Background: To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). Patients and methods: In this randomised, open-label, phase III ...study, patients received cisplatin (80 mg/m2 i.v. day 1) plus oral capecitabine (1000 mg/m2 b.i.d., days 1–14) (XP) or 5-FU (800 mg/m2/day by continuous infusion, days 1–5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). Results: A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 95% confidence interval (CI) 0.63–1.04, P < 0.001 versus noninferiority margin of 1.25. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64–1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). Conclusions: XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.
Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the ...therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.
Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.
Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively.
Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.
NCT02746796.
A proteomics tool capable of identifying single proteins would be important for cell biology research and applications. Here, we demonstrate a nanopore-based single-molecule peptide reader sensitive ...to single–amino acid substitutions within individual peptides. A DNA-peptide conjugate was pulled through the biological nanopore MspA by the DNA helicase Hel308. Reading the ion current signal through the nanopore enabled discrimination of single–amino acid substitutions in single reads. Molecular dynamics simulations showed these signals to result from size exclusion and pore binding. We also demonstrate the capability to “rewind” peptide reads, obtaining numerous independent reads of the same molecule, yielding an error rate of <10
in single amino acid variant identification. These proof-of-concept experiments constitute a promising basis for the development of a single-molecule protein fingerprinting and analysis technology.
The large volume of adult living donor liver transplantations (ALDLTs) at our center affords a unique opportunity to examine the impact of acute‐on‐chronic liver failure (ACLF) among high–Model for ...End‐Stage Liver Disease MELD score patients. From February 1998 to March 2010, 1958 cirrhotic recipients were analyzed to study the relationship between MELD scores and ALDLT outcomes. A total of 327 high‐MELD score recipients were categorized into ACLF and non‐ACLF groups, and their outcomes were compared. The 5‐year graft and patient survival in the high‐MELD group were 75.2% and 76.4%, respectively, which were significantly worse than the low and intermediate MELD groups. The presence of ACLF associated with higher MELD scores appeared to be the dominant factor responsible for the inferior results of patients with MELD score of 30–34 points. The 5‐year graft survivals in the ACLF group was 70.5% and in the non‐ACLF group it was 81.0% (p = 0.035). Therefore, ALDLT should be performed as soon as possible in high‐MELD score patients prior to ACLF development. Moreover, ACLF patients should be separately categorized when analyzing the outcomes of ALDLT. ALDLT for ACLF patients should not be discouraged because favorable outcomes can be expected through timely ALDLT and comprehensive management.
While adult living donor liver transplantation should be performed as soon as possible before acute‐on‐chronic liver failure develops, it should not be discouraged for patients with acute‐on‐chronic liver failure since timely transplantation and comprehensive management can bring a favorable outcome.
This paper presents a technique for in-situ horizontal stress prediction in vertical boreholes based on borehole breakout data using a machine learning-based meta-modelling technique, i.e. Kriging. ...This model is generated based on the deterministic mean function and a stationary Gaussian process function derived from the 106 data points from published experimental studies. To examine the reliability of the model, a leave-one-out cross-validation process is conducted against the published experimental results. The Kriging prediction gives an average error of 10.59% on maximum horizontal principal stress (σH). A total of 23 field data were also extracted from both literature and mine site A with stress measurements conducted at the similar depth. The model yields an average prediction error of 8.4% in comparison with field stress measurement results on σH, which is remarkable considering its simplicity, reliability and low cost. This study limits the scope to σH estimation only due to the nature of the experimental setup, in which minimum horizontal principal stress (σh) values are often kept constant while changing σH. This results in a lot of repetition σh values in training data and it makes the prediction of σh unreliable. By collecting a broader range of data on breakout geometries, stress magnitudes and the rock strength, it is expected that the accuracy and the parameter coverage of this technique can be further improved in practical conditions.
ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the ...largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.
This article presents the clinical results of ABO‐incompatible adult living donor liver transplantation in a single institution.
Two common general anaesthetic methods are total i.v. anaesthesia (TIVA) and inhalation anaesthesia, but it is unclear whether this affects the patient's perception of their quality of recovery. The ...Quality of Recovery-40 questionnaire (QoR-40) is a valid and reliable method to evaluate the extent of functional recovery after surgery with general anaesthesia. This study therefore compared patient recovery using the QoR-40 in surgical patients who received TIVA with those who received desflurane anaesthesia.
Eighty females (20–65 years old) undergoing thyroid surgery were prospectively recruited and randomized to either the TIVA (effect-site target controlled infusion using propofol and remifentanil) or DES (desflurane inhalation with manual infusion of remifentanil) groups. The QoR-40 was administered by an investigator blind to group allocation before surgery, and postoperative days 1 and 2 (POD1 and POD2). Additional data including the incidence of nausea or vomiting, the consumption of antiemetic and analgesic agents in the post-anaesthesia care unit, and the duration of the hospital stay, were collected in all cases.
The QoR-40 score on POD1 was significantly higher in the TIVA group compared with the DES group (174 vs 161, respectively; P=0.004), indicating a better quality of recovery in the TIVA group. Among the five dimensions of the QoR-40, physical comfort and physical independence were significantly better on POD1 and POD2 in the TIVA group.
This study demonstrates that the quality of recovery for female thyroid surgery patients is significantly better with TIVA compared with desflurane anaesthesia.
www.clinicaltrials.org; ref.: NCT01760018.
Purpose Assisted peritoneal dialysis (PD) involving caregivers allows more patients to get started on homebased dialysis with good clinical outcomes, but evidence on patient-reported and ...caregiver-reported outcomes is lacking. This study aimed to compare assisted PD versus self-care PD on quality of life (QoL) and psychosocial outcomes for patients and caregivers. The effect of PD modality automated PD (APD); continuous ambulatory PD (CAPD) in relation to self-care or assisted care was also examined. Methods A cross-sectional sample of 231 PD patients 142 self-care (57 APD/85 CAPD) and 89 assisted care PD (45 APD/44 CAPD), 72 caregivers of assisted PD patients and 39 family members of self-care PD patients completed the Kidney Disease Quality of Life Short Form (KDQOLSF), World Health Organisation Quality of Life Instrument-brief and the Hospital Anxiety and Depression Scale. Caregivers and family members completed the Lay CareGiving for Adults Receiving Dialysis questionnaire and Zarit Burden Interview. Results Case-mix-adjusted comparisons indicated comparable QoL in all dimensions with the exception of physical SF-12 (p = .001) and the KDQOL effects of kidney disease in favour of self-care PD. Levels of anxiety (9.72 ± 4.90; 8.25 ± 5.22) and depression (8.63 ± 3.80; 6.35 ± 4.76) were equivalent in assisted PD and self-care PD, respectively. Assisted PD caregivers reported more task-orientated duties (p = .007), yet levels of perceived burden were equal to those reported by family members of self-care PD. Conclusion Our findings of mostly comparable patient and caregiver outcomes in assisted PD and self-care PD suggest that caregiver burden and QoL should not be a barrier to using assisted PD.
The reactions p¯p→e+e− and e+e−→p¯p are analyzed in the near-threshold region. Specific emphasis is put on the role played by the interaction in the initial or final antinucleon–nucleon (N¯N) system ...which is taken into account rigorously. For that purpose a recently published N¯N potential derived within chiral effective field theory and fitted to results of a new partial-wave analysis of p¯p scattering data is employed. Our results provide strong support for the conjecture that the pronounced energy dependence of the e+e−↔p¯p cross section, seen in pertinent experiments, is primarily due to the p¯p interaction. Predictions for the proton electromagnetic form factors GE and GM in the timelike region, close to the N¯N threshold, and for spin-dependent observables are presented. The steep rise of the effective form factor for energies close to the p¯p threshold is explained solely in terms of the p¯p interaction. The corresponding experimental information is quantitatively described by our calculation.
Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant ...chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC.
The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146).
A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable.
In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
•In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy.•The addition of radiotherapy to chemotherapy did not significantly reduce the rate of recurrence after D2 gastrectomy.•DFS between patients treated with adjuvant chemotherapy and chemoradiotherapy was similar across all subgroups, including Lauren classification.
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