Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Toripalimab (anti-PD-1) versus high-dose interferon-α2b as adjuvant therapy in resected mucosal melanoma: a phase II randomized trial.

BACKGROUND: No standard of care for mucosal melanoma (MM) in the adjuvant setting has been established. Meanwhile, relapse-free survival (RFS) is only ∼5 months after surgery alone. This phase II trial aimed to compare toripalimab versus high-dose interferon-α2b (HDI) as an adjuvant therapy for resected MM. PATIENTS AND METHODS: From July 2017 to May 2019, 145 patients with resected MM were randomized (1 : 1) to receive HDI (n = 72) or toripalimab (n = 73) for 1 year until disease relapse/distant metastasis, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. The secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 26.3 months, the number of RFS, OS, and DMFS events was 51 versus 46, 33 versus 29, and 49 versus 44 in the toripalimab arm and the HDI arm, respectively. The median RFS was 13.6 [95% confidence interval (CI) 8.31-19.02] months and 13.9 (95% CI 8.28-19.61) months in the toripalimab arm and the HDI arm, respectively. The DMFS was not significantly different between the two arms [hazard ratio (HR) 1.00; 95% CI 0.65-1.54]. The median OS was 35.1 months (95% CI 27.93 months-not reached) in the toripalimab arm, with no significant difference in all-cause death (HR 1.11, 95% CI 0.66-1.84) for the two arms. The median sums of the patients' actual infusion doses were 3672 mg and 1054.5 MIU in the toripalimab arm and the HDI arm, respectively. The incidence of treatment-emergent adverse events with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm (87.5% versus 27.4%). CONCLUSIONS: Toripalimab showed a similar RFS and a more favorable safety profile than HDI, both better than historical data, suggesting that toripalimab might be the better treatment option. However, additional translational studies and better treatment regimens are still warranted to improve the clinical outcome of MM.

High efficiency and collimated terahertz pulse from ultra-short intense laser and cone target.

We propose a new, to the best of our knowledge, method to radiate a high-efficiency and collimated terahertz (THz) pulse from a relativistic femtosecond laser and cone target. Particle-in-cell simulations demonstrate that a THz source of 40 mJ, pointing at an angle of ∼20 ∘, can be generated from a laser pulse of 1.9 J by using a cone target whose open angle is 10 ∘. The peak power of the THz pulse is 1011 W. This method, which manipulates the divergence angle and the energy conversion efficiency of the THz source, should promote THz science into the extra strong region with a compact laser system.

[Preliminary effects of toripalimab combined with axitinib in the treatment of advanced renal cell carcinoma].

Objective: To analyze the efficacy and safety of toripalimab combined with axitinib in the treatment of advanced renal cell carcinoma. Methods: Clinical data of 50 patients with advanced renal cell carcinoma who received axitinib combined with toripalimab were retrospectively collected from the database of Peking University Cancer Hospital. ORR, DCR, PFS, and OS were analyzed. Results: Among the 50 patients, 37 were males; median age was 56 (22-73) years; 38 were pathologically diagnosed as clear cell renal cell carcinoma and 12 were non-clear cell carcinoma. Common metastatic sites included lung, bone, lymph node, liver, and so on. 90% of the patients had received at least one-line of systemic therapy. With a median follow-up time of 11.9 months (0.8-24), 27 of the 50 patients are still on treatment, ORR was 34%, DCR was 86%, median PFS was 13.1 months (95%CI 5.8-20.4), and median OS has not yet reached. One-year OS rate was 84.6%. Common adverse reactions were proteinuria, diarrhea, hypertension, abnormal thyroid function, elevated transaminase, and hand-foot syndrome. Most adverse events were grade 1-2. Conclusion: Toripalimab combined with axitinib was efficient in the treatment of advanced renal cell carcinoma, and had manageable adverse reactions.

[Application of branch-first technique in total thoracic aorta replacement: short and medium term effect of 11 cases].

Objective: To examine the short and medium term effect of branch-first technique in total thoracic aorta replacement. Methods: The clinical data of eleven patients with ascending aortic aneurysms or type A aortic dissection+Crawford Ⅰ or Ⅱ total thoracoabdominal aortic aneurysm who were treated at Department of Cardiovascular Surgery in Henan Province Chest Hospital from January 2018 to July 2021 were retrospectively analyzed. There were 7 males and 4 females, aging (38±5) years (range: 28 to 45 years), 7 cases of whom were diagnosed with Marfan syndrome, 1 case was diagnosed with coarctation of aorta. Operations were performed under mild hypothermic and branch-first technique. Firstly, the middle and small incision in the chest was combined with the 6th intercostal incision in the left posterior lateral side. Secondly, four branches artificial blood vessels were anastomosed with the brachiocephalic artery to ensure the blood supply to the brain. After the circulation was blocked, intracardiac and aortic proximal operations were performed. Intercostal artery reconstruction and thoracic descending aorta replacement were completed after opening circulation. Results: The operative time of this group was (645.9±91.7) minutes (range: 505 to 840 minutes). One case had cerebral infarction and 1 case had chylothorax. The patients were followed up 4 to 47 months, 1 patient underwent thoracic and abdominal aorta+iliac artery resection and replacement due to the progression of abdominal aortic aneurysm 3 months after operation. Intercostal artery obstruction occurred in 2 cases, and the rest lived well. Conclusions: One-stage whole thoracic aorta replacement with branch-first technique has satisfactory results in the short and medium term, with no risk of residual aortic aneurysm rupture. It is an effective treatment for young and organs function well patients with complex aortic lesions.

[Clinical diagnosis and treatment characteristics of pancreatic cystic neoplasms in pediatric patients: a report of 13 cases].

Objective: To investigate the clinical characteristics of pancreatic cystic neoplasms in pediatric patients. Methods: The clinical data of 13 patients with pancreatic cystic neoplasm at Wuhan Children's Hospital from July 2007 to November 2019 were collected.There were 5 males and 8 females, with a mean age of 133 months(range: 9 to 170 months). Eleven patients presented with abdominal pain, vomiting, and a palpable mass. Tumors were located in the pancreatic head(n=7), body(n=2) and tail(n=4), respectively. Results: The preoperative diagnosis was confirmed by imaging examination in 11 patients, CT and MRI was significantly superior to ultrasound in the exact diagnosis of the tumor types. In this group, surgical methods mainly included pancreaticoduodenectomy(n=3), pylorus-preserving pancreatoduodenectomy(n=1), duodenum-preserving pancreas head resection(n=3), spleen-preserving distal pancreatectomy (n=3), distal pancreatectomy plus splenectomy(n=2), and tumor enucleation(n=1). Postoperative complications including biochemical leakage(n=1), delayed gastric emptying(grade A) (n=1), adhesive intestinal obstruction(n=1), transient elevation of platelet count(n=2), all were cured by conservative treatment. In one patient biliary leakage occurred and later developed into biliary stricture, this patient underwent the second operation 6 weeks later and recovered smoothly. All patients were diagnosed by postoperative pathology, including solid pseudopapillary neoplasm(n=10), serous cystadenoma(n=1), mucinous cystadenoma(n=1) and cystic lymphangiom(n=1). Three cases were lost in this group, the rest of patients were all accepted outpatient or telephones follow-up. There was no evidence of recurrence or metastasis during 3 to 92 months follow-up. Conclusions: The incidence of pancreatic cystic neoplasm is low in the pediatric patients. Symptomatic patients should receive surgical treatment timely. It's safe and effective to choose the organs and functions-preserving surgical method.

Creation of Electron-Positron Pairs in Photon-Photon Collisions Driven by 10-PW Laser Pulses.

A novel approach is proposed to demonstrate the two-photon Breit-Wheeler process by using collimated and wide-bandwidth γ-ray pulses driven by 10-PW lasers. Theoretical calculations suggest that more than 3.2×10^{8} electron-positron pairs with a divergence angle of 7° can be created per shot, and the signal-to-noise ratio is higher than 10^{3}. The positron signal, which is roughly 100 times higher than the detection limit, can be measured by using the existing spectrometers. This approach, which could demonstrate the e^{-}e^{+} pair creation process from two photons, would provide important tests for two-photon physics and other fundamental physical theories.

Laser Acceleration of Highly Energetic Carbon Ions Using a Double-Layer Target Composed of Slightly Underdense Plasma and Ultrathin Foil.

We report the experimental generation of highly energetic carbon ions up to 48 MeV per nucleon by shooting double-layer targets composed of well-controlled slightly underdense plasma and ultrathin foils with ultraintense femtosecond laser pulses. Particle-in-cell simulations reveal that carbon ions are ejected from the ultrathin foils due to radiation pressure and then accelerated in an enhanced sheath field established by the superponderomotive electron flow. Such a cascaded acceleration is especially suited for heavy ion acceleration with femtosecond laser pulses. The breakthrough of heavy ion energy up to many tens of MeV/u at a high repetition rate would be able to trigger significant advances in nuclear physics, high energy density physics, and medical physics.

[Impact of first-line chemotherapy on renal function in patients with advanced upper tract urothelial carcinoma].

Objective: To observe the impact of first-line chemotherapy on renal function in patients with unresectable/metastatic upper tract urothelial carcinoma(UTUC). Methods: A total of 222 (130 males and 92 females) unresectable/metastatic upper tract urothelial carcinoma patients were included in the study between January 2005 and May 2017, with age of 29 to 87 (62.4±10.1) years old. The serum creatinine level and estimated glomerular filtration rate (eGFR) were compared before and after first-line chemotherapy. And predictive factors for decreased renal function were analyzed in logistic regression model. Results: After the first-line chemotherapy, the average serum creatinine level increased, with a median changing value of 1.5 µmol/L. Howerver, the eGFR improved, with a median changing value of 0.5 ml·min-1· (1.73 m2)-1, but the differences were not statistically significant (all P>0.05). In 149 patients who were treated with cisplatin-based chemotherapy, the average serum creatinine level increased by 1.31 µmol/L and eGFR improved by 0.14 ml·min-1·(1.73 m2)-1, but the differences were not statistically significant (P>0.05). In multivariate logistic regression model, age more than and equal to 60 years old (OR=0.88, P=0.745) and cisplatin-based chemotherapy (OR=0.95, P=0.893) did not increase the risk of renal dysfunction after first-line chemotherapy. If the time interval between surgery and first-line chemotherapy was more than 1 year, the risk of renal dysfunction due to chemotherapy decreased (OR=0.54, P=0.196). Eastern Cooperative Oncology Group Performance Status (ECOG PS) Scale≥1 (OR=1.81, P=0.131), anemia before treatment (OR=1.14, P=0.764), the cycles of first-line chemotherapy (OR=1.41, P=0.398) may lead to increase the risk of renal dysfunction, but the differences were not statistically significant. However in the patients who accepted nephrectomy, the risk of renal dysfunction after chemotherapy increased, but the difference was still not statistically significant (OR=3.06, P=0.089). Conclusions: First-line chemotherapy, especially the cisplatin-based regimen, had no significant impact on renal function in the patients with UTUC. Nephrectomy maybe a predictive risk factor for decreased renal function after chemotherapy. Adequate assessment of renal function before treatment, hydration and close monitoring during chemotherapy can effectively protect renal function of the patients.

The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients.

Background: We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites. Patients and methods: Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites. Results: The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%, P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%, P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively. Conclusions: The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.

BRAF inhibitors: efficacious and tolerable in BRAF-mutant acral and mucosal melanoma.

BRAF inhibitors substantially have impressive clinical efficacy in cutaneous melanoma. However, their role in acral and mucosal melanoma remains unclear. Records were reviewed of patients with metastatic or unresectable BRAF-mutant acral and mucosal melanoma hospitalized and administrated BRAF inhibitors during January 2011 and March 2016. Clinical data were collected to determine PFS, ORR, DCR, OS, and safety. Among 28 acral and 12 mucosal melanoma patients treated with BRAF inhibitors, median PFS were 3.6 (95%CI 3.0-6.4) and 4.4 (95%CI 0.8-12.7) months, median OS were 6.2 (95%CI 6.1-12.1) and 8.2 (95%CI 6.6-19.9) months; ORRs were 38.1% and 20.0%, DCRs were 81.0% and 70.0% in acral and mucosal melanoma, respectively. BRAF inhibitors were well tolerated. The most common adverse effects (AEs) were cutaneous and hematological. Grade 3/4 AEs were relatively rare. In conclusion, BRAF inhibitors have acceptable efficacy and good tolerance in BRAF mutant acral and mucosal melanoma.

[Calculation of the surface radial dose distribution of radioactive biliary stent loaded with 125I seeds by treatment planning system].

OBJECTIVE: To study the surface radial dose distribution of different length radioactive biliary stents in different activity of (125)I seeds by treatment planning system. METHODS: After a radioactive biliary stent was positioned in measurement phantom, which were made of solid paraffin and polymethyl methacrylate, a CT scan was performed to get the stent images. The images were then transferred to the treatment planning system for planning. The maximum dose level slice nearest to the center of the stent was selected to calculate the surface radial dose distribution. RESULTS: The length of the stents (F=3 189.160, P<0.01) and the activity of the (125)I seeds (F= 811.509, P<0.01) can both significantly affect the cumulative radial dose distribution of the radioactive stent. Radial cumulative dose dose (Gy), stent length (cm), (125)I seeds activity (mCi) and distance from the stent surface (cm) meet the regression equation: ln dose =2.565+ 0.208 length+ 1.502 activity-0.738 distance (F=4 929.279, P<0.05). CONCLUSIONS: The choice of suitable activity of radioactive (125)I should be based on treatment purpose in combination with the length and diameter of lesion and also with reference to the dose table. The measurement results are with smaller uncertainty, which can provide reference for the clinical application of dosimetry.

[Efficacy and the multivariate analysis of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma].

Objective: To investigate the efficacy and the influence factors of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma (mRCC). Methods: Clinical data of mRCC patients with sunitinib administered as the first line treatment from August 2008 to December 2015 were retrospectively reviewed. The efficacy and the influence factors of sunitinib treatment was analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results: In all 166 patients who received sunitinib as first-line treatment, objective response rate was 31.9%, disease control rate was 84.3%. The median progression free survival (PFS) and overall survival (OS) were 11.0 months (95% CI: 9.0-14.0) and 28.0 months (95% CI: 19.0-33.0), respectively. Multivariate analysis showed that pathological types (clear cell carcinoma vs non clear cell carcinoma, HR: 1.889 vs 2.353), time from diagnosis to treatment(<1 year vs ≥1 year, HR: 0.293 vs 0.322) and the number of metastatic sites (1 vs ≥1, HR: 2.360 vs 4.351) were the independent prognostic factors for PFS and OS (P<0.05). Conclusions: The efficacy of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma is similar to reports at home and abroad. The patients with renal clear cell carcinoma, time from diagnosis to treatment> 1 year, and only one metastatic site would get better PFS and OS.

Ion Acceleration Using Relativistic Pulse Shaping in Near-Critical-Density Plasmas.

Ultraintense laser pulses with a few-cycle rising edge are ideally suited to accelerating ions from ultrathin foils, and achieving such pulses in practice represents a formidable challenge. We show that such pulses can be obtained using sufficiently strong and well-controlled relativistic nonlinearities in spatially well-defined near-critical-density plasmas. The resulting ultraintense pulses with an extremely steep rising edge give rise to significantly enhanced carbon ion energies consistent with a transition to radiation pressure acceleration.

Mechanism of abnormally slow crystal growth of CuZr alloy.

Crystal growth of the glass-forming CuZr alloy is shown to be abnormally slow, which suggests a new method to identify the good glass-forming alloys. The crystal growth of elemental Cu, Pd and binary NiAl, CuZr alloys is systematically studied with the aid of molecular dynamics simulations. The temperature dependence of the growth velocity indicates the different growth mechanisms between the elemental and the alloy systems. The high-speed growth featuring the elemental metals is dominated by the non-activated collision between liquid-like atoms and interface, and the low-speed growth for NiAl and CuZr is determined by the diffusion across the interface. We find that, in contrast to Cu, Pd, and NiAl, a strong stress layering arisen from the density and the local order layering forms in front of the liquid-crystal interface of CuZr alloy, which causes a slow diffusion zone. The formation of the slow diffusion zone suppresses the interface moving, resulting in much small growth velocity of CuZr alloy. We provide a direct evidence of this explanation by applying the compressive stress normal to the interface. The compression is shown to boost the stress layering in CuZr significantly, correspondingly enhancing the slow diffusion zone, and eventually slowing down the crystal growth of CuZr alloy immediately. In contrast, the growth of Cu, Pd, and NiAl is increased by the compression because the low diffusion zones in them are never well developed.

Bright subcycle extreme ultraviolet bursts from a single dense relativistic electron sheet.

Double-foil targets separated by a low density plasma and irradiated by a petawatt-class laser are shown to be a copious source of coherent broadband radiation. Simulations show that a dense sheet of relativistic electrons is formed during the interaction of the laser with the tenuous plasma between the two foils. The coherent motion of the electron sheet as it transits the second foil results in strong broadband emission in the extreme ultraviolet, consistent with our experimental observations.

[Analysis of surgical approaches and mandibular treatment strategies for different types of tumors involving parapharyngeal space].

In view of the surgical complexity of parapharyngeal space tumors involved, this paper summarized the disease data of patients with parapharyngeal space tumors involved in the Department of Oral and Maxillofacial Surgery, the First Hospital of Shanxi Medical University from January 2015 to January 2021. It also summarized the surgical approach and mandibular management, so as to explore surgical strategies for different characteristics of parapharyngeal space tumors involved. A total of 49 patients, including 28 males and 21 females, median age 52 years (range 24-72 years). They were treated with four surgical approaches for tumor resection, 25 cervical approach, 5 cheek and neck approach, 3 transoral approach, and 16 cervical-maxillary approach. Among the patients treated with cervical-maxillary approach, 3 patients were treated with mandible square resection, and 6 patients were treated with temporary mandible dissection. Seven cases were treated with tumor resection and partial mandibular resection. There are various surgical approaches and mandibular management methods involving tumors in the parapharyngeal space, and clinical decisions should be made based on tumor diameter, location, boundary, blood supply and pathological types.

Generating overcritical dense relativistic electron beams via self-matching resonance acceleration.

We show a novel self-matching resonance acceleration regime for generating dense relativistic electron beams by using ultraintense circularly polarized laser pulses in near-critical density plasmas. When the self-generated quasistatic axial magnetic field is strong enough to pinch and trap thermal relativistic electrons, an overdense electron bunch is formed in the center of the laser channel. In the trapping process, the electron betatron frequencies and phases can be adjusted automatically to match the resonance condition. The matched electrons are accelerated continuously and a collimated electron beam with overcritical density, helical structure, and plateau profile energy spectrum is hence generated.

Linear Breit-Wheeler process driven by compact lasers.

We report a proposal to observe the two-photon Breit-Wheeler process in plasma driven by compact lasers. A high-charge electron bunch can be generated from laser plasma wakefield acceleration when a tightly focused laser pulse propagates in a subcritical density plasma. The electron bunch scatters with the laser pulse coming from the opposite direction and resulting in the emission of high brilliance x-ray pulses. In a three-dimensional particle-in-cell simulation with a laser pulse of ∼10 J, one could produce an x-ray pulse with a photon number higher than 3×10^{11} and brilliance above 1.6×10^{23} photons/s/mm^{2}/mrad^{2}/0.1%BW at 1 MeV. The x-ray pulses collide in the plasma and create more than 1.1×10^{5} electron-positron pairs per shot. It is also found that the positrons can be accelerated transversely by a transverse electric field generated in the plasma, which enables the safe detection in the direction away from the laser pulses. This proposal enables the observation of the linear Breit-Wheeler process in a compact device with a single shot.

A versatile control program for positioning and shooting targets in laser-plasma experiments.

We introduce a LabVIEW-based control program that significantly improves the efficiency and flexibility in positioning and shooting solid targets in laser-plasma experiments. The hardware driven by this program incorporates a target positioning subsystem and an imaging subsystem, which enables us to install up to 400 targets for one experimental campaign and precisely adjust them in six freedom degrees. The overall architecture and the working modes of the control program are demonstrated in detail. In addition, we characterized the distributions of target positions of every target holder and simultaneously saved the target images, resulting in a large dataset that can be used to train machine learning models and develop image recognition algorithms. This versatile control system has become an indispensable platform when preparing and conducting laser-plasma experiments.