[Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer: the preliminary single-center findings of a prospective, multicentre, randomized phase II trial (TORCH)].

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.

Linc00324 promotes the progression of papillary thyroid cancer via regulating Notch signaling pathway.

OBJECTIVE: To explore the expression of linc00324 in papillary thyroid cancer (PTC) and its effect on the biological function of PTC cells. PATIENTS AND METHODS: A total of 60 pairs of PTC and para-carcinoma normal tissues surgically excised were collected. The expression of linc00324 in PTC tissues and cells was detected via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR), and the expression of linc00324 in PTC cells was silenced using the small-interfering RNA (siRNA). Then, the effects of linc00324 on the PTC cell proliferation, apoptosis, and cycle and the downstream Notch signaling pathway were determined via methyl thiazolyl tetrazolium (MTT) assay, colony formation assay, flow cytometry, and Western blotting, respectively. RESULTS: The expression of linc00324 was upregulated in 48 out of 60 cases of PTC tissues, and it was increased in PTC cells compared with that in human thyroid follicular epithelial cells Nthy-ori 3-1. The results of MTT assay and colony formation assay showed that the proliferation of PTC cells declined after interference in linc00324 expression. The findings of flow cytometry revealed that the cell cycle was arrested in G1/G0 phase with a higher apoptosis rate in si-linc00324 group compared with that in the si-NC group. According to the data of Western blotting, the molecular markers for the downstream Notch signaling pathway were altered after interference in linc00324 expression. CONCLUSIONS: The expression of linc00324 is significantly increased in PTC tissues and cells. Silencing linc00324 may inhibit the proliferation of PTC cells, arrest the cell cycle in G1/G0 phase, and promote the apoptosis by inhibiting the Notch signaling pathway.

[Fudan experience of neoadjuvant treatment for rectal cancer].

Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer. Fudan University Shanghai Cancer Center has carried out multiple series of studies to explore the optimization of the neoadjuvant therapy since 2005. On the one hand, the "addition" method refers to a higher intensity treatment at the neoadjuvant stage to obtain better tumor regression. On the other hand, the "subtraction" method reduces some unnecessary treatment from the current triad of surgery, radiotherapy and chemotherapy to improve the quality of life of patients. However, locally advanced rectal cancer is associated with great heterogeneity, and therefore, any single treatment mode will not be optimal for all. Notably, the treatment decision-making should be based on clinical presentations, imaging findings, and molecular biology to precisely stratify patients. Besides, the scheme should be dynamically adjusted according to the therapeutic response, so as to realize the dual goals of prolonging patients' life and improving their quality of life. Meanwhile, the treatment decision-making for target population under the guidance of biomarker should be dynamically and self-adaptively adjusted based on the therapeutic effect. This approach will become the future development direction and objective for the precise medical treatment for rectal cancer.

A chemical-structural model for coherent martensite/parent interface in Mn-based antiferromagnetic shape memory alloys.

The martensite/parent coherent interface of Mn-based shape memory alloys (SMAs) is a significant part in the research of their martensitic transformation, reversible shape memory effect and magnetic shape memory effect. In the present work, a chemical-structural model was proposed to calculate the martensite/parent coherent interfacial energy of Mn-X (X = Cu, Fe) alloys. In this model, the coherent heterophase interfacial energy consists of chemical and structural parts. Resulting from the formation process of the heterophase interface, the chemical interfacial energy is expressed as the incremental value of bond energy, while the structural part is obtained by calculating the interfacial strain energy. The results show that the structural interfacial energy plays the chief role in the total interfacial energy, and the total interfacial energy decreases as the temperature rises when the alloy composition is fixed. In addition, the preferred orientation has noteworthy influence on the total interfacial energy. Using the proposed model, interfacial energy, interfacial entropy, interfacial enthalpy and interfacial heat capacity are found to be correlated with temperature and interface preferred orientation. Furthermore, the influences of alloy composition, modulus softening, and the index of the habit plane on the results were discussed.

Role of pelvic radiotherapy for locally advanced rectal cancer and synchronous unresectable distant metastases.

PURPOSE: To evaluate the efficacy and safety of pelvic irradiation combined systematic chemotherapy in patients with locally advanced (cT3-T4 and/or cN+) rectal cancer and synchronous unresectable distant metastases. PATIENTS AND METHODS: A total of 76 eligible patients who received pelvic radiotherapy and concurrent capecitabine-based chemotherapy were retrospectively reviewed. Patients survival curves were constructed using the Kaplan-Meier method, and a multivariate analysis was performed to identify independent prognostic factors. RESULTS: Most of the adverse events were mild during the period of combined chemoradiotherapy. Twenty-two patients experienced resection of primary tumour and 16 patients underwent radical surgery of all lesions. Only five patients had pelvic progression during the follow-up period. The median progression-free survival and median overall survival were 13 and 30 months, respectively. Radical surgery of all lesions following chemoradiotherapy was found to be an independent prognostic factor according to multivariate analysis. CONCLUSIONS: Pelvic irradiation combined with systematic chemotherapy in patients with locally advanced rectal cancer and synchronous unresectable distant metastases is effective and tolerable, both for pelvic and distant control. A curative resection following chemoradiotherapy was associated with prolonged survival.