Five-year outcomes of treat and extend regimen using intravitreal aflibercept injection for treatment-naïve age-related macular degeneration.

PURPOSE: This study evaluated the long-term outcomes of eyes with neovascular age-related macular degeneration (nAMD) treated with aflibercept according to a treat-and-extend (T&E) regimen for up to 5 years. Methods This retrospective study included 112 eyes of 111 patients with nAMD who received aflibercept according to the T&E regimen. The patients received 3 monthly injections of aflibercept followed by a T&E regimen for at least 12 months. Data, including best-corrected visual acuity (BCVA), treatment interval, presence of exudation, central retinal thickness, and central choroidal thickness were analyzed. RESULTS: Of the 112 consecutive eyes, 66 completed the 5-year follow-up. After 5 years of treatment, BCVA (logMAR) was significantly better than baseline (0.29 ± 0.31 at baseline and 0.18 ± 0.23 at 5 years, P < 0.01). A mean of 7.0 ± 1.5 injections in the first year and 4.9 ± 2.2 injections per year thereafter were required. In eyes with subretinal hyperreflective material (SHRM) at baseline, BCVA at baseline and 5 years were significantly worse than in eyes without SHRM at baseline and 5 years. However, the eyes with SHRM required fewer injections and exhibited greater BCVA improvement. CONCLUSION: This retrospective study demonstrated the effectiveness of the T&E regimen with aflibercept in managing nAMD over a 5-year period, maintaining significant improvements in BCVA.

EFFECTS OF HALF-DOSE PHOTODYNAMIC THERAPY ON CHRONIC CENTRAL SEROUS CHORIORETINOPATHY WITH OR WITHOUT MACULAR NEOVASCULARIZATION ASSESSED USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To assess the effects of half-dose photodynamic therapy on subretinal fluid and macular neovascularization (MNV) using optical coherence tomography angiography in patients with chronic central serous chorioretinopathy. METHODS: Clinical information on 168 patients (168 eyes) with chronic central serous chorioretinopathy obtained before and 6 months after treatment with half-dose photodynamic therapy was retrospectively analyzed. Patients were categorized into a success (145 eyes) or failure (23 eyes) group based on the absence or presence of subretinal fluid, respectively, and clinical data were compared between them. Macular neovascularization was studied in 147 cases with available optical coherence tomography angiography images. P < 0.05 indicated statistical significance. RESULTS: The success group showed a younger patient age, better posttreatment best-corrected visual acuity, and thicker pretreatment central choroidal thickness (all, P < 0.047) than did the failure group. Regarding MNV analysis, nine, eight, and 130 eyes had definite, possible, and no MNV, respectively, at baseline; among them, 100.0%, 75.0%, and 2.3%, respectively, had MNV at 6 months posttreatment. Patients with definite MNV at baseline were less likely to show successful subretinal fluid resolution. CONCLUSION: Although half-dose photodynamic therapy is generally effective for the treatment of chronic central serous chorioretinopathy, coexisting MNV may compromise the outcome; thus, optical coherence tomography angiography-based assessment of chronic central serous chorioretinopathy is important.

Choroidal hemodynamics in central serous chorioretinopathy after half-dose photodynamic therapy and the effects of smoking.

This retrospective study aimed to evaluate choroidal hemodynamics after half-dose photodynamic therapy (PDT) for central serous chorioretinopathy (CSC) and the effects of smoking using laser speckle flowgraphy. This study included 29 eyes of 29 patients treated with half-dose PDT for CSC, who were followed-up for at least 6 months. The mean blur rate (MBR) in the PDT irradiation area (whole area), the pachyvessel (PV) area, non-PV (NPV) area, and filling delay (FD) area were assessed at baseline and 1, 3, and 6 months post-PDT, respectively. The MBR was also assessed by smoking status. The MBR significantly decreased from baseline in the whole, PV, NPV, and FD areas at all time points (P < 0.001). Of the 29 patients, 6 were never smokers, 13 were past smokers, and 10 were current smokers. At baseline, no significant difference was found in the MBR in the whole, PV, NPV, and FD areas among never, past, and current smokers. The MBR changes showed a significantly smaller decrease in current smokers than in never smokers in the whole (P = 0.021), PV (P = 0.009), and NPV (P = 0.034) areas, but not in the FD area (P = 0.172). Half-dose PDT for CSC reduced choroidal blood flow in the PDT-irradiated area, which was blunted by current smoking status.

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real-world treatment outcomes.

Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography-tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure-response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (Ctrough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed Ctrough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related Ctrough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population.Clinical trial registry: Not applicable.

Four-year outcome of aflibercept administration using a treat-and-extend regimen in eyes with recurrent neovascular age-related macular degeneration.

PURPOSE: To investigate the 4-year outcome of aflibercept treatment using a treat-and-extend (TAE) regimen for recurrent neovascular age-related macular degeneration (AMD). STUDY DESIGN: Retrospective observational study. METHODS: Data of eyes with recurrent AMD previously treated with anti-vascular endothelial growth factor agents or photodynamic therapy and had started aflibercept treatment using a TAE regimen for the first time were collected. Best-corrected visual acuity (BCVA), intervals of treatments, the presence of exudation, central foveal thickness (CFT), and central choroidal thickness (CCT) were analyzed. RESULTS: Of 47 consecutive eyes, 30 of the 47 eyes completed a 4-year follow-up. The mean BCVA (logMAR) was sustained over the 4 years (0.37 at baseline, 0.36 at 1 year, 0.36 at 2 years, 0.41 at 3 years, and 0.43 at 4 years, P = 0.21). Of the 30 eyes that completed the follow-up, BCVA of two eyes deteriorated by 0.3 logMAR or more at 4 years. At 4 years, 67% of eyes had extended treatment intervals to > 8 weeks, and 47% of eyes had extended intervals to > 12 weeks. Exudative changes in the macula, seen in all eyes at baseline, were only seen in 50% of the eyes at 4 years. The mean CFT and CCT decreased significantly at 4 years from 332 µm to 248 µm and from 218 µm to 183 µm, respectively. CONCLUSION: In clinical settings, aflibercept treatment using a TAE regimen may successfully maintain visual acuity for up to 4 years even in recurrent cases of AMD.

[Effect of adding X-ray examination to endoscopy in the assessment of the invasion depth of early gastric cancer].

In the assessment of invasion depth of early gastric cancer (EGC), the effect of adding X-ray examination to endoscopy was retrospectively investigated in 84 EGC lesions diagnosed at our hospital, including 62 differentiated and 22 undifferentiated lesions. Overall diagnostic accuracy was 75% with endoscopy and 82.1% when X-ray examination was performed in addition to endoscopy. This demonstrated an increase in the accuracy of 7.1% by adding X-ray examination. In terms of presence of ulceration, the additional effect of X-ray examination was higher for lesions without ulceration for both differentiated and undifferentiated lesions. In terms of tumor diameter, the additional effect of X-ray examination was higher for differentiated lesions of ≤30mm and for undifferentiated lesions of ≥21mm. In terms of tumor location, the additional effect of X-ray examination was higher for lesions located in the upper gastric corpus. Depending on the lesion, the addition of X-ray examination to endoscopy contributed to an increase in the accuracy of the assessment of the invasion depth of EGC.

Evaluating the learning curve associated with laparoscopic left hemicolectomy for colon cancer.

The role of laparoscopic surgery for transverse and descending colon cancer remains controversial. The aim of the present study was to characterize the learning curve for laparoscopic left hemicolectomy including the splenic flexure and to identify factors that influence this learning curve. Data from 120 consecutive patients undergoing laparoscopic left hemicolectomy for transverse and descending colon cancer including the splenic flexure between December 1996 and December 2009 were analyzed. Patients undergoing resection combined with cholecystectomy, hepatectomy, hysterectomy, or gastrectomy were excluded. Operative time was analyzed using the moving average method. The operative time, conversion rate, and postoperative complication rate were evaluated among four groups based on the number of cases required for analysis of operative time. In addition, risk factors that influenced conversion to open surgery were analyzed. Operative time for left hemicolectomy decreased with increasing case number with stabilization at 30 cases. There was no significant difference in the conversion rate or postoperative complications over time. Significant factors for conversion to open surgery were T stage (odds ratio [OR], 5.56; 95% confidence interval [CI], 1.5 to 27.4) and previous abdominal surgery (OR, 5.38; 95% CI, 1.6 to 20.2). The learning curve for laparoscopic left hemicolectomy is steep. Thus, surgeons in the early part of this curve should carefully select patients to allow them to build experience in a stepwise manner. Laparoscopic surgery may become the gold standard for management of colon cancer regardless of stage or tumor location.

Effect of previous abdominal surgery on outcomes following laparoscopic colorectal surgery.

OBJECTIVE: The impact of previous abdominal surgeries on the need for conversion to open surgery and on short-term outcomes during/after laparoscopic colectomy was retrospectively investigated. DESIGN: This retrospective cohort study was conducted from December 1996 through December 2009. SETTING: This study was conducted at Osaka Medical College Hospital. PATIENTS: A total of 1701 consecutive patients who had undergone laparoscopic resection of the colon and rectum were classified as not having previous abdominal surgery (n = 1121) or as having previous abdominal surgery (n = 580). MAIN OUTCOME MEASURES: Short-term outcomes were recorded, and risk factors for conversion to open surgery were analyzed. RESULTS: There were no significant differences in operative time, blood loss, number of lymph nodes removed, or conversion rate between the groups. The rate of inadvertent enterotomy was significantly higher in the previous abdominal surgery group than in the not having previous abdominal surgery group (0.9% versus 0.1%; p = 0.03), and the postoperative recovery time was significantly longer in the previous abdominal surgery group than in the not having previous abdominal surgery group. Ileus was more frequent in the previous abdominal surgery group than in the not having previous abdominal surgery group (3.8% versus 2.1%; p = 0.04). Significant risk factors for conversion to open surgery were T stage ≥3 (OR, 2.81; 95% CI, 1.89-3.75), median incision (OR, 4.34; 95% CI, 1.23-9.41), upper median incision (OR, 2.78; 95% CI, 1.29-5.42), lower median incision (OR, 1.82; 95% CI, 1.09-3.12), and transverse colectomy (OR, 1.76; 95% CI, 1.29-2.41). CONCLUSION: The incidence of successfully completed laparoscopic colectomy after previous abdominal surgery remains high, and the short-term outcomes are acceptable.

Internal hernia projecting through a mesenteric defect to the lesser omental cleft following laparoscopic-assisted partial resection of the transverse colon: report of a case.

We herein report a case of an internal hernia projecting through a mesenteric defect following laparoscopic-assisted colectomy to the lesser omental cleft in a 61-year-old female. We performed laparoscopic-assisted partial resection of the transverse colon to treat transverse colon cancer. Three years and 6 months after the operation, the patient developed a bowel obstruction requiring surgical intervention. When we observed the intraperitoneal space under laparoscopy, we determined that the small intestine had passed into the bursa omentalis through the mesenteric defect. Additionally, an abnormal opening of the lesser omentum was present with a portion of the small intestine escaping into the space inferior to the liver. We performed reintegration of the escaped bowel and closed the mesenteric defect laparoscopically. This is the first case of an internal hernia projecting through a mesenteric defect following laparoscopic-assisted colectomy that we have experienced out of more than 2400 cases. Further research is needed to identify the patients who would benefit from the closure of mesenteric defects during laparoscopic-assisted colectomy.

Activated hepatic stellate cells overexpress p75NTR after partial hepatectomy and undergo apoptosis on nerve growth factor stimulation.

BACKGROUND: Expression of neurotrophins (NTs) and their receptors is increased during hepatic regeneration, but their role is not well understood. METHODS: NTs and their receptors were investigated by RT-PCR and immunostaining in regenerating livers after two-thirds hepatectomy (PH) and in hepatocytes and hepatic stellate cells (HSCs) isolated from regenerating livers in mice. Induction of apoptosis after treatment with NGF and the expression of alpha-smooth muscle actin (SMA), interleukin 6 (IL-6) and hepatocyte growth factor (HGF) were also investigated in regenerating HSCs. RESULTS: Nerve growth factor (NGF) and p75 NT receptor (p75NTR) mRNA were elevated after PH, while other NTs and NT receptors showed no remarkable change. NGF was detected in regenerating hepatocytes, but not in normal hepatocytes. Regenerating HSCs expressed increased p75NTR and SMA in vivo and showed an activated phenotype and the high expression of HGF and IL-6 in vitro. Enhanced cell death was seen in HSCs, both from normal and regenerating liver, after treatment with NGF. CONCLUSIONS: Although activated HSCs may produce the factors that regulate liver regeneration, the de novo NGF production by regenerating hepatocytes may induce the death of activated HSCs via p75NTR, leading to termination of hepatic regeneration.

Expression of NGF in hepatocellular carcinoma cells with its receptors in non-tumor cell components.

Nerve growth factor (NGF) is suggested to have a role in tumor progression in addition to its role in differentiation and survival of neuronal cells. We investigated expression of NGF and its receptors, TrkA and p75NTR, in hepatocellular carcinomas (HCCs). Although hepatocytes and hepatic stellate cells (HSCs) showed respectively weak and intense NGF immunostaining in the background livers of patients suffering from liver cirrhosis (LC) or chronic hepatitis (CH), intense staining was demonstrated in HCC cells of 33 of 54 (61.1%) tumors. RT-PCR detected NGF mRNA in 7 freshly-isolated HCC samples, and in 2 of 4 cases, in which both background livers and tumors could be analyzed, NGF mRNA was more abundant in the tumors than the background livers. TrkA was detected in the smooth muscle cells of hepatic arteries, but it was negative in tumor cells as well as non-neoplastic hepatocytes. p75NTR and alpha-smooth muscle actin (alphaSMA) was expressed in HSCs in the background liver and fibroblast-like cells in stromal septa, whereas HSCs within the HCC tissues were mostly negative for p75NTR but positive for alphaSMA. This suggests that HSCs in HCC have a different property from those in background livers. Furthermore, the stromal septa contained abundant nerve fibers, which may be related to the increased NGF expression in HCC cells. NGF and its receptors are then thought to have a role in cellular interactions involving HCC cells, HSCs, arterial cells and nerve cells in HCC tissues.

[A case report of advanced cardiac cancer showing a complete response to TS-1 as neoadjuvant chemotherapy].

A 69-year-old female had complaints of vomiting, appetite loss and feeling of pharyngeal obstruction. She was diagnosed with a 3'-shaped advanced cardiac cancer with esophageal invasion. A biopsy revealed poorly differentiated adenocarcinoma. The tumor was T3 (SE) N2, Stage IIIB indicating a poor prognosis. After informed consent, TS-1 was administrated as preoperative chemotherapy. Chemotherapy with TS-1 was very effective, and the tumor noticeably decreased. Next, total gastrectomy was performed. Histopathological findings revealed that the primary tumor and lymph node had become scarred and fibrous, indicating a complete response (Grade 3). In the future, TS-1 can be expected to display efficacy in neoadjuvant chemotherapy for patients with advanced gastric cancer who have poor prognoses.