing by multiple professions and established a system to provide appropriate support to cancer doctors. Consecutively, 72 MSI tests were performed between January and November 2021, and 2 patients(2.8%)with MSI-high(1 with endometrial cancer and 1 with colorectal cancer)were referred to the Department of Clinical Genetics for genetic counseling. Through genetic testing, both were diagnosed with Lynch syndrome, and information on future surveillance and health care for blood relatives was provided.

Tibiofemoral Relationship 3 Weeks After Anatomic Triple-Bundle Anterior Cruciate Ligament Reconstruction With 10 N of Initial Tension Is Closer to Normal Knee Versus That With 20 N of Initial Tension.

PURPOSE: This study aimed to clarify the effect of initial graft tension on the ensuing tibiofemoral relationship and on 2-year clinical outcomes after anatomic triple-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 31 patients with primary unilateral ACL rupture (mean age, 25.1 years) were enrolled. Anatomic triple-bundle ACL reconstruction was performed using semitendinosus tendon autografts, and patients were grouped according to the total initial tension at graft fixation: 20 N for 16 patients between January 2012 and December 2012 and 10 N for 15 patients between January 2013 and December 2013. Three-dimensional computed tomography scans were performed preoperatively and at 3 weeks and 6 months postoperatively. The side-to-side difference of the 3-dimensional tibial position relative to the femur was compared at each time point. The side-to-side difference in anterior laxity was sequentially compared preoperatively, immediately after surgery, and at 6 months and 2 years postoperatively. Clinical outcomes at 2 years were likewise compared. RESULTS: One patient in each group was excluded because of secondary ACL injury. At 3 weeks postoperatively, 2.5 ± 1.3 and 1.0 ± 1.3 mm of posterior tibial displacement and 3.8° ± 2.4° and 2.0° ± 1.7° of external rotation were observed in the 20- and 10-N initial tension groups, respectively, with significant differences (P = .006 and .033). At 6 months postoperatively, anterior displacement was 0.1/0.1 mm and external rotation was 0.8°/0.4° in both groups, without any significant differences. The 2-year clinical outcomes were satisfactory, including mean side-to-side difference in anterior knee laxity of 0.5 mm in both groups. CONCLUSION: The tibiofemoral relationship 3 weeks after anatomic triple-bundle ACL reconstruction with 10 N of initial tension is less constrained than that with 20 N. Six-month tibiofemoral relationship and 2-year clinical outcomes are satisfactory in both groups. LEVEL OF EVIDENCE: III, retrospective comparative trial.

The counteracting effect of the friction moment against the tibial rotational moment driven by the ground reaction force in an early stance phase of cutting maneuver among healthy male athletes.

The ground reaction force (GRF) is known to produce tibial internal rotation loading associated with the stress in the anterior cruciate ligament (ACL). However, it is unclear whether the friction moment (FM; the moment due to horizontal shoe-floor friction, acting around the vertical axis at the GRF acting point) facilitates or restrains the effect of GRF-driven tibial rotation loading during cutting. The 45° cutting motions with forefoot/rearfoot strikes were captured simultaneously with GRF and FM data from 23 healthy males. The FM- and GRF-driven tibial rotation moments were calculated. Time-series correlation between FM- and GRF-driven tibial rotation moments and the orientation relationship among those moment vectors was investigated. The FM-driven tibial rotation moment negatively correlated with the GRF-driven one within the first 10% of stance phase. The peak regression slope value was -0.34 [SD 0.33] for forefoot and -1.64 [SD 1.76] for rearfoot strikes, showing significant difference from zero (SPM one-sample t-test, p<0.05). The FM-driven tibial "external" rotation moment counteracted the GRF-driven tibial "internal" rotation moment within first 10% of the stance phase in most trials, suggesting that the FM-driven tibial rotation moment potentially diminishes the effect of GRF-driven one and may reduce ACL injury risk during cutting.

An Experimental Feasibility Study Evaluating the Adequacy of a Sportswear-Type Wearable for Recording Exercise Intensity.

Sportswear-type wearables with integrated inertial sensors and electrocardiogram (ECG) electrodes have been commercially developed. We evaluated the feasibility of using a sportswear-type wearable with integrated inertial sensors and electrocardiogram (ECG) electrodes for evaluating exercise intensity within a controlled laboratory setting. Six male college athletes were asked to wear a sportswear-type wearable while performing a treadmill test that reached up to 20 km/h. The magnitude of the filtered tri-axial acceleration signal, recorded by the inertial sensor, was used to calculate the acceleration index. The R-R intervals of the ECG were used to determine heart rate; the external validity of the heart rate was then evaluated according to oxygen uptake, which is the gold standard for physiological exercise intensity. Single regression analysis between treadmill speed and the acceleration index in each participant showed that the slope of the regression line was significantly greater than zero with a high coefficient of determination (walking, 0.95; jogging, 0.96; running, 0.90). Another single regression analysis between heart rate and oxygen uptake showed that the slope of the regression line was significantly greater than zero, with a high coefficient of determination (0.96). Together, these results indicate that the sportswear-type wearable evaluated in this study is a feasible technology for evaluating physical and physiological exercise intensity across a wide range of physical activities and sport performances.

Validity of Spatio-Temporal Gait Parameters in Healthy Young Adults Using a Motion-Sensor-Based Gait Analysis System (ORPHE ANALYTICS) during Walking and Running.

Motion sensors are widely used for gait analysis. The validity of commercial gait analysis systems is of great interest because calculating position/angle-level gait parameters potentially produces an error in the integration process of the motion sensor data; moreover, the validity of ORPHE ANALYTICS, a motion-sensor-based gait analysis system, has not yet been examined. We examined the validity of the gait parameters calculated using ORPHE ANALYTICS relative to those calculated using conventional optical motion capture. Nine young adults performed gait tasks on a treadmill at speeds of 2−12 km/h. The three-dimensional position data and acceleration and angular velocity data of the feet were collected. The gait parameters were calculated from motion sensor data using ORPHE ANALYTICS, and optical motion capture data. Intraclass correlation coefficients [ICC(2,1)] were calculated for relative validities. Eight items, namely, stride duration, stride length, stride frequency, stride speed, vertical height, stance phase duration, swing phase duration, and sagittal angleIC exhibited excellent relative validities [ICC(2,1) > 0.9]. In contrast, sagittal angleTO and frontal angleIC demonstrated good [ICC(2,1) = 0.892−0.833] and moderate relative validity [ICC(2,1) = 0.566−0.627], respectively. ORPHE ANALYTICS was found to exhibit excellent relative validities for most gait parameters. These results suggest its feasibility for gait analysis outside the laboratory setting.

Low serum albumin concentration is associated with increased risk of osteoporosis in postmenopausal patients with rheumatoid arthritis.

BACKGROUND: The risk of osteoporosis in patients with rheumatoid arthritis (RA) is frequently overlooked, and investigating a simple indicator in routine care may be beneficial to motivate osteoporosis examination. The aim of this retrospective, case-controlled study was to identify the correlation between serum albumin concentrations and the prevalence of osteoporosis in postmenopausal patients with RA. METHODS: This study enrolled 197 patients who underwent dual-energy X-ray absorptiometry of lumbar spine (LS) and proximal femur without osteoporosis treatment [mean age, 67.5 years; disease duration, 12.8 years; Disease Activity Score assessing 28 joints with C-reactive protein, 2.0; prednisolone dose, 4.9 mg/day (usage, 42.6%); and LS T-score, -1.9]. Patients were classified into 2 groups: osteoporosis, defined as ≥ 1 part bone mineral density T-score ≤ -2.5 or history of fragility fracture of the vertebra or proximal femur (121 patients), and non-osteoporosis (76 patients). Groups were then matched by propensity score using clinical backgrounds affecting bone metabolism. RESULTS: In non-matched model, serum albumin concentration was significantly associated with osteoporosis-related factors such as aging, inflammation, physical disability, and glucocorticoid dose. Multivariate logistic regression revealed that serum albumin concentration was independently and significantly associated with osteoporosis risk (odds ratio = 0.22, 95% confidence interval = 0.08, 0.61, p = 0.0033). After propensity score matching, 57 patients for each group showed that in addition to the LS and femoral neck T-scores (p < 0.001), serum albumin concentrations (p = 0.01) remained lower in the osteoporosis group compared to non-osteoporosis group. Receiver operating characteristic curve analysis in non-matched model revealed that when cut-off value of serum albumin concentration for indicating osteoporosis was set at 4.2 g/dl, the area under the curve was 0.69, sensitivity 0.74, and specificity 0.58. CONCLUSIONS: Low serum albumin concentration was significantly and independently associated with the prevalence of osteoporosis, which may be considered as one of the osteoporosis-related factors in postmenopausal patients with RA.

Knot location in arthroscopic inside-out meniscal repair: Cadaveric evaluation.

BACKGROUND: The inside-out repair technique is the gold standard for treatment of meniscal tears, while some soft tissues can be hung as the sutures are tied outside the capsule. The purpose was to clarify the association between the suture site and knot location in the arthroscopic inside-out technique. METHODS: Inside-out meniscal suture was arthroscopically performed on medial and lateral menisci in twenty-three cadaveric knees, on the assumption that longitudinal tear existed. A retractor was inserted above the semi-membranous tendon and anterior to the gastrocnemius for the medial side, while the retractor was placed in the anterior space of the gastrocnemius for the lateral side. After identifying three segments (anterior, middle and posterior segments), eight sutures were inserted into the following eight areas in each knee: anterior (M1, L1) and posterior (M2, L2) areas of the middle segment, and anterior (M3, L3) and posterior (M4, L4) areas of the posterior segment. Twelve knees underwent meniscal repair on femoral side and eleven passed sutures on the tibial side, while knots were tied outside of the joint. Attentive dissection was performed to assess the relation between knot locations and the principal structures around the knee joint. RESULTS: In medial meniscal suture, most sutures for the middle portion (M1, 2) bound medial collateral ligament (MCL), while a few cases included the semi-membranous tendon for the M4 area. In lateral meniscal suture, sutures for the L1 area tied some fibers of lateral collateral ligament (LCL) in high frequency, while popliteal muscles/tendons were tied over at the L3 area. CONCLUSIONS: Most suture knots were located on MCL or capsule in medial meniscus suture, while more than half sutures passed through LCL or popliteal tendon/muscle in lateral meniscus suture. An assistant should retract LCL under direct observation and the surgeon must confirm the direction of needle for lateral meniscal repair.

[A Case Report of Stage â £b Thoracic Esophageal Cancer Responding to Multidisciplinary Treatment].

A 68-year-old man was referred to our hospital because of back pain during swallowing. Upper gastrointestinal endoscopy revealed a lower esophageal type 3 tumor. The patient was diagnosed with esophageal squamous cell carcinoma by the biopsy specimen. CT scan showed thoracic lower esophagus wall thickening, left paracardiac lymph node swelling, and a low-density area in the liver. Therefore, the patient was diagnosed with Stage Ⅳb esophageal cancer. After introducing cisplatin plus 5-FU combination therapy, the liver metastasis disappeared. After 9 chemotherapy courses, the patient received radical chemoradiotherapy. After completing chemoradiotherapy, the patient was followed up without any treatment. After 3 years since the treatment initiation, the patient is surviving without any relapse.

[Case of Robot-Assisted Low Anterior Resection with Total Cystectomy for Rectal Cancer Invading the Urinary Bladder/Prostate in Collaboration with Urologists].

We present a case of a 72-year-old man diagnosed with rectal cancer invading the urinary bladder/prostate. Preoperative chemoradiotherapy substantially reduced the tumor size. In collaboration with urologists, robot-assisted low anterior resection with total cystectomy was performed using the da Vinci Xi system. Depending on the surgical situation, the colorectal surgeon and urologist could smoothly and rapidly play the role of a console surgeon. Although the first robot-assisted multi-organ resection of our institution, the surgery was completed safely without any complications. Although the patient developed urinary tract infection postoperatively, he recovered and was discharged after postoperative 23 days. In conclusion, robot-assisted surgery would be useful in pelvic surgery involving multiple departments such as colorectal surgery, urology, and gynecology.

[Successful Treatment with TACE and RFA for a Hepatocellular Carcinoma Case with Lung Metastasis].

We report a hepatocellular carcinoma(HCC)case with lung metastasis that was successfully treated with transarterial chemoembolization(TACE)and percutaneous radiofrequency ablation(RFA). A man in his 60s took right robe liver resection for HCC after TACE for its rupture. Lung metastasis occurred at S1+2 and S6 in the left lung, and an adverse event interrupted standard molecular target therapies. Because extrahepatic metastasis had been seen only in these two locations for a long time, TACE was performed for both metastases. The feeders for both lesions were each intercostal artery, and controlling the drug inflow was necessary to avoid drug influx into the spinal cord branches when S6 metastasis was treated. The viable lesion remained in the S6 lesion, so RFA was added for both lung metastases. 100% tumor necrosis has been observed since the RFA.

Phase II Study of Panitumumab Monotherapy in Chemotherapy-Naïve Frail or Elderly Patients with Unresectable RAS Wild-Type Colorectal Cancer: OGSG 1602.

LESSONS LEARNED: Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild-type unresectable colorectal cancer. It is especially effective for left-sided tumors; therefore, panitumumab as first-line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin-based or irinotecan-based combination regimens. BACKGROUND: First-line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy-naïve frail or elderly patients with unresectable RAS wild-type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first-line treatment. METHODS: We conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities. RESULTS: Thirty-six patients (median age: 81 [range, 67-88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty-three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty-eight patients (77.8%) had left-sided CRC, whereas eight (22.2%) had right-sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4-67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5-87.7). The RR of patients with left- and right-sided tumors was 65.4% (95% CI, 44.3-82.8) and 0.0% (95% CI, 0.0-36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%). CONCLUSION: Panitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.

Randomized phase II study of SOX+B-mab versus SOX+C-mab in patients with previously untreated recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study).

BACKGROUND: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. METHODS: This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled. RESULTS: Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively). CONCLUSIONS: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. TRIAL REGISTRATION: UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920.

Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro.

INTRODUCTION: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. MATERIALS AND METHODS: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. RESULTS: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. CONCLUSION: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.

Pre-emptive oral clarithromycin reduces the skin toxicity of panitumumab treatment for metastatic colorectal cancer.

PURPOSE: Chemotherapy with panitumumab is expected to be well tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). However, skin toxicities are its most common adverse events. The aim of this trial was to evaluate the efficacy and safety of pre-emptive antibiotic treatment with clarithromycin (CAM) to prevent panitumumab skin toxicities. METHODS: We conducted a phase lll, multicenter, open-label, randomized clinical trial on mCRC patients treated with panitumumab. Eligible patients were randomly assigned 1:1 to pre-emptive antibiotic and control groups. In the pre-emptive group, CAM administration (200 mg twice per day) continued daily through the panitumumab treatment period. The control regimen consisted of skin care only. The primary end point was the incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period. RESULTS: Of 156 enrolled patients, 78 received pre-emptive antibiotic treatment, and 78 received reactive treatment. The number and incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period were 16 (21.3%) and 41 (54.7%) for the pre-emptive and control groups, respectively (HR, 0.32; 95% CI, 0.17-0.56). There was almost no difference in the rate of other adverse events between the two groups, but the incidence of grade ≥ 3 diarrhea in the pre-emptive group was high, at 8% vs. 1.3% in the control group. There were no treatment-related deaths. CONCLUSION: Prophylactic oral CAM together with relatively simple skin care was found to be effective in suppressing the development of grade ≥ 2 skin toxicities induced by panitumumab. CLINICAL TRIAL REGISTRATION: UMIN000011485 DATE OF REGISTRATION: Sep 1st, 2013.

Different effects of the lateral meniscus complete radial tear on the load distribution and transmission functions depending on the tear site.

PURPOSE: To compare the effect of the lateral meniscus (LM) complete radial tear at different tear sites on the load distribution and transmission functions. METHODS: A compressive load of 300 N was applied to the intact porcine knees (n = 30) at 15°, 30°, 60°, 90°, and 120° of flexion. The LM complete radial tears were created at the middle portion (group M), the posterior portion (group P), or the posterior root (group R) (n = 10, each group), and the same loading procedure was followed. Finally, the recorded three-dimensional paths were reproduced on the LM-removed knees. The peak contact pressure (contact area) in the lateral compartment and the calculated in situ force of the LM under the principle of superposition were compared among the four groups (intact, group M, group P, and group R). RESULTS: At all the flexion angles, the peak contact pressure (contact area) was significantly higher (lower) after creating the LM complete radial tear as compared to that in the intact state (p < 0.01). At 120° of flexion, group R represented the highest peak contact pressure (lowest contact area), followed by group P and group M (p < 0.05). The results of the in situ force carried by the LM were similar to those of the tibiofemoral contact mechanics. CONCLUSION: The detrimental effect of the LM complete radial tear on the load distribution and transmission functions was greatest in the posterior root tear, followed by the posterior portion tear and the middle portion tear in the deep-flexed position. Complete radial tars of the meniscus, especially at the posterior root, should be repaired to restore the biomechanical function.