Lymph Node Metastasis Research Articles

Prognostic factors and preoperative therapy in resectable intrahepatic cholangiocarcinoma

To identify prognostic factors and role of preoperative therapy for resectable intrahepatic cholangiocarcinoma (IHCC). We analyzed the results of surgical and combined treatment of IHCC between 1999 and 2023. Immediate and long-term outcomes were evaluated depending on negative prognostic factors and additional therapy. The study included 195 patients. Postoperative complications grade ≥III were observed in 35 (17.9%) case. Mortality rate was 3.1% (n=6). Thirty-eight patients (19.5%) underwent treatment before surgery, 109 (55.9%) ones - after surgery. The median overall survival was 31 months, 5-year overall survival - 32.0%. The following factors worsened overall survival: node size ≥8 cm (HR 1.45; 95% CI 0.97-2.17), invasion (HR 1.63; 95% CI 1.07-2.47), multiple lesion (HR 1.51; 95% CI 1.00-2.28). R1 resection worsened disease-free survival (HR 1.88; 95% CI 1.14-3.10). Lymph node metastases decreased overall (HR 1.96; 95% CI 1.27- 3.04) and disease-free survival (HR 2.37; 95% CI 1.63-3.44). Two and more negative factors worsened overall (p=0.0013) and disease-free survival (p=0.0005). Absence of adjuvant therapy worsened overall (HR 2.12; 95% CI 1.41-3.20) and disease-free survival (HR 1.42; 95% CI 0.99-2.04). There was a trend towards higher overall (p=0.088) and progression-free survival (p=0.029) in case of preoperative therapy (n=195). In unfavorable prognosis group, preoperative therapy (n=33) was superior to standard treatment (resection+capecitabine after surgery, n=26). There was a trend towards higher overall survival (p=0.066) and significantly better progression-free survival (17 vs 13 months, p=0.018). Negative prognostic factors for resectable IHCC are lesion size ≥8 cm, intrahepatic and regional metastases, invasion into neighboring structures, R1 resection. Combination of negative factors worsened prognosis. Adjuvant therapy improved postoperative outcomes. Preoperative therapy may be advisable in case of negative factors and high risk of R1 resection.

Predictive value of enhanced CT and pathological indicators in lymph node metastasis in patients with gastric cancer based on GEE model

ObjectivesA predictive model was developed based on enhanced computed tomography (CT), laboratory test results, and pathological indicators to achieve the convenient and effective prediction of single lymph node metastasis (LNM) in gastric cancer.MethodsSixty-six consecutive patients (235 regional lymph nodes) with pathologically confirmed gastric cancer who underwent surgery at our hospital between December 2020 and November 2021 were retrospectively reviewed. They were randomly allocated to training (n = 38, number of lymph nodes = 119) and validation (n = 28, number of lymph nodes = 116) datasets. The clinical data, laboratory test results, enhanced CT characteristics, and pathological indicators from gastroscopy-guided needle biopsies were obtained. Multivariable logistic regression with generalised estimation equations (GEEs) was used to develop a predictive model for LNM in gastric cancer. The predictive performance of the model developed using the training and validation datasets was validated using receiver operating characteristic curves.ResultsLymph node enhancement pattern, Ki67 level, and lymph node long-axis diameter were independent predictors of LNM in gastric cancer (p < 0.01). The GEE-logistic model was associated with LNM (p = 0.001). The area under the curve and accuracy of the model, with 95% confidence intervals, were 0.944 (0.890–0.998) and 0.897 (0.813–0.952), respectively, in the training dataset and 0.836 (0.751–0.921) and 0.798 (0.699–0.876), respectively, in the validation dataset.ConclusionThe predictive model constructed based on lymph node enhancement pattern, Ki67 level, and lymph node long-axis diameter exhibited good performance in predicting LNM in gastric cancer and should aid the lymph node staging of gastric cancer and clinical decision-making.

FDG PET/CT in 2 Cases of Primary Urothelial Carcinoma of the Prostate.

Primary prostatic urothelial carcinoma is a very rare aggressive tumor with poor prognosis. We describe FDG PET/CT findings in 2 patients with primary prostatic urothelial carcinoma. In 1 patient, FDG PET/CT showed intense activity of the prostate tumor with extraprostatic invasion. In the other patient, FDG PET/CT showed heterogeneous intense activity of the primary tumor and multiple hypermetabolic metastases in the regional lymph nodes, bone, and lung. Both patients had normal serum total prostate-specific antigen levels. These cases highlight the usefulness of FDG PET/CT in detecting and staging of primary prostatic urothelial carcinoma due to high FDG avidity.

Overuse of imaging in prostate cancer staging.

To examine prostate cancer staging in real-world clinical practice. We retrospectively analyzed 698 patients referred to the Department of Urology at Kagawa University Hospital from 25 facilities for prostate cancer treatment from June 2014 to December 2023. Patients treated with dutasteride (n = 10) and who underwent staging at our institution (n = 197) were excluded. The outcomes of interest were the proportion of computed tomography and bone scintigraphy, diagnostic rates of metastasis stratified by D'Amico risk, and incidental findings on computed tomography. We estimated the number of low-risk patients based on the Japan Study Group of Prostate Cancer study and 2019 cancer statistical data. We calculated the staging costs of omitting computed tomography and bone scintigraphy in low-risk patients. The proportion of D'Amico low-, intermediate-, and high-risk patients was 15.7% (n = 77), 45.2% (n = 222), and 39.1% (n = 192), respectively. The percentages of computed tomography and bone scintigraphy performed according to risk were 88.3% and 67.5% for low risk, 98.6% and 80.2% for intermediate risk, and 98.4% and 94.3% for high risk, respectively. The diagnostic percentages for lymph node, organ, and bone metastases by risk were 0%/0%/0%, 0%/0%/0.5%, and 8.9%/0.5%/9.3% for low-, intermediate-, and high-risk, respectively. Incidental findings were present in 2.7% of cases. By omitting computed tomography and bone scintigraphy for low-risk patients, the total staging cost could be reduced by USD 4.07 million (607 million Japanese yen) annually. We highlight the potential overuse of imaging in prostate cancer staging. Recognizing the excessive use of diagnostic imaging can reduce medical costs.

Role of 18F-PSMA-1007 PET/CT-derived quantitative volumetric tumor parameters in cytoreductive radical prostatectomy selection for patients with low-volume metastatic hormone-sensitive prostate cancer: a retrospective study

BackgroundCytoreductive radical prostatectomy (cRP) has emerged as a promising therapeutic approach for low-volume metastatic hormone-sensitive prostate cancer (mHSPC), but the best candidates for cRP are still unknown. This study aims to explore the potential value of 18F-PSMA-1007 PET/CT-derived quantitative volumetric tumor parameters in cRP treatment selection among patients with low-volume mHSPC.MethodsA total of 122 patients with primary low-volume mHSPC who underwent 18F-PSMA-1007 PET/CT followed by systemic therapy alone or plus cRP were included. The whole-body PSMA-derived tumor volume (PSMA-TV) was defined as the total volume of whole-body PSMA-avid tumor lesions, and prostate PSMA-TV was defined as the volume of prostate PSMA-avid tumor lesions. Spearman’s correlation was used to analyze the relationships between whole-body PSMA-TV and clinicopathological characteristics. The primary endpoint was progression-free survival (PFS), and Cox regression analyses were performed to explore the independent predictors for PFS.ResultsAmong 122 patients, 37 (30.32%) underwent systemic therapy plus cRP. The median and optimal cutoff values of the whole-body PSMA-TV were 71.68 cm3 (41.28–157.41 cm3) and 78.57 cm3, respectively. Whole-body PSMA-TV was positively correlated with prostate-specific antigen (PSA), and patients with nonregional lymph node (NRLN) metastases had a greater whole-body PSMA-TV (P = 0.001). Cox regression analyses revealed that cRP, lower whole-body PSMA-TV and the absence of NRLN metastases were associated with better PFS (all P < 0.05). Subgroup analyses revealed that patients with a low whole-body PSMA or no NRLN metastases had a significant improvement in PFS for cRP versus no cRP (HR: 8.26; 95% CI: 2.72–25.06, P = 0.001; HR: 2.71; 95% CI: 1.25–5.93, P = 0.018). Moreover, among patients with higher prostate PSMA-TV and prostate PSMA-TV/whole-body PSMA-TV, cRP also significantly prolonged PFS compared with those without cRP (HR: 3.49; 95% CI: 1.49–8.18, P = 0.004; HR: 8.54; 95% CI: 2.47–29.50, P = 0.013).ConclusionIn management of primary low-volume mHSPC, whole-body and prostate PSMA-TV evaluations based on 18F-PSMA-1007 PET/CT could be helpful to identify the most suitable candidates for cRP.Trial registrationRetrospectively registered.

Gasless single-incision transaxillary endoscopic total thyroidectomy versus conventional open thyroidectomy in patients with papillary thyroid carcinoma based on propensity score matching: a case-control study.

In a previous study, we proposed a modified technique for gasless transaxillary endoscopic total thyroidectomy (ETT) for patients with bilateral papillary thyroid carcinoma (PTC) using a single incision. Whether this method shows non-inferiority to the conventional open approach (COT) remains unclear. This study aims to investigate the safety and feasibility of ETT compared to COT in patients with PTC. We retrospectively analyzed the medical records of cT1-2 PTC patients who underwent total thyroidectomy between April 2020 and December 2022. All patients were diagnosed with bilateral PTC and categorized into ETT and COT groups based on the type of surgery. Propensity score matching (PSM) using nine clinicopathological characteristics was employed to compare the technical safety and short-term oncologic outcomes of ETT and COT, generating 45 pairs of matched patients to reduce potential selection bias. This study was followed by STROBE guideline. After PSM, 90 patients who underwent ETT (n = 45) or COT (n = 45) were included. Age, sex, tumor size, BMI, Hashimoto's thyroiditis, multifocality, extrathyroidal extension, T-stage, and central compartment lymph node metastasis were not different between both groups. Both groups showed similar surgical outcomes, including lymph node yield, complications, and total medical costs. A few patients in each group experienced transient complications, all of which resolved within 6months. No patients had permanent complications. Compared to COT, ETT with a modified technique offers excellent safety and acceptable short-term oncological outcomes in a selected cohort of patients with bilateral papillary thyroid carcinoma. ETT is a safe and feasible alternative to COT.

Distribution of lymph node metastasis and prognosis in duodenal bulb tumors: A multicenter retrospective study.

797 Background: Duodenal tumors, especially duodenal bulb tumors, is a relatively rare malignancy of the gastrointestinal tract. The optimal surgical procedure for primary duodenal tumors has not been established because of its low incidence. The purpose of this study was to examine the distribution of lymph node (LN) metastasis in duodenal bulb tumors. Specifically, in T1a and T1b tumors, we aimed to evaluate the feasibility of distal gastrectomy with duodenal bulb resection combined with lymphadenectomy of regional gastric LNs. Methods: Data from patients who underwent surgery for either adenocarcinoma or neuroendocrine tumor located in the duodenal bulb between 2000 and 2020 were retrospectively analyzed from five high-volume centers in Japan. Patient background, clinicopathological factors, type of surgery, distribution of LN metastasis, and long-term outcomes were evaluated. Results: Of the 128 patients evaluated, LN metastasis was observed in 36%. The frequency of LN metastasis in T1b was 18%. Metastatic LNs were identified in #3, #5, #6, #8a, #8p, #12a, and #13 in T1b. The distribution of LN metastasis in T1b was similar between adenocarcinoma and neuroendocrine tumors. The 3 years overall survival rate in T1a, T1b, and T2–4 was 100%, 93%, and 64%, respectively. ln T1b, while there were three patients with a recurrence, two cases were observed in distant organs without regional LNs, and one patient who underwent pancreaticoduodenectomy had metastasis in the gastric regional LNs. Conclusions: Based on the distribution of LN metastasis with pT1, distal gastrectomy with duodenal bulb resection and regional LN dissection is considered a curative treatment. Conversely, pancreaticoduodenectomy is recommended in tumors with T2 or deeper.

A liquid biopsy analysis of exosomal miRNA to detect lymph node metastasis in early gastric cancer.

469 Background: Additional surgical resection is required to achieve a complete cure in patients with early gastric cancer (EGC) due to the potential risk for lymph node metastasis (LNM) after pathological analysis. However, LNM is estimated to occur in approximately 10% of patients with high-risk EGC. In this study, we investigated a blood-based liquid biopsy assay of exosomal miRNA for the noninvasive detection of LNM in patients with high-risk EGC. Methods: Two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA) were analyzed to prioritize biomarkers in pretreatment plasma samples from clinical training and validation cohorts of GC patients. An integrated exosomal miRNA panel was developed and a risk stratification model combining the miRNA panel with clinical risk factors was established. Results: Using comprehensive expression profiling of public datasets, we identified a transcriptomic panel of four miRNAs (miR-34b, miR-130a, miR-375, and miR-627) that robustly identified patients with LNM [area under the curve (AUC) = 0.86, 95% confidence interval (CI) = 0.77-0.92]. We assessed panel performance in a training cohort (AUC=0.86, 95% CI=0.67-0.96) and validated it in an independent validation cohort (AUC=0.84, 95% CI=0.64-0.95). Our risk stratification model was more accurate than the panel and was an independent predictor of LNM identification (AUC=0.97). Conclusions: A novel noninvasive, liquid biopsy-based method for patients with EGC may predict those traditionally classified as high-risk patients with LNM who are unlikely to benefit from surgical resection.

SOX/FOLFOX+nivolumab followed by conversion surgery for HER2 negative primary gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors: Early results of a consecutive 41 cases.

487 Background: Gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors could be cured by conversion surgery after primary chemotherapy. Because SOX/FOLFOX plus Nivolumab showed high clinical response regardless of CPS score, this nivolumab-based chemotherapy followed by surgery may be promising strategy for these tumors. Methods: The study examined the patients who had HER2 negative primary gastric or gastroesophageal junction cancer with synchronous oligo-metastasis or borderline resectable tumors. Oligo-metastasis was defined as peritoneal dissemination localized to the upper abdomen, para-aortic lymph node metastasis, liver metastasis limited up to 3 segments, mediastinal lymph node metastasis, ovarian metastasis, or esophageal intramural metastasis. Borderline resectable tumors were defined as regional lymph node metastasis forming bulky mass or primary tumors invading adjacent organs. The patients with these tumors were treated with primary chemotherapy with SOX/FOLFOX plus Nivolumab for 3 to 22 months, then were proceeded to conversion surgery in case the tumors are responded to chemotherapy and are considered to achieve R0 resection based on the MDT conference. Results: During November 2021 and February 2024, 41 consecutive patients were included in the study. Disease status was peritoneal dissemination in 1, para-aortic lymph node metastasis in 26, liver metastasis in 5, mediastinal lymph node metastasis in 1, ovarian metastasis in 1, esophageal intramural metastasis in 2, bulky nodal metastasis in 6, and primary tumors invading pancreas in 1 (distant oligo-metastasis in 34 patients and borderline resectable in 7). CPS score was &gt;5 in 13, 5&gt; and &gt;1 in 23, and &gt;1 in 5 patients. Chemotherapy regimen was SOX+Nivo in 38 and FOLFOX+Nivo in 3. Of 41 patients, 33 (80.5%) (SOX+Nivo: 30, FOLFOX+Nivo: 3) were proceeded to the conversion surgery, and 32 patients achieved R0 resection. 6 patients showed disease progression and 2 patients were judged as unresectable. Major pathological response (disappearance more than 80% of the primary tumor) rate was 54.5% (18/33) and pCR rate was 33.3% (11/33). Conclusions: SOX/FOLFOX plus Nivolumab for HER2 negative gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors achieved a high R0-conversion surgery rate and pathological response rate.

Surgical treatment results for oligo-recurrence of gastric cancer.

462 Background: Despite advancements in diverse treatments, approximately 40-50% of advance gastric cancer patients experience recurrence even after curative resection surgery. The condition where there is a limited recurrence after the control of the primary tumor site is referred to as oligo-recurrence. However, there is scarce reporting on oligo-recurrence after gastric cancer surgery. This study compiled cases of patients who underwent surgery for recurrent gastric cancer after R0 surgery. Since there are no specific treatment guidelines for recurrence after gastric cancer surgery, this research could be beneficial in providing insights and assistance. Methods: This retrospective study includes data from 25 patients who underwent surgery for suspected oligo-recurrence of gastric cancer among those who had undergone surgery from June 2008 to May 2018. If a solitary mass suspected of recurrence is identified during surveillance, a PET-CT is performed. Patients with suspicion of peritoneal dissemination, carefully excluded through a multidisciplinary approach, are selectively omitted. All patients undergo excision surgery for both treatment and tissue examination purposes. Results: Out of 25 cases, there were 6 cases of paraaortic lymph node enlargement, 9 cases liver nodules, 8 case lung nodules, and 1 case tumor bed mass. In the postoperative tissue analysis, 4 cases of paraaortic lymph node enlargement, 5 cases of the liver nodules, and 1case tumor bed mass were confirmed to be recurrences of gastric cancer. All of lung nodule were diagnosed with lung cancer. All 10 cases underwent chemotherapy after metastatectomy. Among them, 3 cases experienced recurrence and died an average of 12.3 months after surgery. Seven cases did not experience recurrence and have survived with an average survival time of 102 months to date. Conclusions: The metastatectomy is safe and effective for patients with oligo-recurrence from GC and can improve their prognosis. For an accurate diagnosis, oligometastectomy is essential. However, our results need to be confirmed by more randomized controlled clinical studies. Treatment result after metastatectomy. Case Diagnosis Chemotherapy aftermetastatectomy Recurence after metastatectomy DFS after metastatectomy OS after metastatectomy OS after gastrectomy Status 1 LN metastasis 1/1 15cycles FOLFOX 147 147 156.4 ALIVE 2 LN metastasis 1/1 37cycles TAS-118 liver metastasis 22 40.6 74.9 DEATH 3 LN metastasis 1/3 12cycles FOLFOX 98.1 98.1 125.5 ALIVE 4 LN metastasis 1/1 35cycles FOLFOX 50.9 50.9 71.3 ALIVE 5 Liver metastasis ONO tiral Liver, bone mets. 3.73 27.9 64.6 DEATH 6 Liver metastasis 12cycles FOLFOX 68.3 68.3 122.2 ALIVE 7 Liver metastasis 12cycles FOLFOX 96 96 105.8 ALIVE 8 Liver metastasis 82cycles FOLFOX 55 55 77.4 ALIVE 9 Liver metastasis 12cycles FOLFOX 94.4 94.4 103.9 ALIVE 10 Tumor bed 12cycles FOLFOX 9 25.5 24.4 DEATH

Diagnosis of lymph node metastasis in oral squamous cell carcinoma by an MRI-based deep learning model.

Cervical lymph node metastasis (LNM) is a well-established poor prognosticator of oral squamous cell carcinoma (OSCC), in which occult metastasis is a subtype that makes prediction challenging. Here, we developed and validated a deep learning (DL) model using magnetic resonance imaging (MRI) for the identification of LNM in OSCC patients. This retrospective diagnostic study developed a three-stage DL model by 45,664 preoperative MRI images from 723 patients in 10 Chinese hospitals between January 2015 and October 2020. It was comprehensively processed from training (8:2), multicenter external validation to reader study. The performance of the DL model was accessed and compared with general and specialized radiologists. LNM was found in 36.51% of all patients, and the occult metastasis rate was 16.45%. The three-stage DL model together with a random forest classifier achieved the performance in identification of LNM with areas under curve (AUC) of 0.97 (0.93-0.99) in training cohort and AUC of 0.81 (0.74-0.86) in external validation cohorts. The models can reduce the occult metastasis rate up to 89.50% and add more benefit in guiding neck dissection in cN0 patients. DL models tied or exceeded average performance relative to both general and specialized radiologists. Our three-stage DL model based on MRI with three-dimensional sequences was beneficial in detecting LNM and reducing the occult metastasis rate of OSCC patients.

Short- and long-term outcomes of conversion surgery for initially unresectable advanced gastric cancer: A Japanese multicenter retrospective cohort study.

402 Background: The efficacy of conversion surgery in patients with unresectable advanced gastric cancer at the initial diagnosis who converted to be resectable due to remarkable response to chemotherapy is unclear. To evaluate short- and long-term outcomes of conversion surgery for initially unresectable cStage IVB/pStage IV gastric cancer as the basic data for the JCOG2301 trial, which is a randomized controlled trial comparing conversion surgery with continuation of chemotherapy, a multicenter retrospective cohort study was conducted in the Stomach Cancer Study Group of the Japan Clinical Oncology Group. Methods: Inclusion criteria were as follows; (1)gastric cancer with at least one of following distant metastasis at the initial diagnosis; (i) peritoneal metastasis (PER) diagnosed by imaging examination or P1b or P1c disease diagnosed by laparoscopy or laparotomy, (ii) multiple liver metastasis (HEP) more than three lesions, and (iii) distant lymph node metastasis (LYM) beyond paraaortic lymph node station 16a2/b1, (2) conversion to be resectable after systemic chemotherapy, (3) surgery aiming at an R0 resection of the primary and remaining lesions between April 2010 and September 2017. Clinical data were retrospectively obtained from electronic patient records of 58 institutions. Results: Atotal of 241 patients were included to the study. Initial unresectable factors were PER, HEP, and LYM in 132(55%), 37(15%), and 63(26%) patients, respectively, and 9(4%) patients had two or more factors. Conversion to be resectable obtained during the first and second/later line chemotherapy was in 209 (87%) patients and 32 (13%), respectively. 182(76%), 29(12%), and 30(12%) patients underwent R0, R1, and R2 resection, respectively. The incidence of postoperative complication of Clavien-Dindo Grade II or higher was 24% and no surgery-related death was observed. The median overall survival (mOS) from surgery was 45.4 (95%CI 30.9-61.4) months in R0 resection, 16.6 (11.5-18.5) months in R1, and 20.9 (11.3-35.6) months in R2. In case of R0 resection, the mOS from surgery was 34.4 (95%CI 26.5-59.2) months in PER, 55.9 (21.8-96.7) months in HEP, 54.6 (30.9-98.3) months in LYM, and not reached (19.7-NA) in two or more factors. Conclusions: Conversion surgery appears to be safe and a promising treatment strategy for patients who have initially unresectable advanced gastric cancer and presented remarkable response to systemic chemotherapy.

Negative Impact of Low Serum Cholinesterase on Short- and Long-term Outcomes in Elderly Patients Undergoing Scheduled Surgery for Colorectal Cancer.

Cholinesterase (ChE) is important for estimating nutritional status and can be easily measured. This study aimed to investigate the effect of ChE on the short- and long-term prognoses of elderly patients with colorectal cancer. This study included 120 elderly patients who underwent scheduled surgery for colorectal cancer. ChE is a biomarker that can be easily measured using blood tests. The optimal cut-off level of ChE was determined using receiver operating characteristic analysis. We investigated the relationship of ChE with disease-free and overall survival using univariate and multivariate analyses. Seventy-two (60%) patients had low ChE levels (<255 U/l). In the multivariate analysis, low ChE (p=0.04) was an independent and significant predictor of postoperative complications. Low ChE (p=0.049), low prognostic nutritional index (p=0.04), and lymph node metastasis (p<0.01) were independent and significant prognostic predictors of poor disease-free survival. American Society of Anesthesiologists Physical Status 3 (p<0.01), low ChE (p<0.01), and lymph node metastasis (p<0.01) were independent and significant predictors of poor overall survival. ChE level is a significant predictor of short- and long-term outcomes in elderly patients undergoing scheduled surgery for colorectal cancer.

A phase II study of fruquintinib plus sintilimab as a second-line therapy for advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): Updated results.

407 Background: Preliminary results of the open-label, single-arm phase II study (NCT05625737) had demonstrated the combination of fruquintinib and sintilimab as a second-line therapy had a promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC (ASCO-GI 2024. Poster 332). Here, we update the results with a focus on subgroup analyses. Methods: Patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard treatment were enrolled. Eligible pts received 4mg of fruquintinib orally once daily on days 1-14 and 200 mg of sintilimab intravenously on day 1, with treatment repeated every 3 weeks. An optimal Simon two-stage design was employed. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cut-off (August 25, 2024), 29 pts (7 in the first stage; 22 in the second stage) with median age 51 (range 33–73) years old had been enrolled. 41.4% were male, 37.9% had ECOG PS 1, 69% had lymph node metastasis and 72.4% had previously received immunotherapy. Among the 24 efficacy evaluable pts, the ORR was 33.3% (95% CI 15.6–55.3) and DCR was 66.7% (95% CI 44.7–84.4). After a median follow-up of 13.14 months, the median PFS was 5.13 (95% CI: 2.73–7.03) months and OS result was pending maturity. Pts who had lymph node metastasis exhibited higher ORR compared to pts without lymph node metastasis (ORR-47.1 vs 0%). In particular, pts without prior immunotherapies were more likely to achieve higher response rate (37.5 vs 33.3%) and had an obvious trend for longer PFS than pts with prior immunotherapies (9.00 vs 5.13 months). Majority of treatment-emergent adverse events (TEAEs) were grade 1-2 and the most frequently reported ones (≥20%) were white blood cell decreased (33%), hypertriglyceridemia (25%), lymphocyte count decreased (21%), abdominal pain (21%) and decreased appetite (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation. Conclusions: Fruquintinib combined sintilimab was well tolerated, with encouraging antitumor activity as second-line treatment for advanced GC/GEJC, especially in pts without prior immunotherapies. Further studies in larger cohorts to validate these findings are warranted. Clinical trial information: NCT05625737 .

The impact of type 2 diabetes on melanoma stage (TNM) at the time of diagnosis and its association with sex: A Danish nationwide study.

Cancer has become the leading cause of death among individuals with type 2 diabetes (T2D) in high-income countries. T2D is suggested to directly influence cancer progression. However, the association between T2D and melanoma stage at diagnosis remains uncertain, as well as any potential sex disparities. To investigate the association between T2D and the melanoma TNM stage (Breslow thickness, ulceration status, lymph node metastases, and distant metastases) at the time of diagnosis and to assess whether the association is affected by sex. A nationwide cross-sectional study was conducted, including all patients diagnosed with melanoma between 2004 and 2022 identified in the Danish Cancer Register. T2D status was ascertained using a validated register based algorithm. The association between T2D and melanoma stage was estimated using univariable and multivariable logistic regression analyses adjusted for sex, age, comorbidity, and year of diagnosis. The study included 30,315 individuals with melanoma. The multivariable analyses showed that T2D was associated with an increased adjust odds ratio (aOR) of tumour thickness > 4 mm (aOR 1.30, 95 %CI: [1.10-1.52]), the presence of ulceration (aOR: 1.25, 95 % CI: [1.09-1.43]), lymph node metastases (aOR 1.27 [1.10-1.47]), and distant metastases (aOR: 1.26 [1.01-1.56]). Furthermore, sex stratified analyses showed that T2D was associated with distant metastases in women, but not in men. Individuals with T2D were more likely to be diagnosed with advanced stages of local, regional, and distant melanoma. This highlights the need for greater melanoma awareness and further research into treatment responses in individuals with T2D.

VEGFA Gene Expression in Breast Cancer Is Associated With Worse Prognosis, but Better Response to Chemotherapy and Immunotherapy.

Vascular endothelial growth factor-A (VEGFA) is a key inducer of angiogenesis, responsible for generating new blood vessels in the tumor microenvironment (TME) and facilitating metastasis. Notably, Avastin, which targets VEGFA, failed to demonstrate any significant benefit in clinical trials for breast cancer (BC). This study aimed to investigate the clinical relevance of VEGFA gene expression in BC. A total of 7,336 BC patients across eight independent cohorts: ISPY2 (GSE173839), Sweden Cancerome Analysis Network-Breast (SCAN-B) (GSE96058), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE25066, GSE163882, GSE34138, GSE20194, and The Cancer Genome Atlas (TCGA), were analyzed. The calculated median VEGFA expression level was used to stratify these cohorts into high and low groups. High VEGFA was associated with worse disease-free, disease-specific, and overall survival in the METABRIC cohort, with findings supported by the SCAN-B cohort, which also showed worse overall survival (all P < 0.02). High VEGFA expression was seen in triple-negative breast cancer (TNBC) but not in BC with lymph node metastasis. Additionally, there was a significant correlation between high VEGFA expression and higher silent and non-silent mutations, single-nucleotide variant (SNV) neoantigens, homologous recombination defect, intratumoral heterogeneity, in the TCGA cohort. In the TCGA, METABRIC, and SCAN-B cohorts, high VEGFA BC was also associated with higher cell proliferation: higher Ki67 gene expression, higher Nottingham histological grade, and consistent enrichment of all the Hallmark cell proliferation-related gene sets. Unexpectedly, the angiogenesis gene set was not enriched in any of the cohorts and showed no association with infiltrations of lymphatic or blood vascular endothelial cells besides pericytes. High VEGFA BC had significantly less infiltration of anti-cancer immune cells but higher infiltration of pro-cancer immune cells in TCGA, METABRIC, and SCAN-B cohorts. Interestingly, BC, which had a pathological complete response (pCR) after anthracycline- and taxane-based neoadjuvant therapy, was associated with significantly heightened VEGFA expression in both estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- and TNBC subtypes in the GSE25066 cohort and after immunotherapy in ER+/ HER2- subtype, but not TNBC in the ISPY2 cohort. Our research indicates that high VEGFA BC confers high cell proliferation, reduced immune cell infiltration, and poorer survival, but allows better response to anthracycline- and taxane-based chemotherapy, and immunotherapy.

Safety and efficacy of perioperative chemotherapy combined with PD-1 inhibitor versus chemotherapy with D2 gastrectomy plus PAND in gastric cancer with PALD metastasis: A single-center retrospective cohort study.

368 Background: Gastric cancer with para-aortic lymph node (PALD) metastasis is associated with a poor prognosis. When the metastasis is limited to the PALD, preoperative systemic therapy combined with D2 gastrectomy plus para-aortic lymph node dissection (PAND) may enhance survival. The benefit of perioperative chemotherapy combined with immune checkpoint inhibitors for these patients is unknown. Methods: A total of 133 patients with gastric cancer and limited No.16a2/b1 lymph node metastasis underwent perioperative systemic therapy combined with D2 gastrectomy plus PAND. Patients receiving chemotherapy combined with a PD-1 inhibitor were assigned to Group A (n=62), while those receiving chemotherapy alone were assigned to Group B (n=71). Pathological response, safety, efficacy, and survival outcomes were compared between the two groups. Results: Adverse events occurred at comparable rates between the two groups. No treatment-related deaths occurred in either group. In Group A, all patients (100%) achieved R0 resection, compared to 70 patients (98.6%) in Group B. Group A showed significantly better pathological outcomes than Group B, with higher rates of pathological complete response (pCR) (37.1% vs. 4.2%, P &lt; 0.001), and major pathological response (MPR) (58.1% vs. 22.5%, P &lt; 0.001). Group A showed a higher 2-year overall survival (OS) rate compared to Group B (90.3% vs. 62.9%, P = 0.011). The median overall survival (mOS) in Group B was 35.0 months, while follow-up data for Group A are currently insufficient to assess mOS. Conclusions: The addition of a PD-1 inhibitor to chemotherapy significantly improves the pathological response rate and prognosis in gastric cancer patients with PALD. Notably, the combination did not increase adverse events. These findings suggest that combining PD-1 inhibitor with chemotherapy could be a promising strategy for improving outcomes in this patient population, though further prospective studies are necessary to confirm long-term survival benefits. Postoperative outcomes and pathological response. Variable Group A (n=62) % Group A (n=71) % P Value Vascular tumor embolus 0.005 Negative 43 69.4% 32 45.1% Positive 19 30.6% 39 54.9% Nerve infiltration 0.004 Negative 44 71.0% 33 46.5% Positive 18 29.0% 38 53.5% No.16a2/b1 0.057 Negative 53 85.5% 51 71.8% Positive 9 14.5% 20 28.2% Tumor resection 0.970 Distal 26 41.9% 30 42.3% Total 36 58.1% 41 57.7% Serum CEA (U/mL） 0.805 Normal 56 90.3% 65 91.5% &gt;5 6 9.7% 6 8.5% Serum CA125 (U/mL) 0.280 Normal 30 48.4% 41 57.7% &gt;35 32 51.6% 30 42.3% Serum CA199 (U/mL) 0.783 Normal 56 90.3% 65 91.5% &gt;37 6 9.7% 6 8.5% pT-stage &lt;0.001 ≤T2 37 59.7% 19 26.8% ＞T2 25 40.3% 52 73.2% pN-stage 0.001 N0/1 42 67.7% 27 38.0% N2/3 20 32.3% 44 62.0% TRG ＜0.001 0 23 37.1% 3 4.2% 1 13 21.0% 13 18.3% 2 22 35.5% 47 66.2% 3 4 6.5% 8 11.3% pCR 23 37.1% 3 4.2% ＜0.001 MPR 36 58.1% 16 22.5% ＜0.001

Impact of combined resection of pancreas on long-term survival in patients with gastric cancer.

359 Background: In patients with advanced gastric cancer invading adjacent organs, extended multivisceral resection is required to achieve R0 resection. However, the survival benefit of combined resection of pancreas remains controversial. We investigated the safety and efficacy of combined pancreatic resection in gastric cancer. Methods: This study included 64 patients who underwent gastrectomy with pancreatectomy (pancreaticoduodenectomy (PD) or distal pancreatectomy with splenectomy (PS)) for primary gastric cancer with invasion to the pancreas by primary tumor or lymph node metastasis and invasion to the duodenum. Patients who underwent R2 resection were excluded. Short- and long-term outcomes were assessed. Results: PD was performed in 18 patients (28.1%) and PS in 46 patients (71.9%). Macroscopic invasion to the pancreas by primary tumor was observed in 47 patients (73.4%), by lymph node in 13 patients (20.3%), and the invasion to the duodenum by primary lesion was in 4 patients (6.3%). Pathologically, pancreatic invasion was confirmed in 27 out of 47 patients (57.4%). Postoperative intra-abdominal infectious complications (PIIC) of Clavien-Dindo (CD) Grade III or higher were observed in 33 patients (51.6%). The most common postoperative complication was pancreatic fistula, which was observed in 31 patients (48.4%). There was no mortality within 30 days after surgery. Univariate analysis revealed that invasion the duodenum was highly associated with PIIC (p=0.038). Twelve patients (18%) resulted in R1 resection due to positive peritoneal cytology in 11 patients and positive surgical margin in one patient. The 5-year overall survival (OS) rate was 42.9%, which was 53.6% in R0 resection and 0% in R1 resection. Multivariate analysis revealed R1 resection was an independent prognostic factor for OS (HR:5.315, p&lt;0.001). The 5-year recurrence-free survival (RFS) rate was 44.5%. The 5-year RFS rate was significantly worse in patients with PIIC (28.7%) than in patients without it (58.7%). Multivariate analysis revealed that PIIC was an independent prognostic factor for RFS (HR:2.345, p=0.036). Conclusions: Pancreatic resection for gastric cancer is considered safe and effective when R0 resection is possible. However, surgeon should pay particular attention to avoid the postoperative complications.

The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.

Safety and efficacy of conversion therapy for metastatic esophageal cancer: Exploratory analysis of JCOG1314.

401 Background: Patients with esophageal cancer (EC) with distant metastasis were treated with systemic chemotherapy. Recent advances in multimodal treatments have made conversion therapy (CT) a viable option for patients with metastatic EC. JCOG1314 was a randomized phase III trial to confirm the survival benefit of docetaxel plus cisplatin plus 5-fluorouracil (DCF) versus cisplatin plus 5-fluorouracil (CF) as initial treatment for unresectable or recurrent esophageal cancer. The purpose of this study was to evaluate the safety and survival impact of CT in patients enrolled in JCOG1314. Methods: CT was defined as surgery or chemoradiotherapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to distant metastasis. Clinicopathologic factors, surgical outcomes, toxicities during CRT, and survival were compared between CT and non-CT groups. CTCAE v4.0-JCOG was used to evaluate postoperative complications and adverse events during CRT. Results: Between September 2014 and April 2021, 240 patients were randomized to CF or DCF. Excluding patients with recurrent disease, 154 patients with initially unresectable esophageal cancer due to distant metastasis were selected for this study. Among them, 21 patients received CT which included conversion surgery (n=5) and conversion CRT (n=16). There was no significant difference in the number of metastatic organs, depth of invasion of the primary tumor, lymph node metastasis, and chemotherapy regiment between CT and non-CT groups. The most common M1 factor in CT group was the thoracic lymph node, followed by abdominal lymph node and cervical node. In conversion surgery group, there was no incidence of Grade 3 or higher pneumonia/leakage. Regarding the Grade 3 or higher non-hematological toxicities during conversion CRT, the incidence of appetite loss/ oral mucositis/pneumonia was 2 (13%)/2 (13%)/1 (6%), respectively. The 3-year overall survival (OS) of CT and non-CT groups was 52.4% and 14.3%, respectively. On multivariable analysis, patients with CT showed significantly better OS compared with the non-CT group (HR 0.36, 95% CI 0.19-0.67, p&lt;0.01). In patients who underwent CT, there was no significant difference in OS between conversion surgery and CRT groups. Conclusions: This study demonstrated that CT was safely performed with favorable prognosis. A prospective study is warranted to investigate whether CT would improve survival in metastatic esophageal cancer.