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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (

Ablation of resection margins after EMR of large nonpedunculated colorectal polyps decreases recurrence. Margin marking before EMR (EMR-MM) may represent an alternative method to achieve a healthy resection margin. We aimed to determine the efficacy of EMR-MM in reducing neoplasia recurrence.We conducted a single-center historical control study of EMR cases (EMR-MM vs conventional EMR) for nonpedunculated polyps ≥20 mm between 2016 and 2021. For EMR-MM, cautery marks were placed along the lateral margins of the polyp with the snare tip. EMR was then performed to include resection of the healthy mucosa containing the marks. We compared recurrence at surveillance colonoscopy after EMR-MM versus historical control subjects. Multivariable logistic regression was performed to identify factors associated with recurrence.Two hundred ten patients with 210 polyps (median size, 30 mm; interquartile range: 25-40) underwent EMR-MM (n = 74) or conventional EMR (n = 136). Patient and lesion characteristics were similar between the groups. At a median follow-up of 6 months, the recurrence rate was lower with EMR-MM (6/74; 8%) compared with historical control subjects (39/136; 29%) (P .001). EMR-MM was not associated with an increased rate of adverse events. On multivariable analysis, EMR-MM remained the strongest predictor of recurrence (odds ratio, .20; 95% confidence interval, .13-.64; P = .003) aside from polyp size (odds ratio, 2.81; 95% confidence interval, 1.35-6.01; P = .008).In this single-center historical control study, EMR-MM of large nonpedunculated colorectal polyps reduced the recurrence risk by 80% when compared with conventional EMR. This simple technique may provide an alternative to margin ablation.

ObjectiveOur goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose.MethodsIn this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1–3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis.ResultsThe maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 BRCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3–4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1–2 non-hematologic toxicities.ConclusionsOlaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt.Trial registration numberNCT01650376.

The incidence of surgery for nonmalignant colorectal polyps is rising. The aims of this study were to evaluate referral patterns to surgery for nonmalignant polyps, to compare outcomes between surgery and endoscopic resection (ER), and to identify factors associated with surgery in a university-based, tertiary care center.Patients referred to colorectal surgery (CRS) for nonmalignant colorectal polyps between 2014 and 2019 were selected from the institution's integrated data repository. Clinical characteristics were obtained through chart review. Multivariate analysis was performed to identify factors associated with surgery for nonmalignant polyps.Six hundred sixty-four patients with colorectal lesions were referred to CRS, of which 315 were for nonmalignant polyps. Most referrals (69%) came from gastroenterologists. Of the 315 cases, 136 underwent surgery and 117 were referred for attempt at ER. Complete ER was achieved in 87.2% (n = 102), with polyp recurrence in 27.2% at a median of 14 months (range, 0-72). When compared with surgery, ER was associated with a lower hospitalization rate (22.2% vs 95.6%; P .0001), shorter hospital stay (mean, .5 ± .9 vs 2.23 ± 1 days; P .0001), and fewer adverse events (5.9% vs 22.8%; P = .0002). Intramucosal adenocarcinoma on baseline pathology (odds ratio, 5.7; 95% confidence interval, 1.2-28.2) and referrals by academic gastroenterologists (odds ratio, 2.5; 95% confidence interval, 1.11-5.72) were associated with a higher likelihood of surgery on multivariate analysis.Gastroenterologists commonly refer nonmalignant colorectal polyps to surgery, even though ER is effective and associated with lower morbidity. Both referrals from academic gastroenterologists and baseline pathology of intramucosal adenocarcinoma were factors associated with surgery. All colorectal polyps should be evaluated in a multidisciplinary approach to identify lesions suitable for ER before embarking in surgery.

This paper explores dynamic equations. Dynamic equation has been well researched and developed for centuries. It has applied to a wide variety of fields such as physics, biology, chemistry, engineering, economics, history, and medicine, etc, with significant impacts on human society. A most common and stereotypical example of a dynamic equation is logistic equation. In this paper the logistic equation is thoroughly analysed and discussed about its convergence over a number series at fixed points given different variable ranges. Furthermore, a powerful and tricky theorem of dynamic equation, Coppel’s Theorem, is proved: any dynamic equation series in 0 and 1 without 2-cycles will converge. The proof is difficult but creative and artistic.

ObjectivesTo review the clinicopathologic, immunophenotypic, and molecular features of gastric perivascular epithelioid cell tumor (PEComa).MethodsWe identified two new cases of gastric PEComa and summarized the clinical and pathologic characteristics of this rare neoplasm.ResultsThe first case was a 48-year-old woman who was treated with an endoscopic submucosal dissection (ESD), and the second case was a 64-year-old man who received a distal gastrectomy. Microscopic examination showed one tumor was composed of purely epithelioid cells, while the other was composed of epithelioid and spindle cells. Both tumors were immunoreactive for melanocytic markers (HMB45 and Melan-A), smooth muscle actin, and vimentin. No TFE3 gene rearrangement was identified by fluorescence in situ hybridization in either case.ConclusionsGastric PEComa is an exceedingly rare neoplasm, with only seven other reported cases to date. We are the first to report the results of molecular assays for the TFE3 gene rearrangement associated with gastric PEComa.

The goal of the work was improvement of mechanical and tribological properties of high density polyethylene (HDPE) while finding use for wood sawdust (wood flour). Two chemical modification methods have been used for wood sawdust treatment to improve compatibility between the HDPE matrix and wood sawdust. Traditional silane coupling was used as a first approach to modify the sawdust by 3-methacryloxypropyl-trimethoxysilane (3MPS) and thereby forming C O Si bonds. As a second method, we decided to combine sol–gel process with 3MPS treatment to form Si O Si and C O Si linkages. Silica nanoparticles are filling wood fiber cells and silica rods formation is seen; as a result, thermal expansivity decreases. As expected, the enthalpy of fusion and the degree of crystallinity go down with increasing filler concentration. Tensile modulus goes up as result of filler loading while the tensile strain at break goes down. As the result, brittleness B goes up somewhat, but overall the values of B are quite low. With one exception, residual depth in scratch resistance testing decreases as a consequence of introduction of the fillers. Addition of unmodified wood results in increasing dynamic friction, chemical modification of wood particles results in lowering friction. Combination of focused ion beam milling with scanning electron microscopy shows clearly positive effects of modification on adhesion between the phases.

Purpose To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer. Patients and Methods Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period. Results Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was −3.4% (P < .001) for the spine and −1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma. Conclusion Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.

Purpose This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death. Patients and Methods Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as ≥ two consecutive increasing PSA values while on ADT with castrate testosterone levels. Results Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (≤ v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis. Conclusion In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of ≤ 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis.

Ab initio molecular orbital calculations are used to study the modified Schlenk equilibrium: 2RMgCl ↔ (RMgCl)2 ↔ MgR2 + MgCl2 ↔ Mg(Cl2)MgR2 with R=H and CH3. In the absence of any solvents, calculations indicate that the formation of the various possible bridged dimers (RMgCl)2 is substantially exothermic. However, using dimethylether as a model solvent, we show that the formation of the dimer (Me2O)(CH3)Mg(ΜCl2)Mg(CH3)(OMe2) is exothermic only when entropic effects are included.

Traditionally, tube feedings have been delayed after percutaneous endoscopic gastrostomy (PEG) placement to the next day and up to 24 h postprocedure. However, results from various randomized controlled trials (RCTs) indicate earlier feeding may be an option. We conducted a meta-analysis to analyze the effect of early feedings (or = 4 h) after PEG placement.Multiple databases were searched (November 2007). Only RCTs on adult subjects that compared early (or = 4 h) versus delayed or next-day feedings after PEG placement were included. Meta-analyses for the effect of early and delayed feedings were analyzed by calculating pooled estimates of complications, deathor = 72 h, and significant increases in postprocedural gastric residual volume during day 1.Six studies (N = 467) met the inclusion criteria. No statistically significant differences were noted between early (or = 4 h) and delayed or next-day feedings for patient complications (OR 0.86, 95% CI 0.47-1.58, P = 0.63) or death inor = 72 h (OR 0.56, 95% CI 0.18-1.74, P = 0.31). A statistically significant increase in gastric residual volumes during day 1 was noted (OR 1.80, 95% CI 1.02-3.19, P = 0.04).Early feedingor = 4 h after PEG placement may represent a safe alternative to delayed or next-day feedings. Although an increase in significant gastric residual volumes at day 1 was noted, overall complications were not affected.

5527 Background: To establish the maximum-tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs) and response to therapy of combination therapy with carboplatin/paclitaxel and olaparib, ...

4558 Background: Androgen deprivation therapy (ADT) for prostate cancer leads to loss of bone mineral density (BMD) and increased fracture risk. We hypothesize that intermittent ADT (IADT) may atte...

5134 Background: Patients (pts) with localized PC or BR treated with androgen deprivation therapy (ADT) eventually become androgen independent (AI) and die. We previously defined a model that correlates first cycle IAD PSA nadir and duration off treatment (OFF) with time to AI and death in 53 pts (abstract 5146 ASCO ’07). We now report data on a larger number of evaluable pts and include the analysis of testosterone (T) kinetics. Methods: Eligible pts had histologic diagnosis of PC, no evidence of metastasis by bone and CT scan, and at least 2 consecutive rising PSAs 2 weeks apart. Pts were treated with 9 months of leuprolide acetate and anti-androgen then ADT was stopped. Monthly PSA and T levels were tracked until PSA reached 1 ng/mL if prostate removed or 4 ng/mL if prostate intact, at which time ADT was resumed as before in a new cycle. Pts were treated until AI, defined as 2 rises in PSA while on ADT with castrate T levels (< 0.5 ng/mL). Results: 74 of 102 pts were evaluable for analysis. The previou...

Early Versus Delayed Feeding After Placement of a Percutaneous Endoscopic Gastrostomy: A Meta-Analysis