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Purpose While a wide variety of platelet-rich plasma (PRP) solutions has been developed, innovation continues. In this case, the freeze-dried platelet factor concentrate (PFC-FD) represents another step in PRP refinement. The preparation of PFC-FD at a central laboratory with freeze drying for shelf stabilization should provide additional quality improvements if clinical effectiveness can be demonstrated. Therefore, this study was undertaken to assess the safety and effectiveness of PFC-FD in a prospective open-label trial of patients suffering from knee osteoarthritis (OA). Methods 312 consecutive knee OA patients (67% female, mean age 63 ± 10 years), were prospectively recruited in an outpatient knee clinic in Japan. Of these, 10 (3.2%) were lost to follow-up at < 12 months and 17 (5.5%) sought additional knee therapy during the follow-up period. The primary outcome of interest was achievement of the OMERACT-OARSI responder criteria with secondary outcomes of adverse events and PROMs scores 1, 3, 6, 12 months following a single PFC-FD injection. Results 285 patients (91%) completed 12 month PROMs. The 17 who sought additional therapy were considered failures leaving an effective sample size of 302 for our primary outcome in which 62% of patients achieved OMERACT-OARSI responder status by 12 months. This varied by OA class with Kellgren–Lawrence grade 4 patients 3.6 times less likely to be responders than grade 1–2 patients. 6% of patients experienced a non-serious adverse event, primarily pain or swelling at the injection site. Conclusions PFC-FD provides an observable clinical improvement in 62% of knee OA patients at 12 months post-injection with very little risk of any clinically relevant adverse event. Of course, nearly 40% of patients did not experience an observable clinical improvement, primarily among those with worse KL grades. Level of evidence Therapeutic, Level II.

Knee osteoarthritis (OA) causes pain and disability, and autologous adipose-derived stem cell (ASC) therapy has emerged as a regenerative treatment option. This retrospective cohort study compared short-term outcomes of intra-articular ASC injections between patients with moderate (Kellgren–Lawrence [KL] 2/3) and severe (KL 4) OA. Among 242 treated patients, 98 in each group were analyzed after propensity score matching for age, sex, and body mass index. Pain (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales were evaluated at baseline and 1, 3, and 6 months. Both groups showed significant improvements in pain and function, with KL 2/3 patients exhibiting greater gains in KOOS Total, Activities of Daily Living, Sports/Recreation, Quality of Life, and VAS pain compared with KL 4. KOOS pain and symptoms improved similarly in both groups. Analgesic effects increased over time, and no serious adverse events were observed. Mild transient swelling or discomfort occurred in about 5% to 6% of cases. ASC injections provided meaningful symptom relief and functional improvement, particularly in moderate OA, suggesting that preserved joint structure benefits therapeutic efficacy. In advanced OA, benefits were present but attenuated, indicating limited regenerative potential in end-stage disease.

Purpose The reduction of periosteal compression through the use of a locking plate may minimize disturbances of bone blood supply and may improve the rate of bone union. A single-centre, assessor blinded randomized controlled trial was conducted to compare the clinical effectiveness of a locking plate and a non-locking plate. Methods A total of 52 patients with AO/OTA 44B lateral malleolar fractures were included in this study. All patients underwent surgical fixation using a lag screw and neutralization plate. An identical treatment protocol was used in all patients, with exception of plate selection. The rate of radiographic bone union, defined as the complete disappearance of fracture lines confirmed through anteroposterior, lateral, and internal oblique views was compared at three, six, and 12 months following surgery. In addition, the Medical Outcomes 36-Item Short-Form Health Survey (SF-36) score, the time required for resolution of tenderness at the fracture site and the complication rate were evaluated. Results Twenty-three patients were randomly assigned to undergo fixation using a locking plate, and 29 patients were assigned to undergo fixation using a non-locking plate. Intention-to-treat analysis showed no difference in the radiographic bone union rate of fibula, SF-36 score, the time for resolution of tenderness at the fracture site and complication rates. Conclusion No differences were observed in patients with AO/OTA 44B lateral malleolar fractures undergoing fixation with a locking versus non-locking neutralization plate.

A 49-year-old woman presented with severe swelling and pain of the left little finger, which had exacerbated rapidly, in October 2006. The patient had a history of hepatocellular carcinoma and metastatic lung cancer. She had undergone partial hepatectomy for the hepatocellular carcinoma in September 2001 and pulmonary resection for metastatic lung cancer in November 2005. Roentgenogram of the hand on admission showed complete destruction of the distal phalanx of the left little finger. The final pathological result of the tissue obtained by disarticulation was an extrahepatic metastasis of hepatocellular carcinoma. Extrahepatic metastasis from primary hepatocellular carcinoma to the hand is very rare and only four cases have been reported in the literature. All the patients with extrahepatic metastases from the primary hepatocellular carcinoma to the hand had poor prognoses, but the patient presented in this article exhibited an unusual clinical course. The patient is still alive 1 year after the diagnosis of extrahepatic bone metastasis of the distal phalanx.

Induced pluripotent stem cells (iPSCs) are novel stem cells derived from adult mouse and human tissues by reprogramming. Elucidation of mechanisms and exploration of efficient methods for their differentiation to functional cardiomyocytes are essential for developing cardiac cell models and future regenerative therapies. We previously established a novel mouse embryonic stem cell (ESC) and iPSC differentiation system in which cardiovascular cells can be systematically induced from Flk1(+) common progenitor cells, and identified highly cardiogenic progenitors as Flk1(+)/CXCR4(+)/VE-cadherin(-) (FCV) cells. We have also reported that cyclosporin-A (CSA) drastically increases FCV progenitor and cardiomyocyte induction from mouse ESCs. Here, we combined these technologies and extended them to mouse and human iPSCs. Co-culture of purified mouse iPSC-derived Flk1(+) cells with OP9 stroma cells induced cardiomyocyte differentiation whilst addition of CSA to Flk1(+) cells dramatically increased both cardiomyocyte and FCV progenitor cell differentiation. Spontaneously beating colonies were obtained from human iPSCs by co-culture with END-2 visceral endoderm-like cells. Appearance of beating colonies from human iPSCs was increased approximately 4.3 times by addition of CSA at mesoderm stage. CSA-expanded human iPSC-derived cardiomyocytes showed various cardiac marker expressions, synchronized calcium transients, cardiomyocyte-like action potentials, pharmacological reactions, and ultra-structural features as cardiomyocytes. These results provide a technological basis to obtain functional cardiomyocytes from iPSCs.

The estimation of aortic valve area (AVA) by Doppler echocardiography-derived left ventricular stroke volume (LVSV) remains controversial. We hypothesized that AVA estimated from directly measured LVSV by 3-dimensional echocardiography (3DE) on the continuity equation might be more accurate in classifying aortic stenosis (AS) severity. We retrospectively enrolled 265 patients with moderate-to-severe AS with preserved ejection fraction. Indexed AVA (iAVA) was calculated using LVSV derived by 2D Doppler (iAVADop), Simpson's method (iAVASimp), and 3DE (iAVA3D). During a median follow-up period of 397 days (interquartile range 197 to 706 days), 135 patients experienced the composite end point (cardiac death 9%, aortic valve replacement 24%, and cardiovascular event 27%). Estimated iAVA3D and iAVASimp were significantly smaller than iAVADop and moderately correlated with peak aortic jet velocity. Upper septal hypertrophy was a major cause of discrepancy between iAVADop and iAVA3D methods. Based on the optimal cut-off point of iAVA for predicting peak aortic jet velocity >4.0 m/s, 141 patients (53%) were classified as severe AS and 124 patients (47%) as moderate AS by iAVADop. Indexed AVA3D classified 118 patients (45%) as severe and 147 patients (55%) as moderate AS. Of the 124 patients with moderate AS by iAVADop, 22 patients (18%) were reclassified as severe AS by iAVA3D and showed poor prognosis (hazard ratio 2.7, 95% CI 1.4 to 5.0; p = 0.001). In conclusion, 3DE might be superior in classifying patients with AS compared with Doppler method, particularly in patients with upper septal hypertrophy.

BackgroundOlder or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)–leucovorin plus bevacizumab in such patients.MethodsThe study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety.ResultsForty-one patients were enrolled and eligible. Median age was 76 years (range 56–90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1–53.1%], median PFS was 9.4 months (95% CI 7.4–17.7 months), and median OS was 24.0 months (95% CI 19.9 months—not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths.ConclusionWeekly 5-FU–leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Background Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥75 years with mCRC. Methods This prospective, open-label phase II trial recruited patients aged ≥75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m 2 of oxaliplatin on day 1 of each cycle combined with 2000 mg/m 2 of oral capecitabine per day on days 1–14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival. Results Thirty-six patients (male 58 %; median age 78 years; colon cancer 67 %) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0 months. Twelve patients (33.3 %) experienced adverse effects (AEs) ≥ grade 3 and frequent AEs ≥ grade 3, including neutropenia (22.2 %) and neuropathy (13.9 %). Hypertension was the most frequent AE ≥ grade 3 associated with bevacizumab (11.1 %). Low baseline creatinine clearance associated significantly with the incidence of AEs ≥ grade 3. Response and disease control rates were 55.6 and 91.7 %, respectively. Median progression-free and overall survival times were 11.7 months (95 % confidence interval, 8.0–13.4 months) and 22.9 months, respectively. Conclusion XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit.

The purpose of this study was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) is useful for early detection of the response of hepatic colorectal metastases to hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU). The subjects were 12 patients with hepatic colorectal metastases. The indwelling catheter for HAIC was placed in the hepatic artery, and 1000 mg/m 2 5-FU was given repeatedly once a week. DWI was performed before and 9 days after HAIC. The minimum and mean apparent diffusion coefficient (ADC) values (minADC and meanADC) were measured. The relative change in ADC values (%ADC) and the relative change in tumor size on follow-up CT after 3 months (reduction ratio) were determined. Liver metastases were divided into two groups, responder and nonresponder. The correlation between %ADC and reduction ratio was determined, and %ADC was compared between the two groups. Eleven patients successfully completed HAIC over the 3-month period; 48 metastatic lesions were evaluated. Positive correlations were observed for relative change between %minADC and reduction ratio ( r  = 0.709) and between %meanADC and reduction ratio ( r  = 0.536). Both %minADC and %meanADC were significantly greater in the responder group than in the nonresponder group. With the threshold determined as < 3.5%, the receiver-operating curve analysis showed higher sensitivity and specificity values for %minADC (100% and 92.6%, respectively) than for %meanADC (66.7% and 74.1%, respectively). In conclusion, the relative change in minimum ADC values on DWI may be useful for early detection of the response of liver metastases to HAIC with 5-FU.