Safety and efficacy of trastuzumab biosimilar plus irinotecan or gemcitabine in patients with previously treated HER2 (ERBB2)-positive non-breast/non-gastric solid tumors: a phase II basket trial with circulating tumor DNA analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) (ERBB2)-directed agents are standard treatments for patients with HER2-positive breast and gastric cancer. Herein, we report the results of an open-label, single-center, phase II basket trial to investigate the efficacy and safety of trastuzumab biosimilar (Samfenet®) plus treatment of physician's choice for patients with previously treated HER2-positive advanced solid tumors, along with biomarker analysis employing circulating tumor DNA (ctDNA) sequencing. METHODS: Patients with HER2-positive unresectable or metastatic non-breast, non-gastric solid tumors who failed at least one prior treatment were included in this study conducted at Asan Medical Center, Seoul, Korea. Patients received trastuzumab combined with irinotecan or gemcitabine at the treating physicians' discretion. The primary endpoint was the objective response rate as per RECIST version 1.1. Plasma samples were collected at baseline and at the time of disease progression for ctDNA analysis. RESULTS: Twenty-three patients were screened from 31 December 2019 to 17 September 2021, and 20 were enrolled in this study. Their median age was 64 years (30-84 years), and 13 patients (65.0%) were male. The most common primary tumor was hepatobiliary cancer (seven patients, 35.0%), followed by colorectal cancer (six patients, 30.0%). Among 18 patients with an available response evaluation, the objective response rate was 11.1% (95% confidence interval 3.1% to 32.8%). ERBB2 amplification was detected from ctDNA analysis of baseline plasma samples in 85% of patients (n = 17), and the ERBB2 copy number from ctDNA analysis showed a significant correlation with the results from tissue sequencing. Among 16 patients with post-progression ctDNA analysis, 7 (43.8%) developed new alterations. None of the patients discontinued the study due to adverse events. CONCLUSIONS: Trastuzumab plus irinotecan or gemcitabine was safe and feasible for patients with previously treated HER2-positive advanced solid tumors with modest efficacy outcomes, and ctDNA analysis was useful for detecting HER2 amplification.

Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02.

AIMS: To evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. MATERIALS AND METHODS: LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. RESULTS: Between November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1-2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. CONCLUSION: The addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.

Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC.

BACKGROUND: In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. PATIENTS AND METHODS: BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator's choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. RESULTS: Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. CONCLUSIONS: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.

Relationship between faecal calprotectin and inflammation in peripheral joints and entheses in axial spondyloarthritis.

Objectives: To compare faecal calprotectin levels according to the type of manifestation and to investigate factors associated with increases in faecal calprotectin in patients with axial spondyloarthritis (axSpA). Method: The study enrolled 190 patients fulfilling the imaging arm of the Assessment of SpondyloArthritis international Society axSpA criteria. Faecal calprotectin levels were measured in an enzyme-linked immunosorbent assay. Systemic inflammatory markers and the Ankylosing Spondylitis Disease Activity Score (ASDAS) were also assessed. Peripheral joint involvement was assessed using the 44-joint examination and Spondyloarthritis Research Consortium of Canada Enthesitis Index. Results: Of 190 patients, 34 (18%) had increased faecal calprotectin levels. These patients were more likely to have ongoing peripheral arthritis and enthesitis (p = 0.016 and 0.001, respectively). A history of psoriasis and uveitis, or current uveitis symptoms, had no bearing on faecal calprotectin levels. Faecal calprotectin levels increased along with ASDAS-C-reactive protein (CRP), and correlated with ASDAS-erythrocyte sedimentation rate (ESR) (r = 0.240, p = 0.001), ASDAS-CRP (r = 0.162, p = 0.025), ESR (r = 0.228, p = 0.002), and CRP levels (0.258, p < 0.001). Tender joint and swollen joint counts also correlated with faecal calprotectin levels (r = 0.252 and 0.205, p < 0.001 and p = 0.005, respectively). Faecal calprotectin levels were higher in patients with current peripheral symptoms (p = 0.003). Peripheral symptoms were independently associated with increased faecal calprotectin levels (odds ratio = 4.083; 95% confidence interval 1.580-10.556). Conclusions: Faecal calprotectin levels in axSpA patients were associated with disease activity. Subclinical gut inflammation (assessed by measuring faecal calprotectin) in axSpA is more closely related to peripheral joint inflammation than to axial joint inflammation.

Trabecular bone score value is associated with new bone formation independently of fat metaplasia on spinal magnetic resonance imaging in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate the association between trabecular bone score (TBS) and new bone formation in ankylosing spondylitis (AS) patients, and to investigate whether TBS is independently associated with new bone formation. METHOD: Sixty-eight patients with AS underwent spinal magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry of the lumbar spine to measure TBS and bone mineral density at baseline. Lateral radiographs of the cervical and lumbar spine (baseline and 2 years) were assessed for new bone formation (syndesmophyte formation and/or growth combined), and spinal MRIs were assessed for the presence or absence of fat metaplasia (FM) at the first to fourth lumbar vertebrae. The factors associated with new bone formation were analysed at the patient level and the vertebral level. RESULTS: New bone formation had developed in 17 patients (25%) at 2 year follow-up. Patients with new bone formation had a higher prevalence of FM and lower TBS at baseline than patients without new bone formation (p = 0.013 and p = 0.041). At the patient level, FM on MRI and low TBS (< 1.23) were significantly associated with new bone formation. At the vertebral level, new bone formation had developed in 25 out of 231 vertebrae (11%) after 2 years. Vertebrae with both FM on MRI and low TBS tended to have more new bone formation (p < 0.001). Syndesmophytes and low TBS (< 1.23) independently increased the risk of new bone formation at the level of individual vertebrae. CONCLUSION: At both patient and individual vertebral levels, low TBS was associated with new bone formation independently of FM on MRI.

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies. Patients and methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review. Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated. ClinicalTrials.gov number: NCT02149108 (LUME-Colon 1).

Prevalence and clinical significance of cellular and acellular mucin in patients with locally advanced mucinous rectal cancer who underwent preoperative chemoradiotherapy followed by radical surgery.

AIM: The frequent presence of acellular mucin in specimens showing pathological complete response to preoperative chemoradiotherapy (CRT) and the poor response to preoperative CRT in mucinous rectal cancer have been reported. However, the prevalence and prognostic significance of cellular and acellular mucin have not been evaluated in resected specimens from patients with mucinous rectal cancer who undergo preoperative CRT. METHOD: We retrospectively evaluated the clinicopathological features and prognostic significance of mucin in resected specimens from 59 consecutive patients with mucinous rectal cancer who underwent long-course CRT followed by resection between January 2000 and December 2009. Patients were categorized according to the presence of mucin, as identified by pathological analysis. The clinicopathological findings and oncological results were compared. RESULTS: Mucin was identified in 25 of 59 patients with mucinous rectal cancer (42.4%). Mucin was more frequent in men (hazard ratio = 23.94, 95% confidence interval = 1.875-305.504, P = 0.015) and in specimens showing a good tumour response grade (hazard ratio = 64.26, 95% confidence interval = 6.940-595.045, P < 0.001). With a median follow-up of 67.7 (range 8.6-133.2) months, the 5-year overall survival (60.7% without mucin vs 51.4% with mucin, P = 0.898) and disease-free survival (59.9% without mucin vs 56.9% with mucin, P = 0.813) did not differ between the groups. CONCLUSION: The presence of mucin in rectal cancer with mucinous differentiation after preoperative CRT and resection is associated with male gender and a good tumour response grade, without significant impact on oncological outcome.

Assessment of fracture risk in patients with axial spondyloarthritis: a case-control study using the fifth Korean National Health and Nutrition Examination Survey (KNHANES V).

OBJECTIVES: Axial spondyloarthritis (axSpA) is associated with low bone mineral density (BMD) and fractures, although the true fracture risk is unknown. The present study examined BMD and estimated the 10-year fracture risk in axSpA patients and matched controls and identified factors associated with a high fracture risk. METHOD: In total, 240 axSpA patients and 1200 healthy controls from the fifth Korean National Health and Nutrition Examination Survey (KNHANES V), matched using propensity scores, were included. Dual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine and right femur BMD. Ten-year risks of major osteoporotic and hip fractures were calculated using the Fracture Risk Assessment Tool (FRAX) in subjects aged ≥ 40 years. Multivariate linear regression models were used to explore factors associated with the 10-year fracture risk in axSpA patients. RESULTS: Hip and lumbar spine BMDs were lower in axSpA patients than in matched controls. Osteoporosis was present in 17% of axSpA patients and 3% of controls (p < 0.001). Low BMD was present in 22% of axSpA patients and 4% of controls aged < 50 years (p < 0.001). Ten-year major osteoporotic and hip fracture risks were significantly higher among axSpA patients. High 10-year fracture risk was observed in 10% of axSpA patients and 1.7% of controls (p = 0.003). The severity of sacroiliitis was independently associated with both major osteoporotic and hip fracture risks (p = 0.006 and 0.026, respectively). CONCLUSIONS: Patients with axSpA presented more frequently with low BMD and a higher calculated 10-year fracture risk than matched individuals. The severity of sacroiliitis was independently associated with a high 10-year fracture risk in axSpA patients.

A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer.

BACKGROUND: The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer. METHODS: We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m(-2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity. RESULTS: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively). CONCLUSIONS: The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

The predictors of development of new syndesmophytes in female patients with ankylosing spondylitis.

OBJECTIVES: The formation of spinal syndesmophytes is an important outcome measure in ankylosing spondylitis (AS) but the predictors of new syndesmophyte development in female AS patients are unknown. This longitudinal study aimed to assess the rate and predictors of development of new syndesmophytes over a 2-year period in female AS patients. METHOD: Clinical and radiographic data were collected at baseline and after 2 years in 67 female AS patients. Spinal radiographs were scored using the Stoke AS Spinal Score (SASSS). Univariate logistic regression analyses were performed to identify predictors associated with new syndesmophyte development. RESULTS: Eleven (16%) patients had syndesmophytes at baseline. Nine (13.4%) patients had developed new syndesmophytes in their lumbar spines after 2 years. In the univariate logistic regression analyses, older age, longer disease duration, severe sacroiliitis, elevated C-reactive protein (CRP) levels at baseline, and one or more pre-existing syndesmophytes were associated with the occurrence of new syndesmophytes. After adjustment for baseline SASSS, increases in SASSS were statistically significantly higher in patients with elevated baseline CRP levels (p = 0.002) than in patients with normal CRP at baseline. CONCLUSIONS: Older age, longer disease duration, severe sacroiliitis, the baseline presence of syndesmophytes, and elevated levels of CRP are predictors of the development of new syndesmophytes in female AS patients.

Estimated long-term dietary exposure to lead, cadmium, and mercury in young Korean children.

BACKGROUND: Controlling for day-to-day variation is a key issue in estimating long-term dietary exposure to heavy metals using 24-hour recall (24HR) data from a relatively small number of days. OBJECTIVES: This study was conducted to estimate long-term dietary exposure to lead, cadmium and mercury among Korean children using the Iowa State University (ISU) method and to assess the contributions of different food groups to heavy metal intake. METHODS: We analyzed 2 days of 24HR data from 457 children between 0 and 6 years of age in 2010. Using bootstrapped concentration data for 118 representative foods, 93.5% of total intake was included in the exposure estimates in this study. Using the 2-day exposure data, we estimated long-term exposure by controlling for within-individual variation using the ISU method. RESULTS: The long-term dietary exposure estimates (mean±standard deviation) for lead, cadmium, and mercury were 0.47±0.14, 0.38±0.20, and 0.22±0.08 µg/kg bw/day, respectively. For lead and cadmium, the percentages of children whose exposure was greater than the reference value were 35 and 42%, respectively. Fruits were an important source of lead exposure, and cereal and fish and shellfish made the greatest contributions to the total cadmium and mercury exposure. CONCLUSIONS: Our findings also suggest that the long-term exposure to lead and cadmium was somewhat greater than the reference values, whereas mercury exposure was well below than the reference value in this population. Further studies may be necessary to evaluate the food items contributing to heavy metal exposure, and continuous monitoring is needed to ensure the safety of food intake and dietary patterns among vulnerable groups in Korea.

Nomogram to predict ypN status after chemoradiation in patients with locally advanced rectal cancer.

BACKGROUND: Pelvic lymph node (LN) status after preoperative chemoradiotherapy (CRT) is an important indicator of oncologic outcome in patients with locally advanced rectal cancer. The purpose of this study was to develop a nomogram to predict LN status after preoperative CRT in locally advanced rectal cancer patients. METHODS: The nomogram was developed in a training cohort (n=891) using logistic regression analyses and validated in a validation cohort (n=258) from a prospectively registered tumour registry at Asan Medical Center. The model was internally and externally validated for discrimination and calibration using bootstrap resampling. Model performance was evaluated by the concordance index (c-index) and calibration curve. RESULTS: Pretreatment ypT stage, patient age, preCRT tumour differentiation, cN stage, lymphovascular invasion, and perineural invasion were reliable predictors of LN metastasis after preoperative CRT. The nomogram developed using these parameters had c-indices of 0.81 (training) and 0.77 (validation). The calibration plot suggested good agreement between actual and nomogram-predicted LN status after preoperative CRT. CONCLUSIONS: This nomogram improves prediction of LN status after preoperative CRT in patients with locally advanced rectal cancer. It will be useful for counselling patients as well as for the design and stratification of patients in clinical trials.

INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells.

Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by INCB01424 results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.

Impairment of the proximal to distal tonic gradient in the human diabetic stomach.

BACKGROUND: Little has been known about the contractile characteristics of diabetic stomach. We investigated spontaneous contractions and responses to acetylcholine in the gastric muscle in diabetic patients and non-diabetic control subjects according to the region of stomach. METHODS: Gastric specimens were obtained from 26 diabetics and 55 controls who underwent gastrectomy at Samsung Medical Center between February 2008 and November 2011. Isometric force measurements were performed using circular muscle strips from the different regions of stomach under basal condition and in response to acetylcholine. KEY RESULTS: Basal tone of control was higher in the proximal stomach than in the distal (0.63 g vs 0.46 g, p = 0.027). However, in diabetics, basal tone was not significantly different between the proximal and distal stomach (0.75 g vs 0.62 g, p = 0.32). The distal stomach of diabetics had higher basal tone and lower frequency than that of control (0.62 g vs 0.46 g, p = 0.049 and 4.0/min vs 4.9/min, p = 0.049, respectively). After exposure to acetylcholine, dose-dependent increases of basal tone, peak, and area under the curve (AUC) were noticed in both proximal and distal stomach of the two groups. In the proximal stomach, however, the dose-dependent increase of basal tone and AUC was less prominent in diabetics than in control. CONCLUSIONS & INFERENCES: On the contrary to control, the proximal to distal tonic gradient was not observed in diabetic stomach. Diabetic stomach also had lower frequency of spontaneous contraction in the distal stomach and less acetylcholine-induced positive inotropic effect in the proximal stomach than control.

p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN.

PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.

The evaluation of working casts prepared from digital impressions.

OBJECTIVE: The aim of this study is to evaluate the reproducibility of working casts of a digital impression system by comparing them with the original, virtual, and rapid prototyping casts. MATERIALS AND METHODS: A total of 54 cast sets in clinically stable occlusion were used. They were scanned by an iTero intraoral scanner and converted into STL format virtual casts. Rapid prototyping casts and polyurethane casts were fabricated from the iTero milling system based on the virtual casts. Several horizontal and vertical measurements were performed from the four types of casts, that is, original stone casts, virtual casts, rapid prototyping casts, and polyurethane casts of iTero. Measurement error, intraclass correlation coefficient (ICC), and differences among the casts were calculated and compared. RESULTS: Casts from iTero milling machines exhibited greater dimensional differences and lower ICC values than did other casts. In addition, many of the measurements of the iTero working casts showed statistically significant differences in comparison to the three other types of casts. In contrast, there were no statistically significant differences between the virtual and original casts. CONCLUSION: Virtual casts made by the iTero intraoral scanner exhibited excellent reproducibility. However, the casts from the iTero milling machine showed greater dimensional differences and lower reproducibility compared to other types of casts.

Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer.

BACKGROUND: Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy. METHODS: A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway. RESULTS: For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively. CONCLUSION: LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.

Transcription profiling associated with life cycle of Anopheles gambiae.

Complex biological events occur during the developmental process of the mosquito Anopheles gambiae (Giles). Using cDNA expression microarrays, the expression patterns of 13,440 clones representing 8,664 unique transcripts were revealed from six different developmental stages: early larvae (late third instar/early fourth instar), late larvae (late fourth instar), early pupae (< 30 min after pupation), late pupae (after tanning), and adult female and male mosquitoes (24 h postemergence). After microarray analysis, 560 unique transcripts were identified to show at least a fourfold up- or down-regulation in at least one developmental stage. Based on the expression patterns, these gene products were clustered into 13 groups. In total, eight genes were analyzed by quantitative real-time polymerase chain reaction to validate microarray results. Among 560 unique transcripts, 446 contigs were assigned to respective genes from the An. gambiae genome. The expression patterns and annotations of the genes in the 13 groups are discussed in the context of development including metabolism, transport, protein synthesis and degradation, cellular processes, cellular communication, intra- or extra-cellular architecture maintenance, response to stress or immune-related defense, and spermatogenesis.

Transthoracic needle biopsy using a C-arm cone-beam CT system: diagnostic accuracy and safety.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy and safety of performing transthoracic needle biopsy (TNB) under combined fluoroscopy and CT guidance using a C-arm cone-beam CT (CBCT) system. METHODS: We evaluated the diagnostic accuracy and safety of performing TNB using a C-arm CBCT system. We retrospectively evaluated 99 TNB cases performed in 98 patients using a C-arm CBCT system with an 18-gauge automated cutting needle. We reviewed the diagnostic accuracy according to the size and depth of the lesion, incidence of complications, additional treatment for complications, procedure time, number of needle passes per biopsy and radiation dose. RESULTS: The final diagnoses revealed 72 malignant and 27 benign lesions. The overall malignancy sensitivity, malignancy specificity and diagnostic accuracy were 95.8%, 100% and 97.0%, respectively, and those for small pulmonary nodules <20 mm in size were 94.1%, 100% and 96.6%, respectively. There was no significant difference in the correct diagnosis of malignancy according to lesion size (p = 0.634) or depth (p = 0.542). For benign lesions, a specific diagnosis was obtained in 14 cases (51.9%). TNB induced complications in 19 out of 99 procedures (19.2%), including pneumothorax (16.2%), immediate haemoptysis (2.0%) and subcutaneous emphysema (1.0%). Among these, four patients with pneumothorax required chest tube insertion (2.0%) or pig-tail catheter drainage (2.0%). The mean procedure time, number of needle passes and radiation doses were 11.9 ± 4.0 min, 1.2 ± 0.5 times and 170.0 ± 67.2 mGy, respectively. CONCLUSION: TNB using a C-arm CBCT system provides high diagnostic accuracy with a low complication rate and a short procedure time, particularly for small pulmonary nodules.