Investigation of Antiproliferative Effects of Combinations of White and Black Garlic Extracts with 5-Fluorouracil (5-FU) on Caco-2 Colorectal Adenocarcinoma Cells.

Garlic is rich in bioactive compounds that are effective against colon cancer cells. This study tests the antioxidant and antiproliferative effects of cold-extracted white and black garlic extracts. Black garlic extracted in water (SSU) exhibits the highest antioxidant activity, phenolic content, and flavonoid content, while black garlic extracted in ethanol (SET) shows the lowest values. Caspase-3 activity is notably higher in the white garlic extracted in methanol (BME), white garlic extracted in methanol combines with 5-FU, black garlic extracted in ethanol (SET), black garlic extracted in ethanol combines with 5-fluorouracil (5-FU), and 5-FU treatments compare to the control group (p > 0.05). BME+5-FU displays the highest caspase-8 activity (p < 0.05). A decrease in NF-κB levels is observed in the SET+5-FU group (p>0.05), while COX-2 activities decrease in the BME, SET+5-FU, SET, and 5-FU groups (p>0.05). Wound healing increases in the BME, BME+5-FU, SET+5-FU, and 5-FU groups (p < 0.05). In conclusion, aqueous black garlic extract may exhibit pro-oxidant activity despite its high antioxidant capacity. It is worth noting that exposure to heat-treated food and increased sugar content may lead to heightened inflammation and adverse health effects. This study is the first to combine garlic with chemo-preventive drugs like 5-FU in Caco-2 cells.

Induction of autophagy-dependent and caspase- and microtubule-acetylation-independent cell death by phytochemical-stabilized gold nanopolygons in colorectal adenocarcinoma cells.

Collective functionalization of the phytochemicals of medicinal herbs on nanoparticles is emerging as a potential cancer therapeutic strategy. This study presents the facile synthesis of surface-functionalized gold nanoparticles using Bacopa monnieri (Brahmi; Bm) phytochemicals and their therapeutically relevant mechanism of action in the colorectal cancer cell line, HT29. The nanoparticles were characterized using UV-visible spectroscopy, TEM-EDAX, zeta potential analysis, TGA, FTIR and 1H NMR spectroscopy, and HR-LC-MS. The particles (Bm-GNPs) were of polygonal shape and were stable against aggregation. They entered the target cells and inhibited the viability and clonogenicity of the cells with eight times more antiproliferative efficacy (25 ± 1.5 µg mL-1) than Bm extract (Bm-EX). In vitro studies revealed that Bm-GNPs bind tubulin (a protein crucial in cell division and a target of anticancer drugs) and disrupt its helical structure without grossly altering its tertiary conformation. Like other antitubulin agents, Bm-GNPs induced G2/M arrest and ultimately killed the cells, as confirmed using flow cytometry analyses. ZVAD-FMK-mediated global pan-caspase inhibition and the apparent absence of cleaved caspase-3 in treated cells indicated that the death did not involve the classic apoptosis pathway. Cellular ultrastructure analyses, western immunoblots, and in situ immunofluorescence visualization of cellular microtubules revealed microtubule-acetylation-independent induction of autophagy as the facilitator of cell death. Together, the data indicate strong antiproliferative efficacy and a possible mechanism of action for these designer nanoparticles. Bm-GNPs, therefore, merit further investigations, including preclinical evaluations, for their therapeutic potential as inducers of non-apoptotic cell death.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Appendiceal adenocarcinoma, diagnosed after acute perforated appendicitis: Potential contribution of HIPEC.

INTRODUCTION: Treatment of peritoneal metastasis from appendicular adenocarcinoma consists of cyto-reductive surgery (CRS) and Hyperthermic IntraPEritoneal Chemotherapy (HIPEC). In case of acute appendicular syndrome (AAS) the tumor is likely to be perforated. In that case, there is no treatment recommendation. We propose CRS and HIPEC. MATERIALS AND METHOD: We listed 21 consecutive patients who were addressed for discovery of appendiceal adenocarcinoma. The emergency surgery was performed in a primary-care hospital. We evaluated the therapeutic algorithms, per operative decision, survival and recurrent rate. RESULTS: Among the 21 patients, 4 patients were diagnosed as synchronous appendicular peritoneal metastasis, and underwent CRS and HIPEC. The other 17 patients with diagnosis of adenocarcinoma on anatomopathological samples, without peritoneal metastasis during appendectomy, were addressed. Between them 2 patients were denied CRS. Among the 15 operated patients, 8 patients had no peritoneal metastasis discovery during surgery, and therefore underwent prophylactic CRS and HIPEC. Peritoneal metastasis were discovered for the other 7 patients, who also underwent CRS and HIPEC. For the prophylactic group, the recurrence rate is 12,5 %, overall survival (OS) is 100 %. The rate of grade III-IV surgical complications after CRS and HIPEC was 36 % among the 19 patients who underwent surgery. CONCLUSION: In case of appendectomy in emergency situations for perforated adenocarcinoma, half of the patients may have peritoneal metastasis. In case of non-identified peritoneal metastasis during CRS, performing a prophylactic HIPEC seems to be associated with an encouraging rate of peritoneal disease free situation at 5 years.

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial.

BACKGROUND: Upfront surgery followed by postoperative treatment is a commonly adopted treatment for resectable pancreatic ductal adenocarcinoma (rPDAC). However, the risk of positive surgical margins, the poor recovery that often impairs postoperative treatments, and the risk of recurrence might limit the outcome of this strategy. This study evaluated the safety and the activity of liposomal irinotecan 50 mg/m2 + 5-fluorouracil 2400 mg/m2 + leucovorin 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX) in the perioperative treatment of patients with rPDAC. METHODS: Eligible patients had a rPDAC with < 180° interface with major veins' wall. Patients received 3 cycles before and 3 cycles after resection with NALIRIFOX, days 1 and 15 of a 28-day cycle. The primary endpoint was the proportion of patients undergoing an R0 resection. RESULTS: 107 patients began preoperative treatment. Nine patients discontinued the treatment because of related or unrelated adverse events. Disease-control rate was 92.9%. 87 patients underwent surgical exploration, 11 had intraoperative evidence of metastatic disease, and 1 died for surgical complications. R0 resection rate was 65.3%. 49 patients completed the three postoperative cycles. The most common grade ≥ 3 adverse events were diarrhea and neutropenia. Median overall survival (OS) of ITT patients was 32.3 months (95% CI 27.8-44.3). Median disease-free and OS from surgery of resected patients were 19.3 (95% CI 12.6-34.1) and 40.3 months (95% CI 29-NA), respectively. CONCLUSION: Perioperative NALIRIFOX was manageable and active, and deserves further investigation in randomized trials comparing it with standard upfront surgery followed by adjuvant therapy.

Anal Adenocarcinoma Treated in the Era of Total Neoadjuvant Therapy and Nonoperative Management.

BACKGROUND: Anal adenocarcinoma bears a treatment strategy unique to other anal cancers. OBJECTIVE: This study aimed to describe oncologic outcomes of total neoadjuvant therapy followed by watch-and-wait approach for anal adenocarcinoma. DESIGN: Retrospective analysis. SETTINGS: This study was conducted at a comprehensive cancer center. PATIENTS: Patients with anal adenocarcinoma treated between 2004 and 2019 were selected. INTERVENTIONS: Fifty-four patients received neoadjuvant therapy and were divided into 2 groups according to their treatment strategy: total neoadjuvant therapy versus single neoadjuvant modality therapy. MAIN OUTCOME MEASURES: Organ preservation, tumor regrowth, local failure, distant metastasis rates, recurrence-free survival, and overall survival. RESULTS: This study included 70 patients with anal adenocarcinoma. Fifty-four patients (77%) received neoadjuvant therapy, of whom 30 (42%) received total neoadjuvant therapy and 24 (34%) received single neoadjuvant modality. Twenty-three (33%) patients achieved complete clinical response and were managed by watch-and-wait approach. The proportion of patients able to continue to watch-and-wait approach was higher after receiving total neoadjuvant therapy (60%) compared with single neoadjuvant modality therapy (20%; p = 0.004). A tumor regrowth rate of 22% was observed in the total neoadjuvant therapy group. The 5-year overall survival rate was 70% (95% CI, 59%-83%), including 61% (95% CI, 42%-88%) for the total neoadjuvant therapy and 65% (95% CI, 48%-88%) for the single neoadjuvant modality groups. Colostomy was avoided in 50% of patients who received total neoadjuvant therapy and 83% of watch-and-wait patients. Five-year recurrence-free survival rates of 55% (95% CI, 39%-79%) and 30% (95% CI, 15%-58%) were observed in the total neoadjuvant therapy and single neoadjuvant modality groups. LIMITATIONS: Retrospective nature. CONCLUSIONS: This is the first report in the literature describing the safety and feasibility of nonoperative management for anal adenocarcinoma. Anal adenocarcinoma treated with total neoadjuvant therapy and nonoperative management achieve regrowth rates comparable to those observed in rectal cancer, with oncologic outcomes similar to those of traditional treatment strategies. See Video Abstract . ADENOCARCINOMA ANAL TRATADO EN LA ERA DE LA TERAPIA NEOADYUVANTE TOTAL Y EL TRATAMIENTO NO QUIRRGICO: ANTECEDENTES:El adenocarcinoma anal conlleva una estrategia de tratamiento único para otros cánceres anales.OBJETIVO:Describir los resultados oncológicos de la terapia neoadyuvante total seguida de observar y esperar en adenocarcinoma anal.DISEÑO:Análisis retrospectivo.AJUSTE:Este estudio se llevó a cabo en un centro oncológico integral.PACIENTES:Se seleccionaron pacientes con adenocarcinoma anal tratados entre 2004-2019.INTERVENCIONES:Cincuenta y cuatro pacientes recibieron terapia neoadyuvante y se dividieron en dos grupos según su estrategia de tratamiento: terapia neoadyuvante total versus terapia de modalidad neoadyuvante única.PRINCIPALES MEDIDAS DE RESULTADO:Preservación de órganos, recurrencia tumoral, falla local, tasas de metástasis a distancia, libre de recurrencia y supervivencia general.RESULTADOS:El estudio incluyó a 70 pacientes con adenocarcinoma anal. Cincuenta y cuatro pacientes (77%) recibieron terapia neoadyuvante, de los cuales 30 (42%) recibieron terapia neoadyuvante total y 24 (34%) recibieron modalidad neoadyuvante única. Veintitrés (33%) pacientes presentaron una respuesta clínica completa y fueron tratados con vigilancia y espera. La proporción de pacientes capaces de continuar en observar y esperar fue mayor después de recibir terapia neoadyuvante total (60%) en comparación con la terapia de modalidad neoadyuvante única (20%) ( p = 0,004). Se observó una tasa de recurrencia tumoral del 22% en el grupo de terapia neoadyuvante total. La tasa de supervivencia general a 5 años fue del 70% (IC95% 59%-83 %), incluido el 61% (IC95% 42%-88%) para la terapia neoadyuvante total y el 65% (IC95% 48%-88%) para grupos de modalidad neoadyuvante única. Se evitó la colostomía en el 50% de los pacientes que recibieron terapia neoadyuvante total y el 83% de los pacientes en observar y esperar. Se observaron tasas de supervivencia libre de recurrencia a cinco años del 55% (IC95% 39%-79%) y del 30% (IC95% 15%-58%) en los grupos de terapia neoadyuvante total y modalidad neoadyuvante única, respectivamente.LIMITACIONES:Diseño retrospectivo.CONCLUSIONES:Este es el primer informe en la literatura que describe la seguridad y viabilidad del tratamiento no quirúrgico del adenocarcinoma anal. El adenocarcinoma anal tratado con terapia neoadyuvante total y manejo no quirúrgico logra tasas de recurrencia comparables a las observadas en el cáncer de recto, con resultados oncológicos similares a las estrategias de tratamientos tradicionales. (Traducción-Dr. Fidel Ruiz Healy ).

Identification of Comprehensive Biomarkers in Patients With Mismatch Repair-Deficient Colon Adenocarcinoma Based on Parallel Multiomics.

Immunocheckpoint inhibitors have shown impressive efficacy in patients with colon cancer and other types of solid tumor that are mismatch repair-deficient (dMMR). Currently, PCR-capillary electrophoresis is one of the mainstream detection methods for dMMR, but its accuracy is still limited by germline mismatch repair (MMR) mutations, the functional redundancy of the MMR system, and abnormal methylation of MutL Homolog 1 promoter. Therefore, this study aimed to develop new biomarkers for dMMR based on artificial intelligence (AI) and pathologic images, which may help to improve the detection accuracy. To screen for the differential expression genes (DEGs) in dMMR patients and validate their diagnostic and prognostic efficiency, we used the expression profile data from the Cancer Genome Atlas (TCGA). The results showed that the expression of Immunoglobulin Lambda Joining 3 in dMMR patients was significantly downregulated and negatively correlated with the prognosis. Meanwhile, our diagnostic models based on pathologic image features showed good performance with area under the curves (AUCs) of 0.73, 0.86, and 0.81 in the training, test, and external validation sets (Jiangsu Traditional Chinese Medicine Hospital cohort). Based on gene expression and pathologic characteristics, we developed an effective prognosis model for dMMR patients through multiple Cox regression analysis (with AUC values of 0.88, 0.89, and 0.88 at 1-, 3-, and 5-year intervals, respectively). In conclusion, our results showed that Immunoglobulin Lambda Joining 3 and nucleus shape-related parameters (such as nuclear texture, nuclear eccentricity, nuclear size, and nuclear pixel intensity) were independent diagnostic and prognostic factors, suggesting that they could be used as new biomarkers for dMMR patients.

Transanal minimally invasive surgery for benign and malignant rectal lesions: midterm outcomes from a tertiary center.

BACKGROUND: Although transanal minimally invasive surgery (TAMIS) for rectal neoplasia has gained wide acceptance, the mid-term and long-term outcomes are not widely reported in the literature. OBJECTIVE: Describe the mid-term outcomes of patients who underwent TAMIS for benign and malignant rectal lesions in a single center. DESIGN: Retrospective cohort study. SETTINGS: Tertiary referral center. PATIENTS AND METHODS: Demographic, clinical, and oncological outcomes of patients who underwent TAMIS between January 2015 and December 2022 were prospectively collected. The indication for TAMIS was based on the National Comprehensive Cancer Network guidelines. The follow up for the cancer patients included clinical examination, tumor markers every 6 months and MRI rectum at the end of one year. In addition, colonoscopy and CT scan at years one and three and a final CT scan and colonoscopy at year five. MAIN OUTCOME MEASURES: Mid-term oncological and clinical outcome. RESULTS: Thirty elective TAMIS procedures included adenocarcinoma for 33.3% (n=10) of the patients, 20% (n=6) neuroendocrine tumor and the 40% (n=12) were adenomatous lesions. Negative resection margins were achieved in all malignant lesions. Perioperative complications occurred in 2 patients (6.6%), one patient had breaching into the peritoneal cavity, and postoperative hypotension occurred in another patient. The median follow-up time was 23 months (range: 5-72 months). Two patients with adenoma and positive margins developed recurrent adenoma (6.6%) and one patient with initial polypectomy biopsy of adenocarcinoma, had TAMIS with histopathology of adenoma and distant metastasis had developed. CONCLUSIONS: TAMIS for local excision of rectal neoplasia is a valid option with favorable mid-term outcomes provided there is adherence to careful selection criteria. LIMITATIONS: Retrospective nature and small number of the patients.

In stage IV pulmonary adenocarcinoma patients, treatment with Traditional Chinese Medicine alone gives prognostically superior results to treatment with Platinum-Based Chemotherapy alone.

BACKGROUND: About 30% of pulmonary stage IV adenocarcinomas die within 3 months of diagnosis. Western medical treatments with Platinum-Based Chemotherapy=PBC and tyrosine-kinase inhibitors Targeted Therapy=TT can improve prognosis. In China, Traditional Chinese Medicine herbal treatments (TCM) are often used in addition to PBC and TT. A considerable number of patients refuse Western medical treatments and use TCM alone. However, the survival impact of the latter is unknown. HYPOTHESES TESTED: Treatment with TCM alone is prognostically superior to PBC alone. Addition of PBC or TT or both TT to TCM improves survival. METHODS: In this prospective observational, non-interventional study of 1017 consecutive first-onset stage IV NSCLC patients with up to 10 years follow-up, 261 who Died of Disease (DOD) within 3 months were omitted, as they never got the optimal Western medical therapies. All 218 non-adenocarcinomas were also omitted, leaving 538 stage IV adenocarcinomas treated by TCM alone (n = 29), PBC alone (N = 19) and TCM and other Western medical combinations (299 TCM and PBC, 50 TCM and TT, 141 TCM and PBC and TT) with 3 - 120 months follow-up. Survivals were compared using Alive with Disease (AWD) and DOD as endpoints. RESULTS: The patients treated only with TCM had 7 months better median survival than those that received PBC alone (17 and 10 months). The patients that received TCM and PBC had a better median survival (24 months) than TCM alone and much better than PBC alone. None of the patients that received TCM alone survived > 54 months, whereas 18% of TCM and PBC patients survived much longer. Over the observation period of 3 - 120 months, survivals of TCM and TT, TCM and PBC and TT, and TCM and PBC were not different and therefore grouped as TCM and Western medicines. Median survival times of PBC alone and TCM alone were lower than that of TCM and Western medical treatments (p < 0.0001, 10, 17 and 27 months). CONCLUSIONS: Pulmonary stage IV adenocarcinoma patients with at least 3 months survival, treated with TCM alone have a significantly better survival than those treated with PBC alone. Adding Western PBC, TT or both to TCM further improves prognosis.

Local hyperthermia with built-in endoscopy for radioresistant cervical cancer: a case series.

We evaluated the efficacy and safety of an endoscope-embedded transvaginal laser hyperthermia system for superficial cervical cancer that remained in the cervix after radiotherapy. We developed an innovative endoscope-embedded hyperthermia system consisting of a diode laser device, a temperature control unit, an endoscope control unit, and a transvaginal probe. Superficial lesions of recurrent or residual cervical cancer on the uterine cervix or vaginal wall after radiotherapy were eligible for this study. A total of four cases of three patients were eligible for this treatment. Case 1: The post-chemoradiotherapy residual tumor of a patient with stage IIB squamous cell carcinoma of the cervix was treated with the device. Two months after the laser hyperthermia treatment, the tumor's disappearance was confirmed. Case 2: A post-hysterectomy persistent tumor on the vaginal stump of a patient with stage IIB adenocarcinoma of the cervix was subjected to the laser hyperthermia treatment. Two months after the treatment, the stump's cytology was false positive. Case 3: As in case 2, this patient's recurrence in the anterior vaginal wall was subjected to laser hyperthermia treatment, but the tumor's growth was not controlled. Case 4: A tumor at the vaginal margin was identified during a salvage hysterectomy in a patient with stage IIB squamous cell carcinoma of the cervix who underwent chemoradiotherapy. After laser hyperthermia treatment, the tumor's disappearance was confirmed. Our new endoscope-embedded laser hyperthermia system can be a candidate for treating residual superficial cervical cancer after radiotherapy by accurately capturing superficial lesions.

Diagnostic Accuracy of CT-Guided Percutaneous Pulmonary Biopsy for Distinguishing Benign and Malignant Solitary Pulmonary Nodules.

Background: Isolated pulmonary nodules (SPNs) are small, circular lesions within lung tissue, often challenging to diagnose due to their size and lack of typical imaging features. Timely diagnosis is crucial for treatment decisions. However, the difficulty in qualitative diagnosis necessitates clinical biopsies. Objective: This study aimed to assess the diagnostic accuracy of CT-guided percutaneous lung biopsy for SPNs and identify potential risk factors for malignancy. Methods: We conducted a retrospective analysis of 112 patients with SPNs who underwent CT-guided core needle biopsy (CT-CNB) between June 2020 and June 2022. Histological and cytological results were obtained for all patients, and clinical data and imaging characteristics were compared between benign and malignant SPN groups. Binary logistic regression was used to analyze risk factors for malignancy, and complications were observed. Results: Cytological and histological specimens were successfully obtained for all patients. The cohort consisted of 43 patients with benign SPNs and 69 with malignant SPNs. Among the malignant SPN group, 67 cases were confirmed via CT-CNB and 2 through surgery, resulting in a sensitivity of 97.10% and specificity of 100.00%. The malignant nodules comprised 45 adenocarcinomas, 14 squamous cell carcinomas, 8 metastatic tumors, and 2 small cell carcinomas. Notably, 2 initially diagnosed as malignant cases were found to have chronic inflammation on preoperative biopsy but revealed adenocarcinoma and squamous cell carcinoma post-surgery. The benign nodules encompassed 20 granulomatous inflammation cases, 15 chronic inflammation, 3 fungal granulomas, 2 hamartomas, and 1 fibrous tissue. Cytological smears exhibited a sensitivity of 81.3% and a specificity of 100.0% for malignancy. Significantly, age ≥60, elevated tumor markers, and specific imaging signs (burr, foliation, pleural pull) were identified as risk factors for malignant SPNs using Binary Logistic regression (all P < .05). Conclusions: CT-guided percutaneous lung biopsy demonstrates excellent diagnostic efficacy and safety for distinguishing benign and malignant SPNs.

Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy.

BACKGROUND: This prospective cohort study evaluated the feasibility of using endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples for comprehensive mutational analysis of cancer-related genes using microtissues. METHODS: Fifty patients with suspected pancreatic cancer presenting consecutively at the Kindai University Hospital between January 2018 and January 2019 were enrolled. Cancerous tissues from EUS-FNB were obtained from each tumor and subjected to histological examination and mutational analysis. The primary endpoint was the collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing. Clinical history and genetic variations between the disease control and progressive disease groups of patients on chemotherapy were evaluated as secondary endpoints. RESULTS: The collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing was 93.6%. The cancer panel was sequenced for 25 patients with pancreatic cancer treated initially with systemic chemotherapy. Mutation in p53 and Smad4 were positively and negatively associated, respectively, with disease control at the initial evaluation. The median time to progression in 15 patients with p53 and without Smad4 mutations was 182.0 days; whereas, it was 92.5 days in other 10 patients; this difference was significant (p = 0.020). CONCLUSIONS: Tissue samples from EUS-FNB were suitable for mutational analysis. Pancreatic cancers with p53 and without Smad4 mutations responded better to chemotherapy and had a better prognosis than those others.

Retrospective Analysis of Diagnosis and Treatment of Gastric Cancer at Huzhou Central Hospital.

Objective: To explore the results of lymph node metastasis in patients with gastric cancer in a real-world setting. Methods: Patients (n = 272) who underwent radical gastrectomy with lymph node dissection for gastric cancer from November 2017 to August 2019 at Huzhou Central Hospital, China. The main outcome was the lymph node metastasis rate. The chi-square test was used to compare categorical variables. Binary logistic regression analysis was used to examine the relationship between risk factors and lymph node metastasis in gastric cancer and early gastric cancer. In multivariate analysis, OR and 95% CI were calculated to evaluate the risk. Statistical significance was defined as P < .05. Statistical analysis was performed using SPSS software version 26.0 (SPSS Inc.) and GraphPad PRISM 9.0. Results: Among the 272 patients who underwent surgery, 143 (52.6%) had lymph node metastasis. The proportion of female patients was higher in those under 40 years of age. The incidence of gastric cancer was highest in the lesser curvature of the gastric antrum. The lymph node metastasis rates were 5.3%, 25%, 39%, 78.1%, and 76.8% for invasion to the mucosal layer, submucosal layer, muscular layer, serosal layer, and beyond the serosal layer, respectively. There was a statistically significant difference in lymph node metastasis between invasion to the mucosal layer and the other four layers (P < .05), while there was no statistically significant difference between invasion to the submucosal and muscular layers (P > .05) and between invasion to the serosal layer and beyond (P > .05). Well-differentiated gastric cancer had almost no lymph node metastasis (0%), while moderately differentiated gastric cancer had a lower rate of lymph node metastasis (32%), and there was no statistically significant difference between the two. The lymph node metastasis rates were higher for poorly differentiated adenocarcinoma (66.7%), mucinous adenocarcinoma (63.6%), and signet ring cell carcinoma (57.1%), and there was no statistically significant difference between the three. Conclusion: Lymph node metastasis in gastric cancer is related to the depth of invasion and pathological subtype, and is not related to age, sex, or tumor location.

Neoplasms of the Appendix.

BACKGROUND: Neoplasms of the vermiform appendix are rare. They comprise a heterogeneous group of entities requiring differentkinds of treatment. METHODS: This review is based on publications retrieved by a selective literature search in the PubMed, Embase, and Cochranedatabases. RESULTS: 0.5% of all tumors of the gastrointestinal tract arise in the appendix. Their treatment depends on their histopathologicalclassification and tumor stage. The mucosal epithelium gives rise to adenomas, sessile serrated lesions, adenocarcinomas,goblet-cell adenocarcinomas, and mucinous neoplasms. Neuroendocrine neoplasms originate in neuroectodermal tissue. Adenomasof the appendix can usually be definitively treated by appendectomy. Mucinous neoplasms, depending on their tumorstage, may require additional cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC). Adeno -carcinomas and goblet-cell adenocarcinomas can metastasize via the lymphatic vessels and the bloodstream and should thereforebe treated by oncological right hemicolectomy. Approximately 80% of neuroendocrine tumors are less than 1 cm in diameterwhen diagnosed and can therefore be adequately treated by appendectomy; right hemicolectomy is recommended if the patienthas risk factors for metastasis via the lymphatic vessels. Systemic chemotherapy has not been shown to be beneficial forappendiceal neoplasms in prospective, randomized trials; it is recommended for adenocarcinomas and goblet-cell adenocarcinomasof stage III or higher, in analogy to the treatment of colorectal carcinoma.

Gastric Cancer Surgery in the US: a Contemporary Trend Analysis of Lymphadenectomy and the Impact of Minimally Invasive Approaches.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend harvesting 16 or more lymph nodes for the adequate staging of gastric adenocarcinoma. This study examines the rate of adequate lymphadenectomy over recent years, its predictors, and its impact on overall survival(OS). STUDY DESIGN: The National Cancer Database was utilized to identify patients who underwent surgical treatment for gastric adenocarcinoma between 2006-2019. Trend analysis was performed for lymphadenectomy rates during the study period. Logistic regression, Kaplan-Meier survival plots, and Cox proportional hazard regression were utilized. RESULTS: A total of 57,039 patients who underwent surgical treatment for gastric adenocarcinoma were identified. Only 50.5% of the patients underwent a lymphadenectomy of ≥ 16 nodes. Trend analysis showed that this rate significantly improved over the years, from 35.1% in 2006 to 63.3% in 2019 (p < .0001). The main independent predictors of adequate lymphadenectomy included high-volume facility with ≥ 31 gastrectomies/year (OR: 2.71; 95%CI:2.46-2.99), surgery between 2015-2019 (OR: 1.68; 95%CI: 1.60-1.75), and preoperative chemotherapy (OR:1.49; 95%CI:1.41-1.58). Patients with adequate lymphadenectomy had better OS than patients who did not: median survival: 59 versus 43 months (Log-Rank: p < .0001). Adequate lymphadenectomy was independently associated with improved OS (HR:0.79; 95%CI:0.77-0.81). Laparoscopic and robotic gastrectomies were independently associated with adequate lymphadenectomy compared to open, OR: 1.11, 95%CI:1.05-1.18 and OR: 1.24, 95%CI:1.13-1.35, respectively. CONCLUSION: Although the rate of adequate lymphadenectomy improved over the study period, a large number of patients still lacked adequate lymph node dissection, negatively impacting their OS despite multimodality therapy. Laparoscopic and robotic surgeries were associated with a significantly higher rate of lymphadenectomy ≥ 16 nodes.

Study of anti-tumorigenic actions of essential fatty acids in a murine mammary gland adenocarcinoma by micro-XRF.

In the present work, a statistical experiment based on the microscopy X-ray fluorescence technique was developed to evaluate the effect of diets rich in ω-3 and ω-6 polyunsaturated fatty acids on tumour tissues. Relative variations on the local content of P, S, Ca, Fe, Cu and Zn were analysed in the experiment. Neoplastic tissues were obtained from mammary gland adenocarcinomas inoculated in mice belonging to three different dietary groups: normal, rich in ω-3 and in ω-6 polyunsaturated fatty acids. Slices of 30 microns thick sections of these samples were scanned in the air atmosphere in areas of 5 mm × 5 mm with a spatial resolution of 50 microns using synchrotron radiation. Principal component analysis was employed to analyse the correlation between the X-ray fluorescence signals of P, S, Ca, Fe, Cu and Zn. The subsequent application of the K-means clustering was used for the automatic segmentation of the image scans. By comparison with conventional histological analysis, the clusters were positively identified as tumour parenchyma, transition and necrotic region. The calculation of the mean content of P, S, Ca, Fe, Cu, and Zn in these regions showed that dietary polyunsaturated fatty acids modify elemental content of tumour parenchyma, suggesting its involvement in the antitumour effects of chia oil and protumour effects of safflower oil.

Post-operative weight loss affects 3-year survival in patients with gastric adenocarcinoma after gastrectomy and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Patients with advanced gastric adenocarcinoma are at high risk of malnutrition. Some patients benefit from total gastrectomy associated with hyperthermic intraperitoneal chemotherapy (HIPEC) with or without cytoreduction surgery (CR) as a curative strategy. The aim of this study was to describe pre- and post-operative nutritional assessments and their impact on survival in these patients. MATERIALS AND METHODS: All patients with advanced gastric adenocarcinoma treated with gastrectomy and HIPEC with or without CR at Lyon University Hospital were retrospectively included from April 2012 to August 2017. Carcinologic data, history of weight, anthropometric measures, nutritional biological markers and CT-scan body composition were collected. RESULTS: 54 patients were included. Malnutrition affected 48.1% before and 64.8% after surgery, and severe malnutrition respectively 11.1% and 20.3%. Pre-operative sarcopenia diagnosed by CT scan was found in 40.7% of the patients while 81.1% of the sarcopenic patients had a normal or high body mass index. A loss of ⩾ 20% of usual weight on discharge was a pejorative factor of survival at 3 years of follow-up (p = 0.0470). Only 14.8% of the patients continued artificial nutrition following discharge but artificial nutrition was resumed in 30.4% of the patients within 4 months after discharge owing to weight loss. CONCLUSIONS: Patients with advanced gastric adenocarcinoma undergoing gastrectomy and HIPEC with or without CR are at high risk of malnutrition. Post-operative weight loss has a pejorative impact on outcome. These patients should be systematically screened for malnutrition with early interventionist nutritional care and close nutritional follow-up.

Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation.

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084-1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103-1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.