Preoperative Chemotherapy Research Articles

Preoperative prediction of high-grade osteosarcoma response to neoadjuvant therapy based on a plain CT radiomics model: A dual-center study

ObjectiveTo develop a model combining clinical and radiomics features from CT scans for a preoperative noninvasive evaluation of Huvos grading of neoadjuvant chemotherapy in patients with HOS. Methods183 patients from center A and 42 from center B were categorized into training and validation sets. Features derived from radiomics were obtained from unenhanced CT scans.Following dimensionality reduction, the most optimal features were selected and utilized in creating a radiomics model through logistic regression analysis. Integrating clinical features, a composite clinical radiomics model was developed, and a nomogram was constructed. Predictive performance of the model was evaluated using ROC curves and calibration curves. Additionally, decision curve analysis was conducted to assess practical utility of nomogram in clinical settings. ResultsLASSO LR analysis was performed, and finally, three selected image omics features were obtained.Radiomics model yielded AUC values with a good diagnostic effect for both patient sets (AUCs: 0.69 and 0.68, respectively). Clinical models (including sex, age, pre-chemotherapy ALP and LDH levels, new lung metastases within 1 year after surgery, and incidence) performed well in terms of Huvos grade prediction, with an AUC of 0.74 for training set. The AUC for independent validation set stood at 0.70. Notably, the amalgamation of radiomics and clinical features exhibited commendable predictive prowess in training set, registering an AUC of 0.78. This robust performance was subsequently validated in the independent validation set, where the AUC remained high at 0.75. Calibration curves of nomogram showed that the predictions were in good agreement with actual observations. ConclusionCombined model can be used for Huvos grading in patients with HOS after preoperative chemotherapy, which is helpful for adjuvant treatment decisions.

Free fibula mandible reconstruction for osteoradionecrosis is more challenging than for primary cancer.

Osteoradionecrosis (ORN) of the mandible is an unfortunate potential sequela of radiotherapy for head and neck cancer. In advanced cases of ORN, mandibulectomy, and free fibula flap reconstruction are required. We hypothesized that patients undergoing fibula free flap reconstruction and mandibulectomy for ORN pose unique challenges and experience more complications than patients undergoing fibula free flaps after oncologic mandibulectomy. After IRB approval, we created a database of all free fibula flaps for mandible reconstruction from April 2005 through February 2019. Medical records were retrospectively reviewed for patient and surgical characteristics and postoperative outcomes. Four-hundred seventy-nine patients met the inclusion criteria (168 ORN vs. 311 non-ORN patients). Propensity-matching was performed based on age, BMI, smoking status, preoperative chemotherapy, and virtual surgery planning use, which yielded 159 patients in each group. ORN patients received more double-skin-island fibula flaps than non-OR patients (20.8% vs. 5.7%, p < 0.001). Recipient artery other than the facial artery was utilized more commonly in ORN patients (42.1% vs. 17.0%, p < 0.001). In the unmatched cohort, ORN patients had higher rates of delayed wound healing (26.2% vs. 16.8%, p = 0.01) and surgical site infections (21.4% vs. 13.2%, p = 0.02). Rates of flap loss, return to the operating room, hematoma, operative time, and length of stay were similar between the groups. On logistic regression analysis, osteoradionecrosis was an independent risk factor for delayed wound healing. Based on these data, mandibular reconstruction with fibula flaps for osteoradionecrosis appears more complicated than mandible reconstruction following de novo cancer resection. Surgeons should anticipate employing two skin islands for intraoral and extraoral resurfacing, utilizing unconventional recipient vessels, and managing the delayed wound healing that ensues more commonly than non-ORN patients.

Para-aortic Lymph Node Dissection for Colorectal Cancer: Predicting Pathologic Lymph Node Positivity and Optimizing Outcomes.

In colorectal cancer, the presence of para-aortic lymph nodes (PALN) indicates extraregional disease. Appropriately selecting patients for whom PALN dissection will provide oncologic benefit remains challenging. This study identified factors to predict survival among patients undergoing PALN dissection for colorectal cancer. An institutional database was queried for patients who underwent curative-intent resection of clinically positive PALN for colorectal cancer between 2007 and 2020. Preoperative radiologic images were reviewed, and patients who did and did not have positive PALN on final pathology were compared. Survival analysis was performed to evaluate the impact of pathologically positive PALN on recurrence-free (RFS) and overall survival (OS). Of 74 patients who underwent PALN dissection, 51 had PALN metastasis at the time of primary tumor diagnosis, whereas 23 had metachronous PALN disease. Preoperative chemotherapy ± radiotherapy was given in 60 cases (81.1%), and 28 (37.8%) had pathologically positive PALN. Independent factors associated with positive PALN pathology included metachronous PALN disease and pretreatment and posttreatment radiographically abnormal PALN. On multivariable analysis, pathologically positive PALN was significantly associated with decreased RFS (hazard ratio 3.90) and OS (HR 4.49). Among patients with pathologically positive PALN, well/moderately differentiated histology was associated with better OS, and metachronous disease trended toward an association with better OS. Pathologically positive PALN are associated with poorer RFS and OS after PALN dissection for colorectal cancer. Clinicopathologic factors may predict pathologic PALN positivity. Curative-intent surgery may provide benefit, especially in patients with well-to-moderately differentiated primary tumors and possibly metachronous PALN disease.

An evaluation model of hepatic steatosis based on CT value and serum uric acid/HDL cholesterol ratio can predict intrahepatic recurrence of colorectal cancer liver metastasis.

Intrahepatic recurrence is one of the main causes of treatment failure in patients with colorectal cancer liver metastasis (CRLM). Hepatic steatosis was reported to provide fertile soil for metastasis. The effect of irinotecan-inducted hepatic steatosis on the progression of liver metastasis remains to be verified. Therefore, we aim to clarify the effect of hepatic steatosis on postoperative intrahepatic recurrence in CRLM and whether it is relevant to irinotecan-based chemotherapy. Data for a total of 284 patients undergoing curative surgical treatment for CRLMs were retrospectively reviewed between March 2007 and June 2018. Hepatic steatosis score (HSS) was established by combining Liver to Spleen CT ratio (LSR) and Uric acid to HDL-cholesterol ratio (UHR) to detect the presence of hepatic steatosis. The evaluation model is consistent with pathological results and has high prediction ability and clinical application value. Patients with HSS high risk (HSS-HR) had significantly worse prognosis than those with HSS low risk (HSS-LR) (3-year intrahepatic RFS: 42.7% vs. 29.4%, P = 0.003; 5-year OS: 45.7% vs. 26.5%, P = 0.002). Univariate and multivariate analysis confirmed its essential role in the prediction of intrahepatic RFS. Besides, patients treated with preoperative irinotecan chemotherapy were more likely to end up with HSS-HR than those with non-irinotecan chemotherapy (63.3% vs. 21.8%, P < 0.001). Furthermore, irinotecan chemotherapy is relevant to worse prognosis in baseline HSS-HR patients. In summary, patients with HSS-HR had significantly worse 5-year OS and 3-year intrahepatic RFS. Irinotecan chemotherapy is more likely to lead to HSS-HR and pre-existing hepatic steatosis may be a worse prognostic factor limiting patients underwent IRI-based chemotherapy.

Constructing a prognostic model for colorectal cancer with synchronous liver metastases after preoperative chemotherapy: a study based on SEER and an external validation cohort

BackgroundThe combination of preoperative chemotherapy and surgical treatment has been shown to significantly enhance the prognosis of colorectal cancer with liver metastases (CRLM) patients. Nevertheless, as a result of variations in clinicopathological parameters, the prognosis of this particular group of patients differs considerably. This study aimed to develop and evaluate Cox proportional risk regression model and competing risk regression model using two patient cohorts. The goal was to provide a more precise and personalized prognostic evaluation system.MethodsWe collected information on individuals who had a pathological diagnosis of colorectal cancer between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) Database. We obtained data from patients who underwent pathological diagnosis of colorectal cancer and got comprehensive therapy at the hospital between January 1, 2010, and June 1, 2022. The SEER data collected after screening according to the inclusion and exclusion criteria were separated into two cohorts: a training cohort (training cohort) and an internal validation cohort (internal validation cohort), using a random 1:1 split. Subgroup Kaplan–Meier (K–M) survival analyses were conducted on each of the three groups. The data that received following screening from the hospital were designated as the external validation cohort. The subsequent variables were chosen for additional examination: age, gender, marital status, race, tumor site, pretreatment carcinoembryonic antigen level, tumor size, T stage, N stage, pathological grade, number of tumor deposits, perineural invasion, number of regional lymph nodes examined, and number of positive regional lymph nodes. The primary endpoint was median overall survival (mOS). In the training cohort, we conducted univariate Cox regression analysis and utilized a stepwise regression approach, employing the Akaike information criterion (AIC) to select variables and create Cox proportional risk regression models. We evaluated the accuracy of the model using calibration curve, receiver operating characteristic curve (ROC), and area under curve (AUC). The effectiveness of the models was assessed using decision curve analysis (DCA). To evaluate the non-cancer-related outcomes, we analyzed variables that had significant impacts using subgroup cumulative incidence function (CIF) and Gray’s test. These analyses were used to create competing risk regression models. Nomograms of the two models were constructed separately and prognostic predictions were made for the same patients in SEER database.ResultsThis study comprised a total of 735 individuals. The mOS of the training cohort, internal validation cohort, and QDU cohort was 55.00 months (95%CI 46.97–63.03), 48.00 months (95%CI 40.65–55.35), and 68.00 months (95%CI 54.91–81.08), respectively. The multivariate Cox regression analysis revealed that age, N stage, presence of perineural infiltration, number of tumor deposits and number of positive regional lymph nodes were identified as independent prognostic risk variables (p < 0.05). In comparison to the conventional TNM staging model, the Cox proportional risk regression model exhibited a higher C-index. After controlling for competing risk events, age, N stage, presence of perineural infiltration, number of tumor deposits, number of regional lymph nodes examined, and number of positive regional lymph nodes were independent predictors of the risk of cancer-specific mortality (p < 0.05).ConclusionWe have developed a prognostic model to predict the survival of patients with synchronous CRLM who undergo preoperative chemotherapy and surgery. This model has been tested internally and externally, confirming its accuracy and reliability.

Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy

Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates. To assess the efficacy and tolerability of TNT protocols for LARC. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024. Randomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria. Two authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach. The primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival. Of 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63). In this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

Dynamic Changes in Circulating Methylated Markers in Response to Antitumor Therapy of Rectal Cancer.

Rectal cancer (RC) occupies a leading position in the structure of oncological morbidity and mortality. Aberrant methylation of tumor-suppressor genes and hypomethylation of retrotransposons were shown to be detectable in cell-free DNA, circulating in the blood (cfDNA) of cancer patients, indicating the possibility to use them as diagnostic and prognosis markers. Evaluation of the changes in the methylation level of LINE-1 elements and SEPTIN9 and IKZF1 genes in the cell-surface-bound cfDNA (csb-cfDNA) from the blood of RC patients after antitumor therapy at a long-term follow-up. Blood samples were obtained from RC patients (n = 25) before treatment, after preoperative chemotherapy (3 courses according to the XELOX scheme), 10-15days after surgery, and every 3months during 12months of dynamic observation. The methylation level of LINE-1, SEPTIN9, and IKZF1 in the csb-cfDNA was evaluated by quantitative methyl-specific PCR. The LINE-1 methylation level in the csb-cfDNA increased 1.6 times in RC patients after chemotherapy and 3 times after tumor resection versus methylation level before therapy. The SEPTIN9 gene methylation level in the csb-cfDNA decreased by 1.7 times in RC patients after chemotherapy and by 2.3 times after tumor resection compared with the values before the treatment. The IKZF1 gene methylation level decreased by 2 times in RC patients after combined therapy. Notably, all patients with relapses (n = 5) showed an increase in methylation level for the SEPTIN9 and IKZF1 genes and a decrease of methylation level for the LINE-1 elements by 2 times or more in comparison with the level 10-15days after surgery. There were no changes in the circulating SEPTIN9, IKZF1, and LINE-1 methylation levels during the 12-month follow-up period after the combined therapy of RC patients (n = 20) without relapses. The results indicate that SEPTIN9, IKZF1, and LINE-1 methylation levels in the csb-cfDNA are potential markers of the effectiveness of antitumor therapy and early detection of relapse in RC patients.

Preoperative nivolumab plus SOX in patients with locally advanced gastric or gastro-esophageal junction cancer: A phase 2, single-arm trial.

4074 Background: Preoperative chemotherapy has been widely recommended in patients with locally advanced gastric or gastro-esophageal junction cancer (GC/GEJC), and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. We conducted a single-arm phase II trial (Stimulate-01) to evaluate the efficacy and safe of the anti-PD-1 antibody nivolumab plus SOX regimen in patients with locally advanced GC/GEJC and to explore the biomarker associated with therapy response. Methods: Patients with locally advanced GC/GEJC (cT3-4N+M0) were enrolled and received either 3 preoperative and 3 postoperative cycles of nivolumab (360 mg, IV, d1, Q21d) plus SOX regimen (oxaliplatin 130 mg/m2, IV, d1 with oral S-1 40-60mg, bid, d1-d14, Q21d) therapy, followed by 11 cycles of nivolumab monotherapy. The primary endpoint was the pathological complete response (pCR) rate, while the major pathological response rate (mPR), 3-year-DFS and 3-year-OS as the second endpoint. This clinical trial was registered at Clinicaltrial.gov (NCT05739045). In addition, tissue sample before and after treatment from patients were performed scRNA-seq. Results: Forty-six patients were enrolled from November 2022 to March 2023, with a median age of 66 years (range, 34-74), and 38 were male. The pCR rate was 28.26% [95% confidence interval (CI), 15.2%-41.3%], and the major pathologic response (mPR) [tumor regression grade (TRG)0/1] rate was 41.3% (95% CI, 27.1%-55.5%). All the patients underwent R0 resection. The mPR rate in patients with PD-L1 CPS ≥5 and patients with PD-L1 CPS&lt;5 was 42.86% vs 38.89% ( P= 0.790). In addition, This clinical study period spans from epidemic control to full liberalization in China. The mPR rate in patients infected with COVID-19 was 44.44% (12/27), while the mPR rate in patients who have not been infected with COVID-19 was 36.84% (7/19) ( P=0.146). There were no severe complications or death related to the surgery. The scRNA-seq data revealed that the composition of MHC-II (HLA-DRA, HLA-DPA1, HLA-DRB1, HLA-DPB1 and HLA-DQB1) were significantly over-expressed in cancer cell of treatment-sensitive patients (TRG0/1) compared to that of treatment-insensitive patients (TRG2/3). Then the MHC-II expression in pre-treatment biopsy samples from 240 GC patients who received preoperative immunotherapy plus chemotherapy were performed by immunohistochemistry. The results showed that the mPR rate in patients with MHC-II IHC ≥2 and patients with MHC-II IHC&lt;2 was 58.87% (83/141) vs 21.21% (21/99) ( P&lt;0.001). Conclusions: Nivolumab plus SOX as neoadjuvant therapy showed an encouraging pCR rate, mPR rate, and manageable safety. The long-term efficacy of this combination of regimens will be continued to follow up. In addition, the MHC-II expression may be a potential biomarker for predicting the effectiveness of immunotherapy combined with chemotherapy for GC/GEJC. Clinical trial information: NCT05739045 .

Impact of preoperative chemotherapy on surgical results in 139 patients with locally advanced pancreatic cancer.

The establishment of preoperative chemotherapy (PCT) with FOLFIRINOX and gemcitabine/nab-paclitaxel in recent years has enabled resectability in many patients with initially locally advanced pancreatic cancer (LAPC). Nevertheless, information about the impact of PCT on surgical results is scarce. All patients with initial LAPC who received surgery after chemotherapy at the high-volume centre for pancreatic surgery of St. Josef-Hospital Bochum between 2015 and 2022 were included in this retrospective cohort analysis. A total of 139 patients underwent surgery after pre-treatment with FOLFIRINOX (76.3%), gemcitabine/nab-paclitaxel (11.5%), both (5.8%) and other regimens (6.5%). Eighty-five tumors (61.2%) were resectable after PCT. R0 resection was achieved in 92.9%, R1 in 7.1% and R2 in 0% of cases. Fifty-four tumors were still not resectable at the time of surgery. Surgical results of the patients did not show increased postoperative mortality and morbidity compared to the literature data. Postoperative 30-day mortality was 1.4%. Rates for pancreas-specific complications [postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), and others] were not increased. POPF occurred in 10.5% and DGE in 26.3% after pancreaticoduodenectomy. After distal pancreatectomy, POPF was detected in 37.5% and DGE in 12.5%. Median postoperative survival (31 vs. 13 months) and overall survival after initial diagnosis (40 vs. 20 months) were significantly longer in resected patients (P<0.001). Postoperative recurrence-free survival in resected patients amounted to 12 months. This study underlines that PCT allows resectability of primarily unresectable patients with LAPC without increasing perioperative mortality and morbidity. It may lead to a significant prolongation of recurrence-free and overall survival in resected patients after PCT.

Adjuvant chemotherapy in clinical local advanced CRC following preoperational therapies and pT0-3N0M0 diagnosis (CANWATCH).

TPS3645 Background: Adjuvant chemotherapy is often deemed unnecessary in pathological stage II colorectal cancer (CRC) following initial surgery without high-risk factors for recurrence. However, the efficacy of adjuvant chemotherapy for pT1-3N0M0 CRC following preoperative chemotherapy or chemoradiotherapy remains uncertain. Some cases of clinical locally advanced CRC (cTxN1-2M0), which are down-staged to pT0-3N0M0 after preoperative chemotherapy or chemoradiotherapy, may not truly require adjuvant chemotherapy due to the down-staging effects of preoperative treatments or false-positive imaging diagnosis of lymph nodes. Methods: CANWATCH is a multicenter, open-label, randomized, phase III study with a parallel design conducted in China. Patients were randomly assigned (1:1) to the wait-and-watch group or the adjuvant chemotherapy group. Enrollment and random assignment were performed using a computerized randomization management system. Patients in the wait-and-watch group did not receive adjuvant chemotherapy but were followed up periodically, while patients in the adjuvant chemotherapy group continued to receive adjuvant chemotherapy based on 5-FU or 5-FU analogues (mFOLFOX6 or Capeox). This study is the first prospective randomized controlled study to assess the necessity of adjuvant chemotherapy for patients with locally advanced CRC who received neoadjuvant therapy and achieved a down-staging to pT0-3N0M0. The study aims to provide precise clinical evidence for individualized precision treatment in locally advanced CRC patients. Key inclusion criteria included preoperative clinical tumor stage III (cTxN1-2M0) CRC, pathologically confirmed CRC adenocarcinoma by endoscopic biopsy, postoperative pathological stage T0-3N0M0 without high-risk factors for recurrence, and patient ability to understand and sign written informed consent. Main exclusion criteria were a history of other malignant tumors, complications requiring emergency surgery (occlusion, sub-occlusion, massive hemorrhage, and abscesses), colorectal tumor extension toward the abdominal wall and/or adjacent organs preventing immediate R0 resection of liver metastases, non-resectable lymph node metastasis, American Society of Anesthesiologists (ASA) grading ≥ IV, and/or Eastern Cooperative Oncology Group (ECOG) score ≥ 2. A total of 650 patients are planned to be enrolled in this study, and 301 patients have been enrolled as of February 6, 2024. The study is registered with ClinicalTrials.gov (NCT03748485) and is ongoing. Clinical trial information: NCT03748485 .

Neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma: A prospective phase II trial.

4087 Background: Surgery-based combination therapy is the current primary treatment for nonmetastatic esophageal squamous cell carcinoma (ESCC). An increasing number of results indicate that neoadjuvant chemotherapy alone might be a choice for perioperative treatment. Previously, a retrospective study we conducted showed that neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred to as the APCC regimen) for locally advanced ESCC had achieved promising results. To further confirm the efficacy of this regimen, we conducted this prospective phase II clinical study. Methods: Patients (pts) with locally advanced ESCC (cT2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with the APCC regimen (albumin-bound paclitaxel 125 mg/m2 iv, day 1/8, cisplatin 60 mg/m2 iv day 1, and capecitabine 1750 mg/m2 po bid day 1-14, repeated every 21 days for 4 cycles). The primary endpoint was pathological complete response (pCR), and the secondary endpoints were major pathological response (MPR), the R0 resection rate, disease free survival (DFS), overall survival (OS), and safety. Results: A total of 82 pts were enrolled and all received 4 cycles of preoperative APCC regimen. Of the 80 (97.6%) pts who underwent surgery, the R0 resection rate was 100%, pCR was observed in 23 (28.7%) pts and 50 (62.5%) pts had an MPR. Postoperative pathology revealed that 42 (52.5%) pts had stage I (ypT0-2N0M0). The most common grade 3/4 adverse events of chemotherapy included neutropenia (25%), leukopenia (14.5%), nausea (7.5%) and peripheral neurotoxicity (5.5%). No neoadjuvant chemotherapy related, or perioperative death occurred. As of December 1, 2023, with a median follow-up time of 36.8 months, 16(19.5%) patients had recurrent disease, among which 8 (8.5%) pts had local recurrence, 10 (12.2%) pts had distant metastasis. The 3-year DFS rate was 79.4%. As of the last follow-up, eight pts died, and the 3-year survival rate was 88.8%. Conclusions: The results meet our initial aim that preoperative chemotherapy with albumin-bound paclitaxel, cisplatin and capecitabine is highly active and resulted in a considerable pCR and MPR rate with promising 3-year survival rate in pts with locally advanced ESCC, while well-tolerated. This triplet regimen could be another effective neoadjuvant treatment strategy for locally advanced ESCC. Clinical trial information: NCT04390958 .

Improving outcomes in high-grade goblet cell adenocarcinomas: The interplay of complete cytoreduction, HIPEC and fibrosis.

e16379 Background: High-grade goblet cell adenocarcinomas (GCA), including signet-ring cell type (SRC) and poorly differentiated, behave more aggressively compared to typical GCA and are associated with poor prognosis. Due to GCA’s rarity, the treatment aligns with colon cancer guidelines, including surgery, chemotherapy and/or cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for peritoneal carcinomatosis (PC). In our case series, we assessed the outcome of patients with high grade GCA tumors and PC, who underwent either CRS with HIPEC or tumor debulking. Methods: A prospectively maintained database of patients treated at the Division of Surgical Oncology for Peritoneal Carcinomatosis (PC) from 2007 to 2022 was reviewed retrospectively. Patient selection was based on the primary tumor’s original pathology report and scheduling to undergo CRS/HIPEC for PC. We calculated median overall survival from the time of diagnosed peritoneal carcinomatosis, with focus on the attainment of complete cytoreduction (CC) and HIPEC administration. Results: 385 records were screened and 21 cases of GCA were identified. Thirteen (13) patients had a diagnosis of high-grade GCA with PC. Complete cytoreduction (CC0/CC1) with HIPEC was achieved in 7/13 patients, and 6/13 patients underwent tumor debulking. The median overall survival after diagnosing peritoneal carcinomatosis was 53 months for the patients who underwent CC/HIPEC and 20 months for the patients who received debulking. Of note, in the debulking group, 5/6 patients had a poorly differentiated GCA and exhibited intraoperatively tumor characteristics of infiltration, thickening and fibrosis, confirmed by the pathology report, which rendered CC unsuccessful. In contrast, within the CC/HIPEC group, pathology reported localized fibrosis as a chemotherapy response in only 2/7 patients, which did not impede the achievement of CC. Preoperative 5-FU based chemotherapy was administered to 4/7 patients in the CC/HIPEC group and to 5/6 patients in the debulking group. Conclusions: Our results demonstrate that CC with HIPEC may improve overall survival in patients with high grade GCA with PC. Notably, poorly differentiated GCA and the presence of fibrotic tissue, stemming from the tumor and/or preoperative chemotherapy, influences CC success. Considering the potential impact of fibrosis on surgical outcomes, pathological assessment of fibrosis preoperatively and/or use of fibrosis-specific biomarkers could guide cytoreduction strategies and treatment choices in patients diagnosed with high-grade GCA.

Analysis of effectiveness of FLOT perioperative chemotherapy in resectable locally advanced gastric or esophago-gastric junction cancer in a Kazakhstani population.

e16129 Background: Gastric cancer is the third most common malignancy in Kazakhstan and the second leading cause of cancer-related mortality. Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) perioperative chemotherapy is widely accepted treatment strategy of locally advanced gastric adenocarcinoma in Western countries. However, radical surgery is a preferable approach in Kazakhstan. The objective of this study was to assess the effectiveness and feasibility of FLOT perioperative chemotherapy in curable locally advanced gastric or esophago-gastric junction cancer. Methods: In this study, we reviewed the retrospective data of patients with locally advanced gastric or esophago-gastric junction cancer, who received FLOT perioperative chemotherapy between January 2020 and December 2022 in single center. To evaluate the effectiveness of treatment, histopathological regression, disease free survival (DFS) and 1- and 3-year overall survival outcomes were analyzed. Results: Total 136 patients with stage II and III with gastric or esophago-gastric junction cancer were treated. Fifty-six patients (41%) received FLOT preoperative chemotherapy. 9% (5) patients couldn’t complete all cycles of chemotherapy due to serious adverse events. Disease progression was observed in 10 (19%) patients after FLOT preoperative chemotherapy. Of the 46 radically operated patients, 5 (11%) had complete or near complete pathology response, 33 (72%) patients had partial response, and 8 (17%) patients had no response for preoperative chemotherapy (p = 0,405). 7 patients had not get adjuvant chemotherapy. Overall, 1- and 3-year survival were 78,6% and 34,9% respectively, disease free survival was 76,8% and 39% respectively. Conclusions: The FLOT perioperative chemotherapy was effective and feasible to administer and might be a standard treatment option among patients with locally advanced gastric or esophago-gastric junction cancer.

498TiP Adjuvant trastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: The TRINITY trial

498TiP Adjuvant trastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: The TRINITY trial

Safety and feasibility of esophagectomy following neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Analysis of two phase 2 clinical trials.

4070 Background: Despite the survival benefit of preoperative chemotherapy (CT) or chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC), the prognosis remains dismal. With the potential benefit of combining immune checkpoint inhibitors (ICIs) neoadjuvantly, we initiated two phase II single-armed clinical trials to explore the efficacy, feasibility, and safety of esophagectomy following the combination of preoperative PD-1 inhibitor with CT or CRT in ESCC. Methods: A total of 55 patients with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase 2, single-arm trials underwent neoadjuvant ICIs combined with chemotherapy (nICT) (n=38) (NCT04506138) or chemoradiotherapy (nICRT) (n=17) (NCT03940001) between May 2019 and June 2022 were enrolled. Patients received 2 doses of intravenous PD-1 inhibitor every 3 weeks, combined with 2 cycles of CT or CRT. Data on the pathological complete response (pCR) rates, operative time, blood loss volume, 30-day complications, hospital stay, and 30-day mortality were collected and assessed between these two groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. The primary endpoints of the studies were the safety and feasibility of esophagectomy after the combination of preoperative CT or CRT and PD-1 inhibitor. We also evaluated pCR, primary tumor pCR, operation time, postoperative stay, and 30-day mortality. Results: All the included patients successfully completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group, respectively (p=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group, respectively (p=0.19). Minimally invasive surgery was performed in 89.2% (33/37) of the nICT group and 94.1% (16/17) of the nICRT group. The risk of developing pulmonary, anastomotic, or other complications was similar in the two groups. Conclusions: Esophagectomy was safe after the addition of PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and exploratory endpoints, including biomarker analyses are ongoing. Clinical trial information: NCT03940001 ; NCT04506138 .

Ferroptosis defense mechanisms: The future and hope for treating osteosarcoma

AbstractCurrently, challenges such as chemotherapy resistance, resulting from preoperative and postoperative chemotherapy, postoperative recurrence, and poor bone regeneration quality, are becoming increasingly prominent in osteosarcoma (OS) treatment. There is an urgent need to find more effective ways to address these issues. Ferroptosis is a novel form of iron‐dependent programmed cell death, distinct from other forms of cell death. In this paper, we summarize how, through the three major defense systems of ferroptosis, not only can substances from traditional Chinese medicine, antitumor drugs, and nano‐drug carriers induce ferroptosis in OS cells, but they can also be combined with immunotherapy, differentiation therapy, and other treatment modalities to significantly enhance chemotherapy sensitivity and inhibit tumor growth. Thus, ferroptosis holds great potential in treating OS, offering more choices and possibilities for future clinical interventions.

Identification of lateral pelvic nodes without metastasis in patients with rectal cancer treated with preoperative chemoradiotherapy or chemotherapy based on magnetic resonance imaging.

Intensive localized therapy is promising for the treatment of rectal cancer. In Japan, chemoradiotherapy (CRT) and neoadjuvant chemotherapy (NAC) are used as preoperative treatments for this disease. Magnetic resonance imaging (MRI) is used to diagnose lateral pelvic node (LPN) metastases, but the changes in LPN findings on MRI following preoperative treatment are unclear. Furthermore, there may be patients in whom LPN dissection can be omitted after CRT/NAC. Patients who underwent total mesorectal excision with LPN dissection after CRT/NAC at 13 Japanese Society for Cancer of the Colon and Rectum member institutions between 2017 and 2019 were included. Changes in the short diameter of the LPNs after CRT/NAC and the reduction rate were examined. A total of 101 LPNs were examined in 28 patients who received CRT and 228 in 47 patients who received NAC. Comparison of LPNs before and after CRT/NAC showed that most LPNs shrank after CRT but that the size reduction was variable after NAC. Although some LPNs with a short diameter of <5 mm showed residual metastasis, no metastases were observed in LPNs that were <5 mm in short diameter before and after CRT/NAC and did not shrink after treatment. Although the short diameter of LPNs was significantly reduced by both CRT and NAC, even LPNs with a short diameter of <5 mm could have residual metastases. However, dissection may be omitted for LPNs <5 mm in short diameter that do not shrink after preoperative CRT or NAC.

Obstacles to receiving postoperative radiation therapy following separation surgery for metastatic spine disease.

Obtaining timely postoperative radiotherapy (RT) following separation surgery is critical to avoid local recurrence of disease yet can be a challenge due to scheduling conflicts, insurance denials, and travel arrangements. In patients undergoing metastatic spine surgery for spinal cord compression, the authors sought to: 1) report the rate of postoperative RT, 2) describe reasons for patients not receiving postoperative RT, and 3) investigate factors that may predict whether a patient receives postoperative RT. A single-center retrospective case series was undertaken of all patients who underwent metastatic spine surgery for extradural disease between January 2010 and January 2021. Inclusion criteria were patients with intermediate or radioresistant tumors with evidence of spinal cord compression who underwent surgery. The primary outcome was the occurrence of RT within 3 months following surgery. Multivariable logistic regression analysis was performed controlling for age, BMI, race, total number of decompressed levels, tumor size, other organ metastasis, and preoperative RT or chemotherapy to predict patients receiving postoperative RT. Of 239 patients undergoing spine surgery for metastatic disease, 113 (47.3%) received postoperative RT while 126 (52.7%) did not. In the postoperative RT group, 24 (21.2%) received stereotactic body radiation therapy while 89 (78.8%) received conventional external-beam radiation therapy. The most common reasons for patients not receiving postoperative RT included death or transfer to hospice (31.0%), RT not being recommended by radiation oncology (30.2%), and loss to follow-up (23.8%). On critical review with the radiation oncology department, the authors estimated that 101 of 126 (80.2%) patients who did not receive postoperative RT were potential candidates for postoperative RT. Patients who received postoperative RT had more documented inpatient (48.7% vs 32.5%, p < 0.001) and outpatient (100.0% vs 65.1%, p < 0.001) radiation oncology consultations than those who did not. Additionally, patients who received postoperative RT had a higher rate of postoperative chemotherapy (53.1% vs 25.4%, p < 0.001), while patients who did not receive postoperative RT had a higher rate of preoperative RT (7.1% vs 31.0%, p < 0.001). Multivariable analysis confirmed that patients who received preoperative RT had lower odds of undergoing postoperative RT (OR 0.14, 95% CI 0.06-0.34; p < 0.001), and patients who underwent postoperative chemotherapy had higher odds of undergoing postoperative RT (OR 3.83, 95% CI 2.05-7.17; p < 0.001). In the current study reflecting real-world care of patients with metastatic spine disease after undergoing separation surgery, 47% of patients did not receive postoperative RT, and 80% of those patients were potential candidates for postoperative RT. Radiation oncology consultation and postoperative chemotherapy were significantly associated with receiving postoperative RT, whereas preoperative RT was significantly associated with not receiving postoperative RT. The lack of timely postoperative RT highlights a potential gap in metastatic spine tumor care and underscores the necessity for prompt radiation oncology consultation and effective planning.

Deep learning-based quantitative assessment of tumor-infiltrating lymphocytes from hematoxylin and eosin-stained slides in triple-negative breast cancer: A prognostic study.

553 Background: Tumor-infiltrating lymphocytes (TILs) are pivotal in predicting responses to preoperative chemotherapy in triple-negative breast cancer. Yet, their clinical adoption as a diagnostic marker is limited by the challenge of achieving high accuracy with objective measures. This study introduces a novel AI-based method to quantitatively assess stromal TILs within the tumor bed using hematoxylin and eosin (H&amp;E)-stained slides, examining their correlation with disease-free survival (DFS) and overall survival (OS). Methods: In this study, 68 cases of breast cancer with axillary lymph node metastasis at the time of resection were selected from a total of 3,902 resections conducted between 2002 and 2016. We then developed an AI-based model to detect the epithelium and lymphocytes (CD3/CD20) from H&amp;E-stained slides. This model was trained using annotated datasets, which included 26,509 images of the epithelium and 12,273 images of lymphocytes. The tumor bed areas were precisely defined by pathologists. Subsequently, the AI model identified epithelial and lymphocyte regions within these predefined areas. The TILs score was then calculated as the ratio of the lymphocyte area to the total stromal area within the tumor bed, excluding the epithelial areas identified by the AI model. Finally, we assessed the prognostic significance of the TILs score for DFS and OS through ROC analysis and log-rank tests. Results: ROC analysis identified an optimal TILs score threshold of 0.0042 for both DFS and OS, with an AUC of 0.743 (95% CI, 0.622-0.864) for DFS and 0.686 (95% CI, 0.559-0.812) for OS. This threshold significantly stratified patients into groups with distinct DFS and OS outcomes (P=0.003 and P=0.008, respectively). Conclusions: AI quantification of TILs offers a promising prognostic tool in triple-negative breast cancer, enhancing the objectivity and clinical utility of pathological analyses. Accurate TILs measurement could revolutionize prognostication and treatment planning.

Neoadjuvant treatment with camrelizumab in combination with doxorubicin and ifosfamide: A phase II clinical study of high-risk soft tissue sarcoma.

e23548 Background: Surgery remains the cornerstone in the management of non-metastatic soft tissue sarcomas. However, high rate of recurrence and metastasis are not uncommon in patients(pts) with high-risk soft tissue sarcoma. Although doxorubicin plus ifosfamide resulted in better tumor shrinkage which facilitate surgical resection, approaches of reducing recurrence and metastasis are still needed. Chemotherapy combined with PD-1 antibodies showed promising activity in several tumors. To date, there is no study to evaluate the efficacy and safety of camrelizumab combined with chemotherapy for high-risk Soft Tissue Sarcoma. Methods: This is a phase II, open-label single-arm study (NCT04606108), aimed to include pts aged 14-65 with histopathologically confirmed high risk soft tissue sarcoma and ECOG 0-1, at least one measurable lesion. One course of treatment every three weeks (camrelizumab 200 mg on day 1, doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2, and ifosfamide 3 g/m2 on days 1-3). After completing the 2nd course of chemotherapy, the drug will be stopped for 14 days, and surgery or the next stage of treatment will be carried out according to the efficacy of the treatment. Six courses of preoperative chemotherapy will be administered 2 weeks ± 5 days after surgery based on the effectiveness, followed by radiotherapy (50 Gy in 25 fractions or 60 Gy in 30 fractions.) within 3 months after surgery. The primary objective is the Objective response rate (ORR). Using the Simon minimax 2 stage design, planned sample size is 62 pts with 80% power and alpha of 5% to detect an increase in ORR from 27% to 42%. Interim analysis requiring at least 9 confirmed responses in the first 30 pts to proceed to full accrual. Results: 35 pts completed neoadjuvant therapy and surgery, 30 pts received postoperative adjuvant therapy and 1 patient achieved partial response (PR). Median age was 36.4 years (14-61), 62.8% were females, and 57.1% were ECOG-PS 0. Surgery was performed in 35 pts including 16/35 Synovial Sarcoma (SS), 5/35 Liposarcoma (LPS), 2/35 Myxofibrosarcoma (MFS), 2/35 Undifferentiated pleomorphic sarcoma (UPS), 1/35 Leiomyosarcoma (LMS), 5/35 Malignant mesenchymal tumors and 4/35 other pathologic subtype. The 2-year PFS rate was 84.9%, the 2-year OS rate was 96.77%, and the 2-year RFS rate was 72.6%. The most common grade 3-4 adverse events included leukopenia (37.7%), Neutrophil count decreased (37.7%), Platelet count decreased (20.0%), Blennisthmia (3.1%), and Aspartate aminotransferase increased (0.8%). Conclusions: Camrelizumab combined with doxorubicin, liposomal doxorubicin, and ifosfamide in the perioperative treatment of soft tissue sarcoma pts were safe and tolerable. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of pts with soft tissue sarcoma. Clinical trial information: NCT04606108 .