Acute Adverse Events Research Articles

Intensity-modulated particle beam radiation therapy in the management of olfactory neuroblastoma.

BackgroundTo report the clinical experience and short-term efficacy in the management of olfactory neuroblastoma (ONB).MethodsWe performed a retrospective analysis of 12 ONB patients treated with particle beam radiation therapy (PBRT) between 12/2015 and 5/2019 at the Shanghai Proton and Heavy Ion Center. Four (33.3%) patients presented with Kadish B ONB, and 8 (66.7%) presented with Kadish C or D disease. Eleven patients received proton radiotherapy (PRT) followed by a carbon ion radiotherapy (CIRT) boost, one patient received CIRT only. The 2-year survival rates were calculated using the Kaplan-Meier method. Acute and late adverse events were summarized and scored according to the CTCAE (version 4.03).ResultsWith a median follow-up of 17.5 (range, 2.53–49.9) months, all patients but 1 were alive. Eight patients were alive without evidence of disease, and 2 additional patients achieved partial response and remained alive with residual disease. One patient died of toxicity associated with salvage chemotherapy for distant metastasis and local failure. Another patient developed distant metastasis only and was alive at the time of the last follow-up. The 2-year OS, PFS, LRPFS, and DMFS rates were 83.3%, 75.8%, 87.5%, and 79.5%, respectively. No acute or late toxicities of ≥ grade 3 was observed.ConclusionsIntensity modulated PBRT of ONB is well tolerated. While longer follow-up is needed, early outcomes suggested that PBRT is safe and effective for the treatment of ONB with minimal adverse events.

Stentless Pericarbon Freedom Versus Stented Perimount Aortic Bioprosthesis: Propensity-Matched Long-Term Follow-Up.

Stentless aortic valves have shown superior hemodynamic performance and faster left ventricular mass regression compared to stented bioprostheses. Yet, controversies exist concerning the durability of stentless valves. This case-matched study compared short- and long-term clinical outcomes of stentless LivaNova-Sorin Pericarbon Freedom™ (SPF) and stented Carpentier-Edwards Perimount (CEP) aortic prostheses. From 2003 through 2006, 134 consecutive patients received aortic valve replacement with SPF at our institution. This cohort was matched, according to 20 preoperative clinical parameters, with a control group of 390 patients who received CEP prosthesis during the same time. The resulting 55 + 55 matched patients were analyzed for perioperative results and long-term clinical outcomes. Early mortality was 0% for both groups. Lower transvalvular gradients were found in the SPF group (10.6 ± 2.9 versus 15.7 ± 3.1 mmHg, P < 0.001). Overall late mortality (mean follow-up: 10.03 years) was similar for both groups (50.1% versus 42.8%, P = 0.96). Freedom from structural valve degeneration (SVD) at 13 years was similar for both groups (SPF = 92.3%, CEP = 73.9%, P = 0.06). Freedom from aortic valve reinterventions did not differ (SPF = 92.3%, CEP = 93.5%, P = 0.55). Gradients at 13-year follow-up remained significantly lower in SPF group (10.0 ± 4.5 versus 16.2 ± 9.5 mmHg, P < 0.001). Incidence of acute bacterial endocarditis (ABE) and major adverse cardiovascular and cerebrovascular events (MACCE) was similar. SPF and CEP demonstrated comparable long-term outcomes related to late mortality, SVD, aortic valve reinterventions, and incidence of ABE and MACCE. Superior hemodynamic performance of SPF over time can make this valve a suitable choice in patients with small aortic root and large body surface area.

Relative Hypotension and Adverse Kidney-related Outcomes among Critically Ill Patients with Shock. A Multicenter, Prospective Cohort Study.

Rationale: There are no prospective observational studies exploring the relationship between relative hypotension and adverse kidney-related outcomes among critically ill patients with shock.Objectives: To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor initiation.Methods: At seven multidisciplinary ICUs, 302 patients, aged ≥40 years and requiring ≥4 hours of vasopressor support for nonhemorrhagic shock, were prospectively enrolled. We assessed the time-weighted average of the mean perfusion pressure (MPP) deficit (i.e., the percentage difference between patients' preillness basal MPP and achieved MPP) during vasopressor support and the percentage of time points with an MPP deficit > 20% as key exposure variables. New significant AKI was defined as an AKI-stage increase of two or more (Kidney Disease: Improving Global Outcome creatinine-based criteria).Measurements and Main Results: The median MPP deficit was 19% (interquartile range, 13-25), and 54% (interquartile range, 19-82) of time points were spent with an MPP deficit > 20%. Seventy-three (24%) patients developed new significant AKI; 86 (29%) patients developed MAKE. For every percentage increase in the time-weighted average MPP deficit, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 5.6% (95% confidence interval, 2.2-9.1; P = 0.001) and 5.9% (95% confidence interval, 2.2-9.8; P = 0.002), respectively. Likewise, for every one-unit increase in the percentage of time points with an MPP deficit > 20%, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 1.2% (0.3-2.2; P = 0.008) and 1.4% (0.4-2.4; P = 0.004), respectively.Conclusions: Vasopressor-treated patients with shock are often exposed to a significant degree and duration of relative hypotension, which is associated with new-onset, adverse kidney-related outcomes.Study registered with Australian New Zealand Clinical Trial Registry (ACTRN 12613001368729).

P-258 Evaluation of volumetric modulated arc therapy with simultaneous integrated boost in carcinoma of the anal canal

This study aimed to retrospectively analyze the benefit of simultaneous integrated boost volumetric modulated arc radiotherapy (VMAT-SIB) in patients experiencing acute gastrointestinal, genitourinary and cutaneous adverse events for anal canal cancer patients.

Radiotherapy combined with gefitinib for patients with locally advanced non-small cell lung cancer who are unfit for surgery or concurrent chemoradiotherapy: a phase II clinical trial

BackgroundThe objectives of this study were to determine the objective effective response rate, survival, and safety of radiotherapy combined with gefitinib in patients with locally advanced non-small cell lung cancer (NSCLC) who were unfit for surgery or concurrent chemoradiotherapy.MethodsThe patients with the locally advanced NSCLC who were unfit to receive surgery or concurrent chemoradiotherapy, received thoracic intensity-modulated radiotherapy (IMRT) combined with gefitinib 250 mg daily.Results29 patients were enrolled between July 2014 and March 2017. 28 patients was in the analysis. Of the 28 patients, 21 (75.0%) experienced a partial response, 5 (17.9%) had stable disease, and 2 (7.1%) experienced progression of disease. The objective response rate was 75.0%, and the disease control rate was 92.9%. The median follow-up time was 51 months. The disease progression showed in 25 (89.3%) patients, including local progression in 19 (67.9%) and distant metastasis in 16 (57.1%). The median overall survival and progression-free survival time (PFS) were 26 and 11 months, respectively. The 3-, 4-, 5-year survival rates were 39.0, 30.1 and 30.1%, respectively. The 3-, 4-, 5-year PFS rates were 14.3, 9.5 and 9.5%. Two patients developed grade 3 acute adverse events. Seven patients developed grade 2 acute irradiation pneumonitis, and there was no grade 3 acute irradiation pneumonitis.ConclusionsFor patients with locally advanced NSCLC who are not eligible for surgery or concurrent chemoradiotherapy, IMRT combined with gefitinib can improve the objective effective rate and is generally well-tolerated.

Lymph node–directed simultaneous integrated boost in patients with clinically lymph node–positive cervical cancer treated with definitive chemoradiotherapy: clinical outcomes and toxicity

Lymph node (LN)–positive cervical cancer is associated with a poor prognosis. We report outcomes for women with LN-positive cervical cancer treated with intensity-modulated radiation therapy (IMRT) with dose-escalated simultaneous integrated boost (SIB) to involved LNs. Between 2005 and 2017, 59 women with LN-positive, non-metastatic, cervical cancer underwent definitive chemoradiotherapy (CRT) with an image-guided LN boost to a median dose of 56.25 Gy in 25 fractions. Acute and late adverse events (AEs) were recorded per common terminology criteria for adverse events. The Kaplan-Meier method was used to estimate the overall survival (OS), progression-free survival (PFS), and locoregional control (LRC). Median age was 49 years (IQR 37–56). Women had involved LNs in the pelvis (56%) or pelvis and para-aortic (PA) LNs (44%), with a median of 3 (IQR 2–6) grossly involved LNs per patient. Median follow-up was 30 months (IQR 11–45). Estimated 3-year OS, PFS, and LRC were 67% (95% CI, 51%–84%), 60% (95% CI, 45%–76%), and 89% (95% CI, 76%–99%), respectively. PA LN involvement (HR 2.51; 95% CI, 1.05–5.99; p = 0.04) and the presence of ≥ 4 grossly involved LNs (HR 2.79; 95% CI, 1.16–6.71; p = 0.02) were associated with a higher risk of disease progression on univariate analysis. The incidence of treatment-related acute grade 3+ acute GI or GU AEs was 3%, while late GI or GU treatment-related AEs occurred in 12%. Chemoradiation with a LN-directed SIB for women with LN-positive cervical cancer is well tolerated and is associated with excellent oncologic outcomes. In this report, we evaluated the oncologic efficacy and adverse events associated with definitive chemoradiotherapy with a simultaneous integrated boost to grossly involved lymph nodes for women with lymph node–positive cervical cancer. We have identified acceptable rates of adverse events and excellent oncologic outcomes, even in a very high risk cohort of women with cervical cancer.

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin’s Lymphoma in Children

BackgroundRituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin’s lymphoma are limited.MethodsWe conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin’s lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed.ResultsAnalyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt’s lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab–chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab–chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P=0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab–chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab–chemotherapy group and 24.2% in the chemotherapy group (P=0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab–chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion.ConclusionsRituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin’s lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.)

Predictors of ST Depression Resolution in STEMI Patients Undergoing Primary PCI and Its Clinical Significance.

PurposeST depression resolution (STD-R) in ECG is a prognostic factor indicative of successful fibrinolysis or angioplasty in the treatment of ST elevation myocardial infarction (STEMI) and subsequent mortality. We conducted this study to determine the clinical significance of STD-R and its predictors in patients with anterior STEMI undergoing primary percutaneous intervention (PPCI).MethodsAdmission documents of all patients with diagnosis of anterior STEMI who were admitted to a specialty heart center and underwent PPCI since July 2018 until July 2019 were examined. The amount of ST elevation and depression in all 12 leads of a standard ECG at admission and 90 minutes after PPCI was measured and resolution was determined. All patients were followed-up for 10.8±4.0 months.ResultsA total of 179 patients had ST depression besides elevation in the first ECG. Female gender, diabetes, not smoking, lower hemoglobin, and higher platelet counts were significantly more common in the group with less than 50% resolution of ST depression. STD-R <50% was significantly associated with the incidence of in-hospital acute heart failure and major adverse cardiac events (MACE) (p value: 0.025 and 0.012, respectively) and resolution of ST elevation ≥50% was associated with reduced in-hospital mortality (p value <0.0001). According to Kaplan–Meier curve, survival in the two groups of STE-R ≥50% and STE-R <50% was significantly different (Log rank: 31.18, p value<0.0001).ConclusionSTD-R can be considered to have high predictive power, like STE-R for predicting incidence of in-hospital acute heart failure and major adverse cardiac events.

P1779NOVEL ONCE-DAILY EXTENDED-RELEASE TACROLIMUS VERSUS TWICE -DAILY TACROLIMUS IN DE NOVO KIDNEY TRANSPLANT RECIPIENTS DURING THE EARLY POSTTRANSPLANT PERIOD

Abstract Background and Aims Both under and over-dosing of tacrolimus may compromise clinical outcomes by exposing patients to either the risks of graft rejection or adverse events (AEs) associated with immunosuppressive therapy. This study is designed to compare the clinical follow-up of our kidney transplant recipients receiving once-daily, prolonged-release (PR-T; Advagraf) and twice-daily, immediate-release (IR-T; Prograf) tacrolimus in the early posttransplant period. Method This randomized study included 78 de novo, adult kidney transplant recipients to PR-T 0.15 mg/kg/day (Group I=39) and IR-T 0.15 mg/kg/day (Group II=39) for seven days in the posttransplant period. Demographic features and clinical parameters regarding levels of whole blood tacrolimus and serum creatinine were compared between the two groups. Presence of acute rejection and AEs were investigated. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations in all patients. SPSS 15 for Windows was used for statistical analysis. Results None of the patients suffered from acute rejection and there were no AEs in the early posttransplant period. However, Group II patients were found to have higher whole blood tacrolimus levels on the posttransplant 1st, 4th and 7th days (p=0.02, p=0.009 and p=0.013 respectively). Also serum creatinine levels were significantly increased in Group II patients on the posttransplant 7th day (p=0.02). Conclusion Prolonged release tacrolimus seems promising in preventing acute transplant rejection with adequate blood levels, as well as making it possible to avoid the interindividual variation in absorption and early calcineurin inhibitor toxicity.

A randomized controlled study of 6% gabapentin topical formulation for chronic kidney disease-associated pruritus.

Novel agents with good safety profiles are needed in the management of chronic kidney disease-associated pruritus (CKD-AP). This study aims to assess the efficacy and safety of topical gabapentin in the treatment of CKD-AP. The authors conducted a randomized, double-blind, vehicle-controlled study. The key inclusion criteria were: (i) patients on hemodialysis for at least 8weeks, and (ii) a baseline visual analog scale (VAS) pruritus score ≥5. Patients were randomized into two groups. Topical 6% gabapentin was used in the experimental group while plain permeation cream was used for the control group. The primary endpoint was the mean change in pruritus scores using the VAS (MCPS-VAS) from baseline after 1 and 2weeks of once daily application. Thirty patients (15 per group) were included in the analysis. Treatment with 6% topical gabapentin resulted in significantly decreased mean pruritus scores at 1week (mean score 2.7; range 0-5; P<0.001) and 2weeks (mean score 1.3, range 0-5; P<0.001) from baseline (mean score 5.9; range 5-8). The MCPS-VAS of the two groups were not significantly different (P=0.8) after 1week. However, the MCPS-VAS of the experimental group (mean change -4.6; range 0-7) was significantly greater (P=0.01) compared to control (mean change -2.6; range -1 to 5) after 2weeks. There were no drug-related adverse events reported. Our results suggest that short-term use of topical gabapentin may significantly decrease CKD-AP severity after 2weeks with no reported acute adverse events.

Massive pneumoperitoneum with abdominal pain and fever mimicking delayed perforation following endoscopic resection: A case report

AbstractPneumoperitoneum has been reported as an intraprocedural or acute postprocedural adverse event resulting from advanced endoscopic intervention. Here, we report a case of a massive pneumoperitoneum‐mimicking delayed perforation after colonic endoscopic submucosal dissection. A 60‐year‐old man received endoscopic submucosal dissection for a large colon polyp. Room air was inadvertently used in the first half of the procedure. After 12 hours, the patient developed fever, abdominal pain, and bilateral shoulder pain, and massive pneumoperitoneum was detected through plain film and computed tomography. After urgent diagnostic paracentesis, the patient's symptoms dramatically improved, and laparotomy was avoided. Massive pneumoperitoneum rarely occurs in patients receiving complex and long‐standing endoscopic procedures, and it may manifest similarly to delayed perforation. Prompt diagnostic paracentesis is valuable when the diagnosis is uncertain.

Genetic variations in apoptosis genes are associated with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy

Objective: To investigate the associations between the genetic variations of apoptosis genes and the adverse events of postoperative concurrent chemoradiotherapy in patients with rectal cancer. Methods: We enrolled 362 patients with stage Ⅱ to Ⅲ rectal cancer who received concurrent chemoradiotherapy. Whole blood sample (2 ml) was collected from patient at the time of enrollment before therapy. Sequenom MassARRAY was used to detect the genotypes of 29 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight apoptosis genes, including Fas cell surface death receptor(FAS), Fas ligand(FASL), apoptotic peptidase activating factor 1(APAF1), BCL2 associated X(BAX), TNF-related apoptosis-inducing ligand(TRAIL), TNF-related apoptosis-inducing ligand receptor 1(TRAILR1), TNF-related apoptosis-inducing ligand receptor 2(TRAILR2) and caspase-7(CASP7). The associations between genotypes and adverse events of chemoradiotherapy were measured by unconditional logistic regression model. Results: Three hundred and sixty two patients were treated with total mesorectal excision surgery followed by a total radiation dose of 50 Gy applied in 25 fractions over a period of 5 weeks concurrently with daily administration of capecitabine (1 600 mg/m(2) per day, continuously for 2 weeks and taking a week off every 21-day cycle). One hundred and six patients (29.3%) had grade≥2 myelosuppression. Three SNPs associated with the risk of grade ≥2 myelosuppression included FAS rs1468063 (OR=1.51, 95% CI: 1.07-2.15, P=0.020), APAF1 rs11296996 (OR=0.69, 95% CI: 0.49-0.98, P=0.039) and BAX rs4645904 (OR=0.69, 95% CI: 0.50-0.97, P=0.030). One hundred and sixty one patients (44.5%) developed grade≥2 diarrhea. Five SNPs that significantly associated with risk of grade≥2 diarrhea included APAF1 rs11296996 (OR=1.42, 95% CI: 1.02-2.00, P=0.040), rs74619561 (OR=2.16, 95% CI: 1.27-3.68, P=0.005), CASP7 rs12263370 (OR=1.67, 95% CI: 1.05-2.66, P=0.029), rs12247479 (OR=1.85, 95% CI: 1.12-3.08, P=0.017) and TRAIL rs112822654 (OR=0.68, 95% CI: 0.48-0.96, P=0.027). The remaining SNPs were not related to the adverse events of chemoradiotherapy (all P>0.05). Grade≥2 myelosuppression occurred less frequently in male than in female (P=0.046); Surgical treatment and tumor location had great impact on the occurrence of grade≥2 diarrhea (all P<0.001) and dermatitis (all P<0.05). Conclusions: The genetic variations of FAS, APAF1, BAX, TRAIL and CASP7 are related to the adverse events of concurrent chemoradiotherapy in patients with rectal cancer, which may be potential genetic biomarkers for individualized treatment of rectal cancer.

Phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of head and neck (JCOG1008).

6502 Background: The standard treatment for post-operative high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (CDDP) (100 mg/m2, q3wk, 66 Gy/33Fr; 3-weekly CDDP+RT). However, one concern with 3-weekly CDDP+RT is insufficient CDDP compliance due to high-dose-related toxicities. Weekly CDDP+RT (40 mg/m2, qwk, 66 Gy/33Fr; weekly CDDP+RT) is an alternative regimen with better compliance. Here, we conducted a phase II/III trial of weekly CDDP+RT in post-operative high-risk LA-SCCHN. Methods: This is a multi-institutional randomized phase II/III trial to confirm the non-inferiority of weekly CDDP+RT (Arm B) compared with 3-weekly CDDP+RT (Arm A). The trial enrolled pts aged 20-75 years with post-operative high-risk features (microscopically positive margin and/or extranodal extension) and ECOG-PS 0-1. Pts were randomized in a 1:1 ratio to Arm A or Arm B. Primary endpoint of phase II was the proportion of treatment completion and that of phase III was overall survival (OS). A non-inferiority margin of hazard ratio (HR) was set at 1.32. Results: Between Oct 2012 and Dec 2018, 261 pts were enrolled (Arm A 132 pts, Arm B 129 pts). At the planned second interim analysis in phase III with 76/161 events, the Data and Safety Monitoring Committee recommended terminating the trial and publishing the results because the statistical boundary for OS non-inferiority had met the pre-specified stop criteria. With a median follow-up of 2.2 years in all randomized pts, 3-year OS was 59.1% in Arm A and 71.6% in Arm B with a HR of 0.69 (99.1% CI, 0.374-1.273 [ &lt; 1.32], one-sided p for non-inferiority = 0.00272 &lt; 0.00433). 3-year RFS was 53.0% in Arm A and 64.5% in Arm B with a HR of 0.71 (95% CI, 0.48-1.06). Regarding acute adverse events, neutropenia (≥ grade 3), increased creatinine (≥ grade 2), hearing impairment (≥ grade 2) and mucositis (≥ grade 2) occurred in 48.8%, 8.5%, 7.8% and 55.0% in Arm A and 35.3%, 5.7%, 2.5% and 59.0% in Arm B, respectively. For compliance, median total dose of CDDP was 280 mg/m2 (IQR, 250-299) in Arm A and 239 mg/m2 (IQR, 199-277) in Arm B. Total radiation dose was 66 Gy (IQR, 66-66) in both arms. Proportion of treatment completion was 93.2% in Arm A and 86.8% in Arm B. Conclusions: Weekly CDDP+RT is non-inferior to 3-weekly CDDP+RT for post-operative high-risk LA-SCCHN pts and has a favorable toxicity profile. Weekly CDDP+RT should be considered the new standard treatment option for these pts. Clinical trial information: 000009125 .

Nivolumab (Nivo) and ipilimumab (Ipi) in combination with radiotherapy (RT) in high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

6577 Background: Immune checkpoint inhibitors (ICI) are the standard of care in recurrent/metastatic SCCHN but their role in the curative therapy setting with RT is under study. We evaluated the novel approach of combining Nivo, a PD-1 inhibitor, and Ipi, a CTLA-4 inhibitor, in lieu of chemotherapy, with concurrent RT in pts with high-risk LA SCCHN. Methods: We enrolled newly diagnosed, chemotherapy eligible pts with AJCC 7th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, and larynx. HPV+ OP were T4, N2c or N3 OP. Nivo (3 mg/kg every 2 weeks IV x 17 doses) and Ipi (1 mg/kg every 6 weeks x 6 doses) were administered starting 2 weeks prior to the start of RT. RT was prescribed to a dose of 70 Gy delivered in 2 Gy/fraction/day using VMAT. The primary objective was safety of combination ICI with RT. Secondary objectives included 1-year progression-free survival (PFS), overall survival, and correlative studies. Results: 24 pts were enrolled; median age of 60 (range 48-77); 20 were male; 16 oropharynx (14 HPV+), 2 hypopharynx, and 6 larynx; AJCC 7th edition stage IVA (23), IVB (1). Grade 3 acute in-field adverse events (AEs) occurred in 17/24 (71%) of patients during concurrent ICI-RT (9 mucositis, 6 dysphagia, 5 dermatitis, 4 odynophagia, 1 dysphonia); there were no grade 4/5 AEs during ICI-RT. During ICI maintenance 5 pts developed in-field ulcerations at the primary site detected at an average of 3 months post RT; 1 of them died of bleeding due to erosion into the carotid artery with no evidence of active cancer; 4 additional pts developed in-field necrosis. 7 pts discontinued ICI treatment at &gt; 3 months post-RT: 1 due to immune AE, 5 due to in-field ulcerations, 1 due to persistent mucositis without ulceration. 4 pts (17%) had grade 3 immune AEs: 1 elevation of lipase, 1 colitis, and 2 rash. There were no grade 4/5 immune AEs. The median follow-up is 16 months (range, 6.3-30.6). 21 of 24 pts (87.5%) are alive with no evidence of disease progression. 2 pts recurred at distant sites: 1 had a solitary lung lesion at 11 months and was treated with RT; 1 in mediastinal lymph nodes at 9 months and was treated with chemo-RT. Locoregional control remains at 100%. Conclusions: RT plus dual ICI combination was feasible and resulted in no locoregional relapses so far in 24 high-risk LA SCCHN pts. Longer follow-up is needed to fully assess PFS and locoregional control as well as post-treatment in-field ulceration/necrosis that may be attributed to the potent radiosensitizing effect of dual PD-1 and CTLA-4 blockade. Clinical trial information: NCT03162731 .

Adjuvant chemotherapy after concurrent chemoradiation therapy for locally advanced cervical cancer.

6031 Background: Standard treatment nowadays for locally advanced cervical cancer (LACC) is concurrent chemoradiation therapy (CCRT). However, due to distant metastasis, survival outcomes are still not optimistic. We tried to evaluate the clinical efficacy and safety of adjuvant chemotherapy for patients with LACC after treated with concurrent chemoradiation therapy (CCRT). Methods: Patients diagnosed between May, 2013 to May, 2018 with stage IIA-IIIB LACC were retrospectively analyzed. All the patients received platinum-based radical concurrent chemoradiotherapy and were divided into two groups: adjuvant chemotherapy after CCRT (CCRT+ACT group) and observation after CCRT (CCRT group). Overall survival (OS), progression free survival (PFS) and adverse effects were recorded and analyzed. Kaplan–Meier method and log-rank test were used to calculate and compare differences between survival outcomes. Toxicities were analyzed using chi-square test. Results: In total, 375 patients were included in this study, and 262 patients accepted ACT after CCRT while the remaining 113 patients chose to observe. With a median follow-up of 40 months (range 5-73 months), no significant differences were found in both overall survival (OS) and progression free survival (PFS) between two groups referring as 88.5% vs. 90.3% ( P= 0.904) and 83.2% vs. 87.6% ( P= 0.374). OS rates for patients in CCRT+ACT and CCRT groups at 1 year and 3 years were 97.3% vs. 94.7% ( P= 0.195) and 90.2% vs. 88.4% ( P= 0.694), respectively. Meanwhile, PFS rates at 1 year and 3 years were 92% vs. 94.7% ( P= 0.371) and 87.5% vs. 85.5% ( P= 0.761) for two arms separately. 3-4 grades acute adverse events happened more frequently in CCRT+ACT group than in CCRT group, with significant differences in neutropenia and anemia ( P &lt;0.05). Conclusions: In this study, adjuvant chemotherapy after concomitant chemoradiotherapy did not show benefit of survival but do induce adverse effects. We do not suggest it unless further large scale randomized controlled trials are executed to verify it.

Phase 2 Study of Stereotactic Body Radiation Therapy for Patients with Oligometastatic Esophageal Squamous Cell Carcinoma

This study aims to assess the safety and efficacy of stereotactic body radiation therapy (SBRT) for patients with oligometastatic esophageal squamous cell carcinoma (ESCC). From April 2015 to December 2018, a prospective, single-arm, phase 2 trial was conducted. The main inclusion criteria were ESCC patients with 3 or fewer metastases and a controlled primary malignancy after radical treatment, with all metastatic lesions amenable to SBRT. The enrolled patients were assigned to SBRT for all metastatic lesions and then received chemotherapy for at least 4 cycles starting from 0 to 15 days after SBRT. The primary endpoint was progression-free survival (PFS). Overall survival, local control, and toxicities were assessed in all patients. The study is listed at clinicaltrials.gov, number NCT03000816. Thirty-four patients with 40 oligometastatic lesions, including 25 in distant organs and 15 in nonregional lymph nodes, were treated with SBRT. All metastases belonged to genuine oligometastatic disease. Seventeen patients (50.0%) received a median of 4 cycles (interquartile range, 3-6 cycles) of chemotherapy after SBRT. At a median follow-up time of 18.2 months (interquartile range, 11.1-35.0 months), the median PFS time was 13.3 months (95% confidence interval, 10.7-15.9); the 1- and 2-year PFS rates were 55.9% and 33.8%, respectively. The 1- and 2-year overall survival rates were 76.2% and 58.0%, respectively. The 1- and 2-year local control rates were both 92.1%. Grade 3 acute toxicities were observed in only 1 patient. No grade ≥4 acute adverse events or grade ≥3 late adverse events due to SBRT occurred in this study. For well-selected patients with oligometastatic ESCC, SBRT with or without chemotherapy is a well-tolerated and efficacious treatment modality. The prognosis of oligometastatic ESCC is quite different from that of extensively metastatic ESCC, so treatment with an accurate stratification for patients with metastatic ESCC is necessary.

Diclofenac does not reduce the risk of acute pancreatitis in patients with primary sclerosing cholangitis after endoscopic retrograde cholangiography.

The European Society of Gastrointestinal Endoscopy recommends rectal indomethacin or diclofenac before endoscopic retrograde cholangiopancreatography (ERCP) to prevent post-ERCP pancreatitis. However, data on the prophylactic effect in patients with primary sclerosing cholangitis (PSC) are lacking. This was a retrospective case-control study. In 2009-2018, a total of 2000 ERCPs were performed in 931 patients with PSC. Case procedures (N = 1000 after November 2013) were performed after administration of rectal diclofenac. Control procedures (N = 1000 before November 2013) were performed with the same indication but without diclofenac. Acute post-ERCP pancreatitis and other ERCP-related adverse events (AEs) were evaluated. Post-ERCP pancreatitis developed in 49 (4.9%) procedures in the diclofenac group and 62 (6.2%) procedures in the control group (p = 0.241). No difference existed between the groups in terms of the severity of pancreatitis or any other acute AEs. The risk of pancreatitis was elevated in patients with native papilla: 11.4% in the diclofenac group and 8.7% in the control group (p = 0.294). In adjusted logistic regression, diclofenac did not reduce the risk of pancreatitis (odds ratio (OR) = 1.074, 95% confidence interval 0.708-1.629, p = 0.737). However, in generalised estimation equations with the advanced model, diclofenac seemed to diminish the risk of pancreatitis (OR = 0.503) but not significantly (p = 0.110). In this large patient cohort in a low-risk unit, diclofenac does not seem to reduce the risk of post-ERCP pancreatitis in patients with PSC. The trend in the pancreatitis rate after ERCP is decreasing. The evaluation of the benefits of diclofenac among PSC patients warrants a randomised controlled study targeted to high-risk patients and procedures.

Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis

SummaryBackgroundMalaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women.MethodsWe did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013.FindingsOf the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57–14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14–0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34–0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18–0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29–23·82).InterpretationEfficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.FundingThe Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.

A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens.Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model.Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9–77.2 months). Median OS (21.9 months; 95% CI: 16.9–27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3–5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31–10.87; p = .01). The occurrence of grades 3–5 late toxicities was not different between treatment groups.Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC.

Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown. To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events. A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network. The administration of CAR T-cell therapy. Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined. The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs. The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.