The mechanism of cadmium exposure-induced lymph node necroptosis and inflammation in piglets: Activation of CYP450 through VDR / CREB1 pathway.

Cadmium (Cd) is toxic non-essential heavy metal that precipitates adverse health effects in humans and animals, but the effect of Cd on lymph node toxicity of piglets is still unclear. In order to explore the possible molecular mechanism of Cd toxicity to lymph nodes of piglets, ten 6-week-old male weaned piglets were randomly divided into two groups, C group and Cd group. Group C was fed with basal diet, while group Cd was fed with basal diet supplemented with CdCl2 (20 mg/kg) for 40 days, the pigs were euthanized and the mesenteric, inguinal and submandibular lymph nodes (MLN, ILN, SLN) were collected. The results indicated that Cd could induce the inflammatory cell infiltration, microvascular hemorrhage, microthrombosis and cell necrosis in MLN, ILN and SLN of piglets, induced Cytochrome P450 proteins (CYP1A1、CYP2E1、CYP2A1 and CYP3A2) mRNA levels and the protein levels of Vitamin D receptor (VDR) and cAMP response element binding protein 1 (CREB1). In addition, Cd exposure upregulated the mRNA and protein levels of dynamin-related protein 1 (DRP1), receptor-interacting protein kinase 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), and increased tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), interleukin-2 (IL-2), interleukin-4 (IL-4), cyclooxygenase 2 (COX-2) protein levels, and the damage degree of three kinds of lymph nodes was similar after Cd exposure. In general, these results manifest that Cd exposure regulates VDR/CREB1 pathway, activates CYP450s, induces necroptosis of lymph nodes, and leads to inflammation.

The minimum number of examined lymph nodes was 24 for optimal survival of pathological T2-4 gastric cancer: a multi-center, hospital-based study covering 20 years of data.

INTRODUCTION: The current National Comprehensive Cancer Network (NCCN) guidelines recommend that at least 16 lymph nodes should be examined for gastric cancer patients to reduce staging migration. However, there is still debate regarding the optimal management of examined lymph nodes (ELNs) for gastric cancer patients. In this study, we aimed to develop and test the minimum number of ELNs that should be retrieved during gastrectomy for optimal survival in patients with gastric cancer. METHODS: We used the restricted cubic spline (RCS) to identify the optimal threshold of ELNs that should be retrieved during gastrectomy based on the China National Cancer Center Gastric Cancer (NCCGC) database. Northwest cohort, which sourced from the highest gastric cancer incidence areas in China, was used to verify the optimal cutoff value. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: In this study, 12,670 gastrectomy patients were included in the NCCGC cohort and 4941 patients in the Northwest cohort. During 1999-2019, the average number of ELNs increased from 17.88 to 34.45 nodes in the NCCGC cohort, while the number of positive lymph nodes remained stable (5-6 nodes). The RCS model showed a U-curved association between ELNs and the risk of all-cause mortality, and the optimal threshold of ELNs was 24 [Hazard ratio (HR) = 1.00]. The ELN ≥ 24 group had a better overall survival (OS) than the ELN < 24 group clearly (P = 0.003), however, with respect to the threshold of 16 ELNs, there was no significantly difference between the two groups (P = 0.101). In the multivariate analysis, ELN ≥ 24 group was associated with improved survival outcomes in total gastrectomy patients [HR = 0.787, 95% confidence interval (CI): 0.711-0.870, P < 0.001], as well as the subgroup analysis of T2 patients (HR = 0.621, 95%CI: 0.399-0.966, P = 0.035), T3 patients (HR = 0.787, 95%CI: 0.659-0.940, P = 0.008) and T4 patients (HR = 0.775, 95%CI: 0.675-0.888, P < 0.001). CONCLUSION: In conclusion, the minimum number of ELNs for optimal survival of gastric cancer with pathological T2-4 was 24.

The Current Treatment Trends and Survival Patterns in Melanoma Patients with Positive Sentinel Lymph Node Biopsy (SLNB): A Multicenter Nationwide Study.

BACKGROUND: In melanoma treatment, an approach following positive sentinel lymph node biopsy (SLNB) has been recently deescalated from completion lymph node dissection (CLND) to active surveillance based on phase III trials data. In this study, we aim to evaluate treatment strategies in SLNB-positive melanoma patients in real-world practice. METHODS: Five-hundred-fifty-seven melanoma SLNB-positive patients from seven comprehensive cancer centers treated between 2017 and 2021 were included. Kaplan-Meier methods and the Cox Proportional-Hazards Model were used for analysis. RESULTS: The median follow-up was 25 months. Between 2017 and 2021, the percentage of patients undergoing CLND decreased (88-41%), while the use of adjuvant treatment increased (11-51%). The 3-year OS and RFS rates were 77.9% and 59.6%, respectively. Adjuvant therapy prolonged RFS (HR:0.69, p = 0.036)), but CLND did not (HR:1.22, p = 0.272). There were no statistically significant differences in OS for either adjuvant systemic treatment or CLND. Lower progression risk was also found, and time-dependent hazard ratios estimation in patients treated with systemic adjuvant therapy was confirmed (HR:0.20, p = 0.002 for BRAF inhibitors and HR:0.50, p = 0.015 for anti-PD-1 inhibitors). CONCLUSIONS: Treatment of SLNB-positive melanoma patients is constantly evolving, and the role of surgery is currently rather limited. Whether CLND has been performed or not, in a group of SLNB-positive patients, adjuvant systemic treatment should be offered to all eligible patients.

Prognostic indicators for colorectal peritoneal metastases are different for patients with complete versus incomplete cytoreductive surgery.

BACKGROUND: In the management of peritoneal metastases in patients with colorectal cancer, the completeness of cytoreduction has consistently been the most prominent prognostic indicator. Other clinical and histologic features have been described that may also have an impact on survival. METHODS: The colorectal peritoneal metastases patients treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy were divided into two groups. One group had complete CRS and the second group had an incomplete CRS. The prognostic variables in these two groups of patients were statistically analyzed for their impact on survival. RESULTS: In the complete CRS group of 124 patients lymph node positivity, poorly differentiated histopathology, asymptomatic status following treatment with systemic chemotherapy, incomplete response to systemic chemotherapy, and moderate to high peritoneal cancer index showed a significantly reduced survival. All five of these prognostic variables ceased to show statistical significance in the group of 82 patients with incomplete cytoreduction. CONCLUSION: The cause for significance of five prognostic indicators identified in patients with complete cytoreduction versus loss of significance of these indicators in patients with incomplete cytoreduction has not been determined. An absence of residual disease in complete CRS patients and a widely variable extent of residual disease in incomplete CRS patients may be important. Prognostic indicators in patients with colorectal peritoneal metastases find their greatest usefulness in patients who have had a complete cytoreduction.

Deep epigastric lymph nodes implication in patients' recurrence pattern after cytoreductive surgery in ovarian peritoneal metastases.

INTRODUCTION: Although complete cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) offers a good prognosis in patients with peritoneal metastasis of ovarian cancer (PMOC), recurrences are quite common. These recurrences can be intra-abdominal or systemic in nature. Our objective was to study and illustrate the global recurrence pattern in patients operated for PMOC, shedding light on a previously overlooked lymphatic basin at the level of the epigastric artery, the deep epigastric lymph nodes (DELN) basin. PATIENTS AND METHODS: This was a retrospective study including patients with PMOC who underwent surgery with curative-intent, from 2012 until 2018, at our cancer center, and who presented with any type of disease recurrence on follow-up. CT-scans, MRIs and PET-scans were reviewed in order to determine solid organs and lymph nodes (LN) recurrences. RESULTS: During the study period, 208 patients underwent CRS ± HIPEC, 115 (55.3%) presented with organ or lymphatic recurrence over a median follow-up of 81 months. Sixty percent of these patients had radiologically enlarged LN involvement. The pelvis/pelvic peritoneum was the most common intra-abdominal organ recurrence site (47%), while the retroperitoneal LN was the most common lymphatic recurrence site (73.9%). Previously overlooked DELN were found in 12 patients, with 17.4% implication in lymphatic basin recurrence patterns. CONCLUSION: Our study revealed the potential role of the DELN basin, previously overlooked in the systemic dissemination process of PMOC. This study sheds light on a previously unrecognized lymphatic pathway, as an intermediate checkpoint or relay, between the peritoneum, an intra-abdominal organ, and the extra-abdominal compartment.

A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Discussion on the necessity of bilateral inguinal lymphatic area irradiation for cervical cancer with invasion of the lower one-third of the vagina.

Context: According to the National Comprehensive Cancer Network guidelines for cervical cancer, patients with cervical cancer invading the lower one-third of the vagina require bilateral inguinal lymphatic area preventive irradiation. However, it is not clear whether they need preventive inguinal area irradiation. Aims: The aim of this study is to evaluate the necessity of bilateral inguinal lymphatic area irradiation for patients with cervical cancer with invasion of the lower one-third of the vagina. Settings and Design: Patients without inguinal lymph node metastasis were divided into preventive radiotherapy and nonpreventive radiotherapy groups. The occurrence of inguinal skin damage, lower extremity edema, and femoral head necrosis was observed during and after treatment. Methods and Material: In total, 184 patients with cervical cancer with invasion of the lower one-third of the vagina were selected. A trial and control method was used to select 180 patients without inguinal lymph node metastasis. Statistical Analysis: Comparison between groups was performed using a t test. Data were enumerated using frequency (percentage), and comparison between groups was performed using a Chi-square test. Results: Imaging examination revealed inguinal lymph node enlargement in 7.07% of patients, and only four cases (2.17%) were further confirmed by pathology. The inguinal lymph node metastasis rate in these patients was very low. The prophylactic irradiation group showed a high occurrence rate of side injury. In the follow-up of both groups, no recurrence was detected in the inguinal lymph nodes. Conclusions: Prophylactic irradiation of inguinal lymph nodes is not essential for patients without pathological metastasis.

Accuracy of sentinel node mapping in patients with biopsy-proven metastatic axillary lymph nodes and upfront surgery: preliminary results of the Multimodal Targeted Axillary Surgery (MUTAS) trial.

Background: Some studies suggested that the patients included in the Z0011 trial may represent patients with ultrasound-negative axillary nodes and axillary invasion diagnosed by sentinel node (SN) biopsy. Nevertheless, the National Comprehensive Cancer Network (NCCN) guidelines recommend SN mapping if 1 or 2 suspicious lymph nodes are identified on axillary ultrasound (AU). The aim of this preliminary phase of the Multimodal Targeted Axillary Surgery (MUTAS) trial was to establish the accuracy of SN mapping in patients with axillary involvement undergoing upfront surgery. Methods: Between September 2019 and March 2022, we recruited patients with biopsy-proven metastatic axillary nodes and upfront surgery from a single center. We performed SN mapping in these patients before the surgical intervention, which included axillary lymph node dissection. The biopsy-proven metastatic node, SNs and the remaining axillary nodes were excised separately. SN status was considered representative of the status of the remaining axillary nodes. We calculated the sensitivity, specificity, negative predictive value and positive predictive value of the SN, overall and in patients with palpable nodes, in those with non-palpable nodes and an AU leading to diagnosis of axillary involvement, in those with 1 or 2 suspicious nodes on AU, and in patients with a single suspicious node on AU. We evaluated clinical, imaging and pathology features as predictors of the status of the remaining axillary nodes, false-negatives, and false-positives. Results: We included 25 patients in this phase. The false-negative rate of SN mapping was 28% overall, 21.42% for patients with palpable nodes, 36.36% for patients with non-palpable nodes and an AU diagnosis of axillary involvement, 28.75% for those with 1 or 2 suspicious nodes on AU, and 15.38% in patients with a single suspicious node on AU. The negative predictive value was highest in patients with a single suspicious node on AU (75%). The only significant predictive factor was that FN showed a higher Ki67 index score. Conclusions: In this study, SN mapping was not reliable in patients with biopsy-proven metastatic axillary nodes and upfront surgery for any of the subgroups studied. Further research should elucidate the best staging pathways in these patients to avoid premature de-escalation.

Survival Outcome of Gastric Signet Ring Cell Carcinoma Based on the Optimal Number of Examined Lymph Nodes: A Nomogram- and Machine-Learning-Based Approach.

The optimal number of examined lymph nodes (ELNs) for gastric signet ring cell carcinoma recommended by National Comprehensive Cancer Network guidelines remains unclear. This study aimed to determine the optimal number of ELNs and investigate its prognostic significance. In this study, we included 1723 patients diagnosed with gastric signet ring cell carcinoma in the Surveillance, Epidemiology, and End Results database. X-tile software was used to calculate the cutoff value of ELNs, and the optimal number of ELNs was found to be 32 for adequate nodal staging. In addition, we performed propensity score matching (PSM) analysis to compare the 1-, 3-, and 5-year survival rates; 1-, 3-, and 5-year survival rates for total examined lymph nodes (ELNs < 32 vs. ELNs ≥ 32) were 71.7% vs. 80.1% (p = 0.008), 41.8% vs. 51.2% (p = 0.009), and 27% vs. 30.2% (p = 0.032), respectively. Furthermore, a predictive model based on 32 ELNs was developed and displayed as a nomogram. The model showed good predictive ability performance, and machine learning validated the importance of the optimal number of ELNs in predicting prognosis.

Application value of psTg combined with lymph node ratio in prognosis of papillary thyroid cancer patients treated with 131I / 中华核医学与分子影像杂志

Objective:To explore the value of pre-ablation stimulated thyroglobulin (psTg) before 131I treatment combined with lymph node ratio (LNR) in predicting 131I treatment response in patients with papillary thyroid cancer (PTC). Methods:From January 2016 to December 2018, 178 PTC patients (47 males, 131 females; age (43.2±12.6) years) treated with 131I in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. According to 131I treatment response, patients were divided into excellent response (ER) group and non-ER group. The clinical data of the two groups were compared by χ2 test, independent-sample t test and Mann-Whitney U test. The cut-off values and AUCs of psTg and LNR to predict treatment response were calculated according to the ROC curve. Factors affecting 131I treatment response were analyzed by logistic multivariate regression analysis. Results:There were 118 patients (66.3%, 118/178) in ER group and 60 patients (33.7%, 60/178) in non-ER group, and there were significant differences in N stage ( χ2=11.15, P=0.004), 131I treatment dose ( χ2=12.65, P<0.001), American Thyroid Association (ATA) initial risk stratification ( χ2=15.25, P<0.001), number of metastatic lymph nodes ( χ2=22.63, P<0.001), LNR ( U=1 506.00, P<0.001) and psTg ( U=919.00, P<0.001) between the two groups. The cut-off values of psTg and LNR predicting ER were 3.97 μg/L and 0.29, with the AUC of 0.870 and 0.787 respectively. PsTg (odds ratio ( OR)=10.88, 95% CI: 4.67-25.36, P<0.001) and LNR ( OR=5.30, 95% CI: 1.85-15.23, P=0.002) were independent factors to predict 131I treatment response in PTC patients. When psTg≥3.97 μg/L, LNR ( OR=9.40, 95% CI: 2.06-42.92, P=0.004) was an independent factor affecting 131I treatment response in PTC patients. Conclusions:PsTg and LNR are independent factors affecting 131I treatment response in PTC patients. When psTg≥3.97 μg/L, LNR can be used as a supplementary factor to predict 131I treatment response. The combination of psTg and LNR can better predict 131I treatment response in PTC patients.

Factores asociados con la recidiva de cáncer de mama en pacientes con cirugía conservadora / Factors associated with breast cancer recurrence in patients with conservative surgery

Resumen OBJETIVO: Identificar los factores asociados con la recidiva de cáncer de mama en pacientes con cirugía conservadora. MATERIALES Y MÉTODOS: Estudio observacional, de cohorte retrospectiva, efectuado a partir de expedientes de pacientes con cáncer de mama en estadios tempranos e intervenidas con cirugía conservadora. Parámetros de estudio: estadio, subtipo histológico, perfil de expresión de receptores hormonales, tiempo de seguimiento, recidiva y periodo libre de enfermedad. La tasa de recidiva, el periodo libre de enfermedad y la identificación de los factores asociados con recidiva se hicieron con análisis estadístico. RESULTADOS: Se estudiaron 53 pacientes con edad media de 51.0 ± 9.4 años. El subtipo histopatológico más frecuente fue el ductal en 49 de las 53 pacientes; en 48 de ellas los tumores fueron positivos para receptores de progesterona, en 7 de 53 para Her-2 y en 3 de 53 triple negativo. La tasa de recidiva de cáncer de mama fue de 13.2% (es decir: 7 de 53 pacientes). El tiempo libre de enfermedad en quienes recayeron fue de 30.6 ± 24.8 meses. En el análisis bivariado se asociaron significativamente con recidiva: los ganglios linfáticos positivos, la expresión de receptores de progesterona y de estrógenos, los tumores triple negativo y el tratamiento complementario con quimioterapia. En el análisis multivariado solo se asociaron con recidiva: tener un tumor triple negativo (OR = 51.8; IC95%: 4.9- 548.4; p = 0.001) y recibir quimioterapia (OR = 8.0; IC95%: 1.4-46.1; p = 0.020). CONCLUSION: Los factores asociados con la recidiva fueron los ganglios linfáticos positivos, la expresión de receptores de progesterona y de estrógenos, tumores triple negativo y recibir quimioterapia.

Abstract OBJECTIVE: To identify factors associated with breast cancer recurrence in patients undergoing conservative surgery. MATERIALS AND METHODS: Observational, retrospective cohort study conducted on the records of patients with early-stage breast cancer who underwent conservative surgery. Study parameters: stage, histologic subtype, hormone receptor expression profile, follow-up time, recurrence and disease-free period. Statistical analysis was performed to estimate recurrence rate and disease-free period and to identify factors associated with recurrence. RESULTS: Fifty-three patients with a mean age of 51.0 ± 9.4 years were evaluated. The most common histopathologic subtype was ductal in 49 of 53 patients; tumors were progesterone receptor positive in 48, Her-2 positive in 7 of 53, and triple negative in 3 of 53. The breast cancer recurrence rate was 13.2% (i.e., 7 of 53 patients). Disease-free time in those who relapsed was 30.6 ± 24.8 months. In bivariate analysis, positive lymph nodes, progesterone and estrogen receptor expression, triple-negative tumors, and adjuvant chemotherapy were significantly associated with recurrence. In multivariate analysis, only having a triple-negative tumor (OR = 51.8; 95%CI: 4.9-548.4; p = 0.001) and receiving chemotherapy (OR = 8.0; 95%CI: 1.4-58.4; p = 0.001) were associated with recurrence. CONCLUSION: Factors associated with recurrence were positive lymph nodes, expression of progesterone and estrogen receptors, triple-negative tumors, and receipt of chemotherapy.

Adjuvant Radiotherapy in Surgically Treated HPV-Positive Oropharyngeal Carcinoma with Adverse Pathological Features.

Purpose: HPV-positive oropharyngeal carcinoma (HPV-OPC) is increasingly treated with primary surgery. The National Comprehensive Cancer Network (NCCN) recommends adjuvant therapy for surgically treated HPV-OPC displaying adverse pathological features (AF). We evaluated adjuvant radiotherapy patterns and outcomes in surgically treated AF-positive HPV-OPC (AF-HPV-OPC). Methods: The National Cancer Database was interrogated for patients ≥ 18 years with early-stage HPV-OPC from 2010 to 2017 who underwent definitive resection. Patients that had an NCCN-defined AF indication for adjuvant radiotherapy were assessed, including positive surgical margins (PSM), extranodal extension (ENE), lymphovascular invasion, and level 4/5 cervical lymph nodes. Overall survival (OS) was evaluated using Cox proportional hazards models and Kaplan−Meier analysis in whole and propensity score matched (PM) cohorts. Results: Of 15,036 patients meeting inclusion criteria, 55.7% were positive for at least one AF. Presence of any AF was associated with worse OS (hazard ratio (HR) = 1.56, p < 0.001). In isolation, each AF was associated with worse OS. On PM analysis, insurance status, T2 category, Charlson-Deyo comorbidity score, ENE (HR = 1.81, p < 0.001), and PSM (HR = 1.58, p = 0.002) were associated with worse OS. Median 3-year OS was 92.0% among AF-HPV-OPC patients undergoing adjuvant radiotherapy and 84.2% for those who did not receive adjuvant radiotherapy (p < 0.001, n = 1678). The overall rate of patients with AF-HPV-OPC who did not receive adjuvant radiotherapy was 13% and increased from 10% in 2010 to 17% in 2017 (ptrend = 0.007). Conclusions: In patients with AF-HPV-OPC, adjuvant radiotherapy is associated with improved survival. In the era of de-escalation therapy for HPV-OPC, our findings demonstrate the persistent prognostic benefit of post-operative radiotherapy in the setting of commonly identified adverse features. Ongoing clinical trials will better elucidate optimized patient selection for de-escalated therapy.

Far Infrared Radiation Therapy for Gynecological Cancer-Related Lymphedema Is an Effective and Oncologically Safe Treatment: A Randomized-Controlled Trial.

Background: Gynecological cancer-related lymphedema (GCRL) is a devastating condition that adversely influences function, health, and quality of life. We conducted a randomized-controlled clinical study as well as in vitro experiments to investigate the efficacy and safety of far infrared radiation (FIR) to treat lymphedema in patients having previously undergone surgery for gynecological tumors. Materials and Methods: Seventy-four women with GCRL, cancer free for 5 years or more, were randomly allocated into two treatment groups: standard of care with bandage treatment and treatment with FIR plus bandage. Variations of fluid, circumference of lymphedematous limbs, serum tumor markers (cancer antigen 125 [CA125]), inguinal-pelvic lymph nodes, vagina, lungs, and adverse reactions were assessed after 1 year. In vitro experiments examined the effects on cell viability, proliferation, apoptosis, and the cell cycle of fibroblast, A2780, SKOV-3, HELA, and Ishikawa cells. Results: The FIR+bandage group showed significantly decreased tissue fluid and reduced limb circumference (p < 0.05) in comparison with the control group at 1 year. There was no increase of serum CA125 in both groups, and no recurrence of neoplasia or lymphadenopathy was detected. No adverse reactions were recorded. In addition, no changes were detected after FIR treatment for fibroblast, A2780, SKOV-3, HELA, and Ishikawa cells in cell viability, proliferation, apoptosis, and cell cycle. Conclusion: FIR can be used to treat patients with GCRL following gynecological cancer treatment. Following clinical and experimental studies, we confirm that FIR is an oncologically safe treatment for lymphedema in gynecological tumor patients.

A novel targeted multifunctional nanoplatform for visual chemo-hyperthermia synergy therapy on metastatic lymph nodes via lymphatic delivery.

BACKGROUND: Distant metastasis to vital organs is the major contributor to breast cancer mortality, and regional lymph node metastasis is an important facilitator of distant metastasis and recurrence in this cancer. The early diagnosis and precise treatment of lymph node metastasis are crucial for staging and prognosis in breast cancer. Herein, we report a visualized precision medicine nanoplatform of metastatic lymph nodes for ultrasonic/photoacoustic (US/PA) dual modal imaging-guided in situ targeted hyperthermia-combined chemotherapy. RESULTS: Carbon nanoparticles (CNs), approved by the China Food and Drug Administration, were loaded with docetaxel and rationally combined with anti-hypoxia-inducible factor 1α antibody-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the combination of passive targeting at the lymph nodes and intracellular targeting at HIF 1α factor. The accumulation and retention of nanoparticles in metastatic lymph nodes via lymphatic delivery were enhanced. Docetaxel could be effectively offloaded by CNs that have active carbon nanoparticles, and the PLGA membrane prevented drug leakage. The nanoparticles exhibited excellent photothermal performance with a photothermal conversion efficiency of 28.9%, killing tumor cells in metastatic lymph nodes through hyperthermia. In vitro and in vivo systematic evaluations revealed that hyperpyrexia triggered the rupture of nanoparticles caused by the phase transition of perfluorohexane, resulting in docetaxel release for achieving in situ hyperthermia-combined chemotherapy. CONCLUSIONS: The laser-triggered highly efficient in situ chemotherapy nanosystem achieves targeted synergistic chemo-hyperthermia treatment of metastatic lymph nodes, and lymphatic delivery represents a strategy to avoid additional injury caused by drugs entering the blood circulation.

Efficacy of lactic acid bacteria supplementation against Fusarium graminearum growth in vitro and inhibition of Zearalenone causing inflammation and oxidative stress in vivo.

Fusarium graminearum invasion and Zearalenone (ZEN)-mycotoxin contamination are considered the most global threat to food and feed. This study investigates the effect Lactobacillus plantarum MON03 viable cells (LPVC) and LP free cells supernatant (LPFCS) against Fusarium graminearum growth and ZEN production in vitro and evaluates if treatment with LP viable cells can counteract the negative effect of ZEN on inflammation and oxidative stress in mesenteric lymph nodes and serum biochemical parameters in mice. For the in vitro study, 7 days of LPVC, LPFCS and F. graminearum co-incubation at different concentrations was done in order to determine the antifungal activity and ZEN- production inhibition. Regarding the in vivo study, Balb/c mice were treated as following: Control, ZEN group, LP group and ZEN + LP group for 30 days. In vitro, LPVC showed an excellent antifungal activity after 7 days of co-incubation (103 CFU/ml). LPVC was succeeded also to inhibit ZEN production by the fungi. In vivo, ZEN has shown an important oxidative damage. As a result of the exposure to ZEN, an increase cytokines, as effectors of an inflammatory response, were observed in the mesenteric lymph nodes (MLN) of intoxicated mice. In parallel, a serum biochemical change was also observed. LPVC induced a reduction of ZEN-induced oxidative stress and counteracts also the biochemical parameters damage and the inflammatory markers increased by ZEN. LPVC can be valorized as an anti-cating agent in the vitro and in the gastro-intestinal tract to decrease ZEN-toxic effects.

Lymph-Node-Targeted Cholesterolized TLR7 Agonist Liposomes Provoke a Safe and Durable Antitumor Response.

Toll-like receptor (TLR) agonists as the potent stimulants of an innate immune system hold promises for applications in anticancer immunotherapy. However, most of them are limited in the clinical translation due to the uncontrolled systemic inflammatory response. In the current study, 1V209, a small molecule TLR7 agonist, was conjugated with cholesterol (1V209-Cho) and prepared into liposomes (1V209-Cho-Lip). 1V209-Cho-Lip exerted minimal toxic effects and enhanced the transportation ability in lymph nodes (LNs) compared with 1V209. 1V209-Cho-Lip treatment inhibited tumor progression in CT26 colorectal cancer, 4T1 breast cancer, and Pan02 pancreatic ductal cancer models through inducing effective DC activation and eliciting CD8+ T cell responses. Furthermore, 1V209-Cho-Lip induced tumor-specific memory immunity to inhibit cancer recurrence and metastasis. These results indicate that cholesterol conjugation with 1V209 is an effective approach to target lymph nodes and to reduce the adverse effects. This work provides a rational basis for the distribution optimization of TLR agonists for potential clinical use.

Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses.

The sympathetic nervous system (SNS) controls various physiological functions via the neurotransmitter noradrenaline. Activation of the SNS in response to psychological or physical stress is frequently associated with weakened immunity. Here, we investigated how adrenoceptor signaling influences leukocyte behavior. Intravital two-photon imaging after injection of noradrenaline revealed transient inhibition of CD8+ and CD4+ T cell locomotion in tissues. Expression of ß-adrenergic receptor in hematopoietic cells was not required for NA-mediated inhibition of motility. Rather, chemogenetic activation of the SNS or treatment with adrenergic receptor agonists induced vasoconstriction and decreased local blood flow, resulting in abrupt hypoxia that triggered rapid calcium signaling in leukocytes and halted cell motility. Oxygen supplementation reversed these effects. Treatment with adrenergic receptor agonists impaired T cell responses induced in response to viral and parasitic infections, as well as anti-tumor responses. Thus, stimulation of the SNS impairs leukocyte mobility, providing a mechanistic understanding of the link between adrenergic receptors and compromised immunity.

Recurrencia de carcinoma papilar de tiroides en pacientes tiroidectomizados del Servicio Autónomo Oncológico del estado Lara / Recurrence of papillary carcinoma of thyroid in thyroidectomized patients from the Autonomous Oncological Service of Lara state

Con el objetivo de describir las recidivas de carcinoma papilar de tiroides (CPT) en pacientes tiroidectomizados atendidos en el Servicio Autónomo Oncológico del estado Lara, se realizó un estudio descriptivo transversal de recolección retrospectiva de datos de 140 historias clínicas de pacientes con diagnóstico de CPT registrados durante el lapso 2006-2017. Los pacientes incluidos se caracterizaron por un promedio de edad de 46,67 ± 13,94 años, siendo los más afectados los grupos de 41-50 años y 51-60 años; se observó un predominio del sexo femenino (86,33%). La intervención quirúrgica más realizada en estos pacientes fue la tiroidectomía total (44,29%) y tiroidectomía total con vaciamiento ganglionar (41,43%); 35,71% de los pacientes recibieron Iodo-131 como tratamiento adyuvante. El porcentaje de recidivas fue de 4,29%, siendo las recidivas más frecuentes la local y regional (33,33%, respectivamente); 66,67% de los casos de recidiva aparecieron en los primeros 5 años. De los pacientes con recidivas, 50% se les practicó tiroidectomía total y recibieron Iodo-131. Con estos resultados se aporta información epidemiológica actual sobre el CPT en nuestro centro con el fin de contribuir en la preparación de los servicios de cirugía y oncología para la atención de este grupo de pacientes(AU)

With the aim of describing the recurrences of papillary thyroid carcinoma in thyroidectomized patients treated at the Autonomous Oncology Service of Lara State, a cross-sectional descriptive retrospective study was conducted examining 140 medical records of patients with a diagnosis of papillary thyroid carcinoma registered during the period 2006-2017. Patients had an average age of 46.67 ± 13.94 years, being the most affected the 41-50 years and 51-60 years groups (26.43%, respectively); a predominance of females was observed (86.33%). The most performed surgical intervention was total thyroidectomy (44.29%) and total thyroidectomy with lymph node dissection (41.43%). Likewise, 35.71% received Iodine-131 as adjuvant treatment. The percentage of recurrences was 4.29%, being the most frequent local and regional with a prevalence of 33.33%, respectively; in addition, 66.67% of recurrences appeared during the first 5 years; 50% of these patients underwent total thyroidectomy and received Iodine-131. With these results, current information is provided in order to contribute to the preparation of surgical and oncological services for the care of cases of papillary thyroid carcinoma. It is important to maintain oncological follow-up in order to evaluate the evolution and prognosis of the different types of recurrences according to the place of appearance(AU)

Prognostic significance of lymph node yield in patients with synchronous colorectal carcinomas.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines recommend examination of a minimum of 12 lymph nodes (LNs) for accurate staging of a single case of colorectal cancer. However, the guidelines do not support the examination of LNs in synchronous colorectal carcinoma (SCC). This study aimed to investigate the association between lymph node yield and the prognosis of SCC patients. METHODS: Synchronous colorectal carcinoma patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database over a 10-year interval (2004 to 2013). Systematic dichotomization for optimal cut-off point identification was performed using X-tile. The baseline for the two LNs groups generated was balanced using the propensity score matching (PSM) method. RESULTS: A total of 4616 patients met the inclusion criteria. The cut-off number for lymph node retrieved from a single patient was 15 and 12 for the first- and second-time diagnosis of SCC, respectively. Age, T category, N category, tumor grade, tumor site, tumor size, and radiation sequence were not balanced in the two groups. After adjusting the baseline in the two groups, the same results were observed. Age, T category, N category, tumor site had a partial effect on lymph node yield. There might be some biological characteristics of the tumor that influence lymph node yield. CONCLUSIONS: Retrieval of fewer than 15 LNs at the first time of SCC diagnosis indicates worse SCC prognosis. Because factors such as manner of surgical examination influence SCC prognosis, specimens should be preserved for at least 6 months to enable reevaluation should there be a need. Irb: IRB approval is not required because the SEER data are freely accessible.

Local and systemic immunosuppression in pancreatic cancer: Targeting the stalwarts in tumor's arsenal.

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.