microRNAs combined to radiomic features as a predictor of complete clinical response after neoadjuvant radio-chemotherapy for locally advanced rectal cancer: a preliminary study.

OBJECTIVE: To define a predictive Artificial Intelligence (AI) algorithm based on the integration of a set of biopsy-based microRNAs expression data and radiomic features to understand their potential impact in predicting clinical response (CR) to neoadjuvant radio-chemotherapy (nRCT). The identification of patients who would truly benefit from nRCT for Locally Advanced Rectal Cancer (LARC) could be crucial for an improvement in a tailored therapy. METHODS: Forty patients with LARC were retrospectively analyzed. An MRI of the pelvis before and after nRCT was performed. In the diagnostic biopsy, the expression levels of 7 miRNAs were measured and correlated with the tumor response rate (TRG), assessed on the surgical sample. The accuracy of complete CR (cCR) prediction was compared for i) clinical predictors; ii) radiomic features; iii) miRNAs levels; and iv) combination of radiomics and miRNAs. RESULTS: Clinical predictors showed the lowest accuracy. The best performing model was based on the integration of radiomic features with miR-145 expression level (AUC-ROC = 0.90). AI algorithm, based on radiomics features and the overexpression of miR-145, showed an association with the TRG class and demonstrated a significant impact on the outcome. CONCLUSION: The pre-treatment identification of responders/NON-responders to nRCT could address patients to a personalized strategy, such as total neoadjuvant therapy (TNT) for responders and upfront surgery for non-responders. The combination of radiomic features and miRNAs expression data from images and biopsy obtained through standard of care has the potential to accelerate the discovery of a noninvasive multimodal approach to predict the cCR after nRCT for LARC.

Evaluation of response using FDG-PET/CT and diffusion weighted MRI after radiochemotherapy of pancreatic cancer: a non-randomized, monocentric phase II clinical trial-PaCa-DD-041 (Eudra-CT 2009-011968-11).

BACKGROUND: Pancreatic cancer is a devastating disease with a 5-year survival rate of 20-25%. As approximately only 20% of patients diagnosed with pancreatic cancer are initially staged as resectable, it is necessary to evaluate new therapeutic approaches. Hence, neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e., [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy. METHODS: Patients with histologically proven resectable, borderline resectable or unresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the standardized uptake value (SUV) measured with FDG-PET. Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was performed using contrast-enhanced CT and contrast-enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen. RESULTS: A total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal SUV (SUVmax) during therapy (p < 0.001). Using the mean apparent diffusion coefficient (ADC), response was not detectable with DW-MRI. After neoadjuvant treatment 16 patients underwent surgery. In 12 (48%) patients tumor resection could be performed. The median overall survival of all patients was 25 months (range: 7-38 months). CONCLUSION: Based on these limited patient numbers, it was possible to show that this trial design is feasible and that the neoadjuvant therapy regime was well tolerated. FDG-PET/CT may be a reliable method to evaluate response to the combined therapy. In contrast, when evaluating the response using mean ADC, DW-MRI did not show conclusive results.

The response to neoadjuvant chemoradiotherapy with 5-fluorouracil in locally advanced rectal cancer patients: a predictive proteomic signature.

BACKGROUND: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard treatment for patients with locally advanced non-metastatic rectal cancer is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU) followed by surgery, but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. METHODS: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic rectal cancer patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-three patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. RESULTS: We have highlighted 384 differentially abundant proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially abundant proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Data are available via ProteomeXchange with identifier PXD008440. CONCLUSIONS: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic rectal cancer. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.

Quality of life in non-early rectal cancer treated by neoadjuvant radio-chemotherapy and endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) versus laparoscopic total mesorectal excision.

BACKGROUND: In selected patients with N0 rectal cancer, endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to laparoscopic total mesorectal excision (LTME). Aim of this study is to evaluate the short- and medium-term quality of life (QoL) from a retrospective analysis of prospectively collected data in patients with iT2-iT3 N0-N+ rectal cancer, who underwent ELRR by TEM or LTME after neoadjuvant radio-chemotherapy (n-RCT). METHODS: Thirty patients with iT2-iT3 rectal cancer who underwent ELRR by TEM (n = 15) or LTME (n = 15) were enrolled in this study. The choice for one operation or the other was made on the basis of predefined criteria. QoL was evaluated by EORTC QLQ-C30 and QLQ-CR38 questionnaires at admission, after n-RCT and 1, 6, and 12 months after surgery. RESULTS: No statistically significant differences in QoL evaluation were observed between the two groups, both at admission and after n-RCT. At 1 month after surgery, significantly better results in the ELRR group were observed by QLQ-C30 in: Nausea/Vomiting (p = 0.05), Appetite Loss (p = 0.003), Constipation (p = 0.05), and by QLQ-CR38 in: Body Image (p = 0.05), Sexual Functioning (p = 0.03), Future Perspective (p = 0.05) and Weight Loss (p = 0.036). At 6 months after surgery, a statistically significant worse impact after LTME was observed by QLQ-C30 in: Global Health Status (p = 0.05), Emotional Functioning (p = 0.021), Dyspnea (p = 0.008), Insomnia (p = 0.012), Appetite Loss (p = 0.014) and by QLQ-CR38 in Body Image (p = 0.05) and Defecation Problems (p = 0.001). At 1 year, the two groups were homogenous as assessed by QLQ-C30, whereas the QLQ-CR38 still showed better results of ELRR versus LTME in Body Image (p = 0.006), Defecation Problems (p = 0.01), and Weight Loss (p = 0.005). CONCLUSIONS: Based on the present series, in selected patients, earlier restoration of patients' functions is observed after ELRR by TEM than after LTME.

Influence of Neoadjuvant Therapy on Success of Endoscopic Vacuum Therapy in Anastomotic Leakage after Rectal Resection Because of Rectal Cancer.

Background: For locally advanced rectal cancer, neoadjuvant therapy (NT) is an established element of therapy. Endoscopic vacuum therapy (EVT) has been a relevant treatment option for anastomotic leakage after rectal resection since 2008. The aim was to evaluate the influence of NT on the duration and success of EVT in anastomotic leakage after rectal resection for rectal cancer. Methods: This was a monocentric, retrospective cohort study including patients who underwent rectal resection with primary anastomosis because of histologically proven carcinoma of the rectum in the Department for General and Visceral Surgery of Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin over a period of ten years (2012 to 2022). Results: Overall, 243 patients were included, of which 47 patients (19.3%) suffered from anastomotic leakage grade B with consecutive EVT. A total of 29 (61.7%) patients received NT and 18 patients (38.3%) did not. The median duration of EVT until the removal of the sponge did not differ between patients with and without NT: 24.0 days (95% CI 6.44-41.56) versus 20.0 days (95% CI 17.03-22.97); p = 0.273. The median duration from insertion of EVT until complete healing was 74.0 days with NT (95% CI 10.07-137.93) versus 62.0 days without NT (95% CI 45.99-78.01); p = 0.490. Treatment failure-including early persistence and late onset of recurrent anastomotic leakage-was evident in 27.6% of patients with NT versus 27.8% without NT; p = 0.989. Ostomy was reversed in 19 patients (79.2%) with NT compared to 11 patients (68.8%) without NT; p = 0.456. Overall, continuity was restored in 75% of patients in the long term after EVT. Conclusion: This trial comprised-to our knowledge-the largest study cohort to analyze the outcome of EVT in anastomotic leakage after rectal resection for rectal cancer. We conclude that neoadjuvant therapy neither prolongs EVT nor the time to healing from anastomotic leakage. The rates of treatment failure of EVT and permanent ostomy were not higher when neoadjuvant therapy was used.

Review of definition and treatment of upper rectal cancer.

While the treatment of locally advanced lower and middle rectal cancer with total mesorectal excision (TME) after neoadjuvant therapy is now well defined, the treatment of locally advanced upper rectal cancer (LAURC) remains controversial. Although most teams and academic societies recommend upfront surgery (US) with partial mesorectal excision (PME), as this appears to be sufficient for these tumors, the literature remains conflicting regarding the additional use of neoadjuvant therapy and TME. Current recommendations for the treatment of LAURC do not reflect actual clinical practice. Notably, there is a paucity of published data specific to the treatment of LAURC since most of the data are from sub-analyses of different cohorts. Another important point responsible for the inconsistent data situation is the fact that the current definition of upper rectal cancer is based on anatomical criteria that are difficult to reproduce and therefore also differ between international professional societies. The aim of this review is to provide a deeper insight into the issues surrounding the treatment of LAURC based on an analysis of the current literature, including anatomic and embryologic data.

Results of Tri-Modality Therapy for Rectal Cancer in Elderly Patients.

BACKGROUND/AIM: Elderly cancer patients are more prevalent and require special attention. This study focused on the outcome of elderly (≥65 years) rectal cancer patients treated with tri-modality therapy. PATIENTS AND METHODS: A total of 105 patients receiving neoadjuvant radio-chemotherapy and resection for locally advanced rectal cancers were retrospectively evaluated. Nine characteristics were analyzed for loco-regional control (LRC), metastases-free survival (MFS) and overall survival (OS) including tumor location, gender, age, performance status, radiotherapy technique, primary tumor/lymph node categories, downstaging and histological grading. RESULTS: The 5-year rates of LRC, MFS and OS were 91%, 78% and 87%, respectively. Radio-chemotherapy was not completed in 12 patients (11%) due to toxicity; 18 patients (17%) experienced grade 3 toxicities. A total of 29 patients (28%) had surgical complications. On multivariate analyses, MFS was significantly associated with downstaging (p=0.003) and OS with lower histological grade (p=0.013). CONCLUSION: Tri-modality therapy resulted in promising outcomes and was tolerated reasonably well by elderly patients. Prognostic factors were identified that may help personalize future treatment.

Role of Neoadjuvant Radio-chemotherapy for the Treatment of High Rectal Cancer.

BACKGROUND/AIM: Controversy exists regarding treatment of high rectal cancer. The role of neoadjuvant radio-chemotherapy was investigated. PATIENTS AND METHODS: Fifty-four patients receiving neoadjuvant radio-chemotherapy (50.4 Gy & 2 courses of concurrent chemotherapy) for stage II/III high rectal cancer (10.1-15.0 cm from anal verge) were retrospectively analyzed. Following microscopicallly complete resection of primary tumor and involved lymph nodes in all patients, ≤6 courses of chemotherapy were given. RESULTS: Five-year rates of local control (LC), metastases-free survival (MFS) and overall survival (OS) were 90%, 79% and 77%. On multivariate analyses, LC was associated with lower pathological UICC-stage at surgery (p=0.003) and successful downstaging (p=0.007), MFS with higher regression grade (p=0.014) and OS with lower Union for International Cancer Control (UICC)-stage (p=0.017) and downstaging (p=0.034). Grade 3 acute toxicities occurred in 19% of patients; grade ≥3 late toxicities were not observed. Manageable surgery-related complications occurred in 43%. CONCLUSION: Neoadjuvant radio-chemotherapy for high rectal cancer was well tolerated and led to promising results. Comparative studies are required to investigate whether it is superior to postoperative chemotherapy alone.

Breast reconstruction after neoadjuvant radio chemotherapy: review and personal technique IDEAL concept REV-EJMR-D-15-00268.

Neoadjuvant radio chemotherapy and immediate reconstruction for breast cancer are still under debate. But there are recent abstracts and articles which show that neoadjuvant radio chemotherapy is feasible and could improve the clinical outcome of breast cancer patients. The aim of this review is to present the authors' techniques and approaches with regard to neoadjuvant radiation of breast cancer patients. It seems that the concept of immediate implant delayed autologous breast reconstruction could be a safe procedure that is at least equivalent to primary autologous reconstruction.

Perioperative and Palliative Chemotherapy for Esophageal Cancer.

Perioperative and palliative chemotherapy for esophageal carcinoma has undergone substantial changes in recent years. The implementation of trastuzumab in the treatment of HER2-positive advanced adenocarcinoma is a milestone as it marked the introduction of the first molecularly targeted treatment of gastric cancer. Current studies are investigating whether anti-HER2-directed treatment also proves effective in the perioperative setting. Data from the CROSS study on neoadjuvant radio-/chemotherapy with paclitaxel and carboplatin have helped to establish a new standard of care for the treatment of localized esophageal cancer. Finally, preliminary experience in potentially curative treatment approaches for oligometastatic tumor stages may offer new treatment options for patients with stage IV gastric cancer. However, some of these innovative approaches urgently require validation in larger, prospective, and controlled multicenter studies. Highly active forms of radiotherapy, radio-/chemotherapy, or chemoimmunotherapy can achieve complete tumor remissions in some patients. Despite these advances, life expectancy unfortunately continues to be very limited in the majority of patients with locally advanced or metastatic esophageal carcinoma.