Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Direct Observation of HONO Emissions from Real-World Residential Natural Gas Heating in China.

Atmospheric nitrous acid (HONO) is an important precursor of atmospheric hydroxyl radicals. Vehicle emissions and heterogeneous reactions have been identified as major sources of urban HONO. Here, we report on HONO emissions from residential natural gas (RNG) for water and space heating in urban areas based on in situ measurements. The observed HONO emission factors (EFs) of RNG heating vary between 6.03 and 608 mg·m-3 NG, which are highly dependent on the thermal load. The highest HONO EFs are observed at a high thermal load via the thermal NO homogeneous reaction. The average HONO EFs of RNG water heating in winter are 1.8 times higher than that in summer due to the increased thermal load caused by the lower inlet water temperatures in winter. The power-based HONO EFs of the traditional RNG heaters are 1085 times and 1.7 times higher than those of gasoline and diesel vehicles that meet the latest emission standards, respectively. It is estimated that the HONO emissions from RNG heaters in a typical Chinese city are gradually close to emissions from on-road vehicles when temperatures decline. These findings highlight that RNG heating is a non-negligible source of urban HONO emissions in China. With the continuous acceleration of coal-to-gas projects and the continuous tightening of NOx emission standards for vehicle exhaust, HONO emissions from RNG heaters will become more prominent in urban areas. Hence, it is urgently needed to upgrade traditional RNG heaters with efficient emission reduction technologies such as frequency-converted blowers, secondary condensers, and low-NOx combustors.

Antiemetic prophylaxis for chemoradiotherapy-induced nausea and vomiting in locally advanced head and neck squamous cell carcinoma: a prospective phase II trial.

BACKGROUND: There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). METHODS: Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m2 (33 mg/m2/days [d]1-3) every 3 weeks for two cycles. All patients were given oral aprepitant 125 mg once on d1, then 80 mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8 mg on d2-5. The primary endpoint was complete response (CR). Pursuant to δ = 0.2 and α = 0.05, the expected CR rate was 80%. RESULTS: A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% confidence interval [CI]: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free and nausea-free responses in the overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related toxicity with antiemetic usage. CONCLUSION: The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy.

Preoperative versus postoperative chemo-radiotherapy for locally advanced gastric cancer: a multicenter propensity score-matched analysis.

BACKGROUND: Peri-operative chemo-radiotherapyplayed important rolein locally advanced gastric cancer. Whether preoperative strategy can improve the long-term prognosis compared with postoperative treatment is unclear. The study purpose to compare oncologic outcomes in locally advanced gastric cancer patients treated with preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT). METHODS: From January 2009 to April 2019, 222 patients from 2 centers with stage T3/4 and/or N positive gastric cancer who received pre-CRT and post-CRT were included. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between pre- and post-CRT groups. RESULTS: The median follow-up period was 30 months. 120 matched cases were generated for analysis. Three-year LC, DMFS, DFS and OS for pre- vs. post-CRT groups were 93.8% vs. 97.2% (p = 0.244), 78.7% vs. 65.7% (p = 0.017), 74.9% vs. 65.3% (p = 0.042) and 74.4% vs. 61.2% (p = 0.055), respectively. Pre-CRT were significantly associated with DFS in uni- and multi-variate analysis. CONCLUSION: Preoperative CRT showed advantages of oncologic outcome compared with postoperative CRT. TRIAL REGISTRATION: ClinicalTrial.gov NCT01291407 , NCT03427684 and NCT04062058 , date of registration: Feb 8, 2011.

Down-staging depth score could be a survival predictor for locally advanced gastric cancer patients after preoperative chemoradiotherapy.

OBJECTIVE: The predictive effect of preoperative chemoradiotherapy (CRT) is low and difficult in guiding individualized treatment. We examined a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT. METHODS: From April 2012 to April 2019, 95 patients with locally advanced gastric cancer who received preoperative concurrent CRT and who were enrolled in three prospective studies were included. All patients were stage T3/4N+. Local control, distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were evaluated. Clinicopathological factors related to long-term prognosis were analyzed using univariate and multivariate analyses. The down-staging depth score (DDS), which is a novel method of evaluating CRT response, was used to predict long-term outcomes. RESULTS: The median follow-up period for survivors was 30 months. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve predicted by the DDS was 0.728, which was better than the pathological complete response (pCR), histological response and ypN0. Decision curve analysis further affirmed that DDS had the largest net benefit. The DDS cut-off value was 4. pCR and ypN0 were associated with OS (P=0.026 and 0.049). Surgery and DDS are correlated with DMFS, DFS and OS (surgery: P=0.001, <0.001 and <0.001, respectively; and DDS: P=0.009, 0.013 and 0.032, respectively). Multivariate analysis showed that DDS was an independent prognostic factor of DFS (P=0.021). CONCLUSIONS: DDS is a simple, short-term indicator that was a better surrogate endpoint than pCR, histological response and ypN0 for DFS.

A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol.

BACKGROUND: Since the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8-2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC. METHODS: This two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA-IVB [UICC 2002]; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5-6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial. DISCUSSION: In unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated. TRIAL REGISTRATION: clinicaltrials.gov ( NCT03308552 , November 1, 2017).

LncRNA and mRNA signatures associated with neoadjuvant chemoradiotherapy downstaging effects in rectal cancer.

Radiotherapy plays a crucial role in combined treatment modality in local advanced rectal cancer (LARC). While neoadjuvant chemoradiotherapy responses were variable in LARC patients, so, it is important to identify genes that closely associated with short-term and long-term responses to radiotherapy. In this study, we profiled long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression values of LARC patients with different neoadjuvant chemoradiotherapy downstaging depth score based on Agilent Arraystar Human LncRNA V3.0 Array(Agilent, CA). LncRNAs and mRNAs with aberrant expression values between the two groups of LARC patients were identified and lncRNA-miRNA-mRNA regulation network was also obtained through the combination of miRcode and miRTarBase database. Gene interaction network and module analysis of differential expression mRNAs contained in the lncRNA-miRNA-mRNA network identified five hub genes, including KRAS, PDPK1, PPP2R5C, PPP2R1B, and YES1, that should be closely associated with LARC's response to chemoradiotherapy. Besides, Kaplan-Meier analysis based on the Cyber Research Center (CRC) data set from The Cancer Genome Atlas indicated that aberrant expression of the five hub genes is significantly associated with CRC overall survival. In conclusion, we obtained several biomarkers that should be associated with neoadjuvant chemoradiotherapy response in LARC, which should be helpful for individual treatment and prognosis improvement.

A prospective phase I study of hypo-fractionated neoadjuvant radiotherapy for locally advanced gastric cancer.

BACKGROUND: Previous studies have reported that neoadjuvant chemoradiotherapy can downstage the advanced gastric cancer. However, no studies are available on the application of hypo-radiotherapy to neoadjuvant radiotherapy. This study sought to assess the maximum tolerated dose (MTD) and dose-limited toxicity (DLT) of hypo-fractionated chemoradiotherapy for local advanced gastric cancer. METHOD: Patients with cT3-4 and/or lymph node-positive locally advanced gastric cancer or Siewert II/III esophagogastric junction adenocarcinoma were enrolled. Preoperative chemoradiation was followed by 3 cycles of oxaliplatin + S-1 neoadjuvant chemotherapy with an interval duration of 3-4 weeks. D2 resection was performed 2-4 weeks after neoadjuvant therapy. Three cycles of adjuvant chemotherapy were planned after surgery. Intensity-modulated radiotherapy (IMRT) was used. The radiotherapy dose level was defined using three levels, namely, 40.0 Gy/2.5 Gy, 41.6 Gy/2.6 Gy, 43.2 Gy/2.7 Gy delivered concurrently with S-1 at 80 mg/m2. RESULTS: From May 2016 to Dec 2016, nine patients with a median age of 63 years were enrolled in this study. The most common grade I-III adverse events were leukopenia (88.9%), nausea (88.9%), vomiting (77.8%) and weight loss (66.7%). Grade III adverse events consisted of vomiting and weight loss. CONCLUSION: The MTD of hypo-fractionated radiotherapy for locally advanced gastric cancer was 40.0 Gy/2.5 Gy, and the DLTs were vomiting and weight loss. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03427684 (Retrospectively registered on February 9, 2018).

Down-staging depth score to predict outcomes in locally advanced rectal cancer achieving ypI stage after neoadjuvant chemo-radiotherapy versus de novo stage pI cohort: A propensity score-matched analysis.

OBJECTIVE: Prognosis of patients with locally advanced rectal cancer (LARC) but achieving ypT1-2N0 stage after neoadjuvant concurrent chemo-radiotherapy (CRT) has been shown to be favorable. This study aims to determine whether the long-term outcome of ypT1-2N0 cases can be comparable to that of pT1-2N0 cohort that received definitive surgery for early disease. METHOD: From January 2008 to December 2013, 449 consecutive patients with rectal cancer were treated and their outcome maintained in a database. Patients with LARC underwent total mesorectal excision (TME) surgery at 4-8 weeks after completion of CRT, and those achieving stage ypI were identified as a group. As a comparison, stage pI group pertains to patients whose initially limited disease was not upstaged after TME surgery alone. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between ypI and pI groups. Down-staging depth score (DDS), a novel method of evaluating CRT response, was used for subset analysis. RESULTS: Of the 449 patients, 168 matched cases were generated for analysis. Five-year LC, DMFS, DFS and OS for stage pI vs. ypI groups were 96.7% vs. 96.4% (P=0.796), 92.7% vs. 73.6% (P=0.025), 91.2% vs. 73.6% (P=0.080) and 93.1% vs. 72.3% (P=0.040), respectively. In the DDS-favorable subset of the ypI group, LC, DMFS, DFS and OS resulted in no significant differences in comparison with the pI group (P=0.384, 0.368, 0.277 and 0.458, respectively). CONCLUSIONS: LC was comparable in both groups; however, distant metastasis developed more frequently in down-staged LARC than de novo early stage cases, reflecting the need to improve the efficacy of systemic treatment despite excellent pathologic response. DDS can be an indicator to identify a subset of the ypI group whose long-term oncologic outcomes are as good as those of stage pI cohort.

Can rewiring strategy control the epidemic spreading?

Relation existed in the social contact network can affect individuals' behaviors greatly. Considering the diversity of relation intimacy among network nodes, an epidemic propagation model is proposed by incorporating the link-breaking threshold, which is normally neglected in the rewiring strategy. The impact of rewiring strategy on the epidemic spreading in the weighted adaptive network is explored. The results show that the rewiring strategy cannot always control the epidemic prevalence, especially when the link-breaking threshold is low. Meanwhile, as well as strong links, weak links also play a significant role on epidemic spreading.

Linking myosin heavy chain isoform shift to mechanical properties and fracture modes in skeletal muscle tissue.

Muscle fibers play a crucial role in the mechanical action of skeletal muscle tissue. However, it is unclear how the histological variations affect the mechanical properties of tissues. In this study, the shift of myosin heavy chain (MHC) isoforms is used for the first time to establish a linkage between tissue histological variation and passive mechanical properties. The shift of MHC isoform is found not only to induce significant differences in skeletal muscle passive mechanical properties, but also to lead to differences in strain rate responses. Non-negligible rate dependence is observed even in the conventionally defined quasi-static regime. Fidelity in the estimated constitutive parameters, which can be impacted due to variation in MHC isoforms and hence in rate sensitivity, is enhanced using a Bayesian inference framework. Subsequently, scanning electron microscopy and fluorescence microscopy are used to characterize the fracture morphology of muscle tissues and fibers. The fracture mode of both MHC I and II muscle fibers exhibited shearing of endomysium. Results show that the increase in strain rate only leads to stronger rebounding of the muscle fibers during tissue rupture without changing fracture modes.

A deep neural network predictor to predict the sensitivity of neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Neoadjuvant chemoradiotherapy (NCRT) is widely used for locally advanced rectal cancer (LARC). This study aimed to conduct an effective model to predict NCRT sensitivity and provide guidance for clinical treatment. Biomarkers for NCRT sensitivity were identified by applying transcriptome profiles using logistic regression and subsequently screened out by Spearman correlation analysis and four machine learning algorithms. A deep neural network (DNN) predictor was constructed by using in-house dataset and validated in two independent datasets. Additionally, a web-based program was developed. Wnt/ß-catenin signaling and linoleic acid metabolism (LA) pathways were associated with NCRT sensitivity and prognosis in LARC, antagonistically. A DNN predictor with an 18-gene signature was conducted within in-house datasets. In two validation cohorts, area under ROC curve (AUC) achieved 0.706 and 0.897. The DNN subtypes were significantly associated with NCRT sensitivity, survival status et al. Moreover, NK and cytotoxic T cells were observed contribution to NCRT sensitivity while regulatory T, myeloid-derived suppressor cells and dysfunction of CD4 T effector memory cells could impede NCRT response. A DNN predictor could predict NCRT sensitivity in LARC and stratify LARC patients with different clinical and immunity characteristic.

Residual Stress Control Using Process Optimization in Directed Energy Deposition.

This paper mainly analyzes the typical thermodynamic response (thermal history, thermal strain and residual stress) in a conventional continuous-wave (CW) laser during Directed Energy Deposition (DED). The influence of process parameters (laser power and scanning speed) on the temperature gradient in the heat-affected zone, thermal strain and residual stress are studied, and the corresponding relationship are established. The results show that a reduction in residual stress can be obtained by decreasing the temperature gradient. However, the method of reducing the temperature gradient by changing process parameters leads to low forming quality and low density. A pulse-wave laser (PW) is proposed to actively control the residual stress of the deposited sample. This laser mode can reduce not only the temperature gradient in the process of DED but also the in situ release of thermal stress, correspondingly greatly reducing the residual stress.

Efficacy and acceptability of supervised group exercise for mild to moderate major depressive disorder: A feasibility study.

BACKGROUND: Exercise can efficiently reduce the symptoms of major depression disorder (MDD). This study aims to examine the efficacy and acceptability of supervised group exercise intervention among patients in an acute phase of mild to moderate MDD. METHODS: We enrolled patients in the psychiatric clinic of Beijing Anding Hospital affiliated to Capital Medical University in a prospective, single-arm objective performance criteria (OPC) trial. A total of 40 adults aged 18-50 who had a diagnosis of an episode of depression and the 17-item Hamilton Rating Scale for Depression (HRSD-17) score of 7-20 were recruited. Supervised exercise group intervention was applied on participants with a new episode of mild to moderate depression 3 times a week for 8 weeks without any other treatment. Every exercise session should meet the standard of moderate intensity, defined as approximately equal to 50 %-80 % of the maximal heart rate for 150 min every week. The primary end point was the clinical response at week 8, defined as a 50 % reduction in the baseline HRSD-17 score. Meanwhile, the secondary end points included the acceptability of the supervised group exercise intervention for both patients and investigators, remission rate (defined as an HRSD-17 score of 7 or less), the change of Patient Health Questionnaire (PHQ-9) and the Quality of Life, Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF). RESULTS: Among the 46 screened patients, 40 were enrolled. Of them, 4 people dropped out, while 36 received all the planned sessions of the supervised group exercise therapy and completed the week-8 assessment. At week 8, the response rate was 89 % (95 % confidence interval [CI] 74 % to 97 %) and the remission rate was 83 % (95%CI 67 % to 94 %). The overall acceptance of the supervised group exercise based on the VAS score (range 0-10) was 9.19 ± 1.27 for patients and 9.67 ± 0.62 for investigators. The least-squares mean (±SE) change from baseline at week 8 was-9.99 in the PHQ-9 score and 25.15 in the Q-LES-Q-SF score. No serious adverse events were reported during this trial. The percentage of any adverse event was 5 %. CONCLUSION: Supervised group exercise intervention is effective in patients with acute mild to moderate MDD and has good acceptance rate among both patients and investigators.

Induction Immune Checkpoint Inhibitors and Chemotherapy Before Definitive Chemoradiation Therapy for Patients With Bulky Unresectable Stage III Non-Small Cell Lung Cancer.

PURPOSE: In the era of immunotherapy, the treatment for bulky, locally advanced non-small cell lung cancer (LA-NSCLC) remains challenging. This study explored the feasibility of induction immune checkpoint inhibitors (ICIs) plus chemotherapy before definitive chemoradiation therapy (CRT) for bulky LA-NSCLC. METHODS AND MATERIALS: Patients with bulky, unresectable stage III NSCLC (primary tumor ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter) receiving ICIs and chemotherapy before CRT from 2018 to 2022 were identified. Survival outcomes and toxic effects were analyzed. Radiation therapy plans on computed tomography images before and after 2 cycles of induction chemoimmunotherapy were simulated to evaluate dosimetric outcomes. RESULTS: Seventy-five patients were included. One- and 2-year overall-survival (OS) rates were 91.5% (95% CI, 85.2%-98.3%) and 75.1% (95% CI, 64.1%-88.0%), respectively. One- and 2-year progression-free-survival (PFS) rates were 85.8% (95% CI, 78.0%-94.4%) and 64.2% (95% CI, 52.5%-78.6%), respectively. Median OS was not reached (NR). Median PFS was 30.6 months (95% CI, 25.9 months to NR). Grade 2 and ≥3 pneumonitis occurred in 26.7% and 9.3% of patients, respectively. Grade ≥3 pneumonitis was significantly associated with poorer OS (P = .003) and PFS (P = .018). Treatment discontinuation was significantly associated with shorter OS (P = .023) and PFS (P = .047). Patients with consolidation ICIs exhibited numerically better OS than those without consolidation ICIs (2-year OS, 85.8% vs 64.2%; P = .170). The objective response rate was 76.1% for induction treatment and 86.7% for induction treatment plus CRT. The disease control rate after 2 cycles of induction therapy was significantly greater than after 4 (P = .046) or more cycles (P = .025). Simulated radiation plans indicated that all target volumes, mean lung dose, and volume of lung parenchyma receiving ≥5 Gy, ≥20 Gy, and ≥30 Gy significantly decreased after 2 cycles (all P < .005). CONCLUSIONS: Two cycles of induction ICIs plus chemotherapy before definitive CRT were feasible for bulky LA-NSCLC, with significant tumor reduction and normal lung protection. Further investigations on CRT combined with induction and consolidation ICIs are warranted.

Efficacy and Safety of Concurrent Chemoradiotherapy Combined with Nimotuzumab in Elderly Patients with Esophageal Squamous Cell Carcinoma: A Prospective Real-world Pragmatic Study.

BACKGROUND: Concurrent or definitive chemoradiotherapy is the standard treatment of locally advanced esophageal squamous cell carcinoma (ESCC). Elderly patients could not tolerate the standard concurrent chemotherapy and were treated with radiotherapy because of weak physical status and multiple comorbidities. OBJECTIVE: The efficacy and safety profile of concurrent (chemo) radiotherapy combined with nimotuzumab in elderly patients with ESCC were investigated. METHODS: Eligible elderly (≥70 years) patients with locally advanced ESCC were enrolled in this prospective, real-world pragmatic study and received concurrent chemoradiotherapy or radiotherapy combined with nimotuzumab. The primary endpoint was overall survival (OS). Secondary endpoints were objective response rate, disease control rate, progression-free survival (PFS), and adverse drug reactions. RESULTS: Fifty-three elderly patients were enrolled. Thirty-two (60.4%) were treated with radiotherapy combined with nimotuzumab (RT+N), and 21 (39.6%) with concurrent chemoradiotherapy combined with nimotuzumab (CRT+N). The median age was 75.8 years. Fourteen (56.0%) patients achieved a partial response, and 11 (44.0%) patients achieved stable disease at 3 months. The median follow-up duration was 24.4 (95%CI, 21.6-26.7) months. Median OS (mOS) was 27.0 (95%CI, 14.8-48.4) months. Median PFS (mPFS) was 22.6 (95%CI, 12.4-not reached) months. Higher mPFS (not reached vs. 12.0 months; p=0.022) and mOS (48.4 vs. 15.3 months; p=0.009) were observed in the CRT+N group compared with the RT+N group. Most adverse reactions were grade 1-2 (46, 86.8%). CONCLUSIONS: Concurrent chemoradiotherapy or radiotherapy combined with nimotuzumab was safe and well-tolerated in elderly patients with locally advanced ESCC. ESCC patients treated with CRT+N could live longer.

Metastasis risk stratification and response prediction through dynamic viable circulating tumor cell counts for rectal cancer in a neoadjuvant setting.

PURPOSE: Distant metastasis (DM) and neoadjuvant treatment response prediction remain critical challenges in the management of locally advanced rectal cancer (LARC). The aim of this study was to investigate the clinical relevance of viable circulating tumor cells (CTCs) for DM or response in patients with LARC in a neoadjuvant setting. METHODS: The detection of viable CTCs at different stages of treatment was planned for consecutive patients from a prospective trial. The Kaplan-Meier method, Cox proportional hazards model, and logistic regression model were utilized to analyze factors associated with DM or pathological complete response (pCR) and clinical complete response (cCR). RESULTS: Between December 2016 and July 2018, peripheral blood samples from 83 patients were collected before any treatment (median follow-up time, 49.3 months). CTCs were present in 76 of 83 patients (91.6%) at baseline, and more than three CTCs detected in the blood sample was considered high risk. Only the CTC risk group was significantly associated with 3-year metastasis-free survival (MFS) (high risk vs. low risk, 57.1% (95% CI, 41.6-72.6) vs. 78.3% (95% CI, 65.8-90.8), p = 0.018, log-rank test). When all the important variables were entered into the Cox model, the CTC risk group remained the only significant independent factor for DM (hazard ratio (HR), 2.74; 95% CI, 1.17-6.45, p = 0.021). The pCR and continuous cCR rates were higher in patients with a decreased number of CTCs of more than one after radiotherapy (HR, 4.00; 95% CI, 1.09-14.71, P = 0.037). CONCLUSIONS: The dynamic detection of viable CTCs may strengthen pretreatment risk assessment and postradiotherapy decision making for LARC. This observation requires further validation in a prospective study.

Efficacy and safety of definitive chemoradiotherapy with or without induction immune checkpoint inhibitors in patients with stage III non-small cell lung cancer.

Background: In the era of immunotherapy, the optimal combination of immune checkpoint inhibitors (ICIs) and chemoradiotherapy (CRT) for stage III non-small cell lung cancer (NSCLC) is not defined. The current study investigated the efficacy and safety of definitive CRT(dCRT) plus consolidation ICIs with or without induction ICIs in stage III NSCLC. Methods: 123 consecutive patients treated with dCRT followed by consolidation ICIs at our institution from 2018 to 2022 were retrospectively reviewed. Failure patterns, survival outcomes, and toxicity profiles were analyzed. Results: The 1- and 2- year PFS rates were 75.3% and 56.9%, respectively, and median PFS was 30.83 months from the start of treatment. In-field failure (18.7%) was the most common failure pattern. The most common adverse event (AE) was pneumonitis caused by ICIs or RT. The incidence of Grade 3-4 and Grade 5 pneumonitis was 5.7% and 1.6%, respectively. Further analysis showed that the induction plus consolidation ICIs group has significantly lower cumulative incidence of distant metastasis rates (HR: 0.30, 95%CI: 0.09-1.00, p=0.043) and higher incidence of pneumonitis (p=0.039) compared with patients in the consolidation ICIs group. Conclusions: Combined CRT and consolidation ICIs achieved encouraging efficacy and manageable toxicity in patients with stage III NSCLC in China. Induction plus consolidation ICIs might reduce distant metastasis and deserve further investigation.

Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study).

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage I-II NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary. Methods: This randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus non-squamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments. Discussion: The InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response. Clinical trial registration: ClinicalTrials.gov, identifier NCT05888402.