Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy.

BACKGROUND: The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon. METHODS: Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels. RESULTS: The abscopal effect was further amplified in the "cold" tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response. CONCLUSIONS: Bi was used as an artificially implanted anaerobic target to cause a transient "infection" at the tumor, causing the tumor to become locally inflamed and "hot", and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.

Targeted modulation of gut and intra-tumor microbiota to improve the quality of immune checkpoint inhibitor responses.

Immune checkpoint inhibitor (ICI) therapies, such as those blocking the interaction of PD-1 with its ligands, can restore the immune-killing function of T cells. However, ICI therapy is clinically beneficial in only a small number of patients, and it is difficult to predict post-treatment outcomes, thereby limiting its widespread clinical use. Research suggests that gut microbiota can regulate the host immune system and affect cancer progression and treatment. Moreover, the effectiveness of immunotherapy is related to the composition of the patient's gut microbiota; different gut microbial strains can either activate or inhibit the immune response. However, the importance of the microbial composition within the tumor has not been explored until recently. This study describes recent advances in the crosstalk between microbes in tumors and gut microbiota, which can modulate the tumor microbiome by directly translocating into the tumor and altering the tumor microenvironment. This study focused on the potential manipulation of the tumor and gut microbiota using fecal microbiota transplantation (FMT), probiotics, antimicrobials, prebiotics, and postbiotics to enrich immune-boosting bacteria while decreasing unfavorable bacteria to proactively improve the efficacy of ICI treatments. In addition, the use of genetic technologies and nanomaterials to modify microorganisms can largely optimize tumor immunotherapy and advance personalized and precise cancer treatment.

Seven preoperative factors have strong predictive value for postoperative pneumonia in patients undergoing thoracoscopic lung cancer surgery.

Background: Postoperative pneumonia (POP) is a hospital acquired pneumonia that occurs >48 hours after tracheal intubation. The diagnosis of POP should be based on clinical and radiological findings within 30 days after surgery. It is a common complication after thoracoscopic surgery for lung cancer patients. However, the specific impact of preoperative comorbidities on the incidence of POP remains unclear. This study aimed to analyze the preoperative data of patients with lung cancer to help surgeons predict the risk of incidence of POP after thoracoscopic lung resection. Methods: This study is a prospective study that included patients with lung cancer who were scheduled for thoracoscopic surgery in 1 year. All cases came from two medical centers. Preoperative demographic information, tumor information, preoperative comorbidities, quality of life scores, and incidence of POP were collected. Variables were screened by univariate analysis and multivariate regression. Finally, a prediction model was constructed. A total of 53 preoperative factors were included as candidate predictors. The binary outcome variable was defined as the presence or absence of POP. The incidence of POP was the primary outcome variable. The predictive performance of the model was verified internally through 1,000 iterations of bootstrap resampling. Results: A total of 1,229 patients with lung cancer who underwent thoracoscopic surgery were enrolled. In addition, 196 cases (15.95%) had POP; 1,025 (83.40%) patients had comorbid conditions. The total number of comorbidity diagnosed in all samples was 2,929. The prediction model suggested that patients with advanced age, high body mass index (BMI), smoking, poor physical condition, respiratory diseases, diabetes, and neurological diseases were more likely to develop POP. The area under the curve (AUC) and Brier scores were 0.851 and 0.091, respectively. The expected and observed results were in strong agreement, according to the likelihood of POP calibration curve. Conclusions: The constructed model is capable of evaluating the probability of POP occurrence in patients with lung cancer. Seven preoperative factors in patients with lung cancer were found to be associated with increased probability of having pneumonia after thoracoscopic lung resection. This model can help predict the incidence of POP after surgery.

Association of KRAS, NRAS, BRAF and PIK3CA gene mutations with clinicopathological features, prognosis and ring finger protein 215 expression in patients with colorectal cancer.

The relationships of KRAS, NRAS, BRAF and PIK3CA gene mutations with the clinicopathological features and prognosis of colorectal cancer (CRC) in patient are lacking. Furthermore, the role of ring finger protein 215 (RNF215) in CRC patients with KRAS, NRAS, BRAF and PIK3CA mutations remains unclear. In the present study, 182 surgical resection specimens from patients with primary CRC for retrospective analysis, were collected. KRAS/NRAS/BRAF/PIK3CA gene mutations were confirmed by an amplification-refractory mutation system. Immunohistochemistry (IHC) was conducted to confirm KRAS, NRAS, BRAF and PIK3CA protein expression. RNF215 expression in patients with CRC was evaluated using TIMER 2.0 database and IHC. The individual mutation rates of KRAS, NRAS, BRAF and PIK3CA were 40.7% (74/182), 4.4% (8/182), 4.4% (8/182) and 3.3% (6/182), respectively. The KRAS exon 2 mutation rate was the highest (61.5%, 64/104), and these mutations mainly occurred at codons 12 and 13. KRAS/NRAS/BRAF/PIK3CA wild-type CRC patients had significantly longer overall survival and disease-free survival than mutated KRAS/NRAS/BRAF/PIK3CA CRC patients (P<0.05). Overall, 45.4% (5/11) of patients with PIK3CA mutations had concomitant KRAS mutations. The KRAS/NRAS/BRAF/PIK3CA gene mutation rate in patients with lymph node metastasis (76.1%, 35/46) was significantly higher than that in patients without lymph node metastasis (50.8%, 69/136) (P=0.0027). There were no significant differences in IHC expression between patients with and without KRAS, NRAS, BRAF and PIK3CA mutations (P>0.05). The TIMER 2.0 analysis showed that RNF215 expression was significantly higher in the mutated BRAF group than in the wild-type BRAF group in CRC (P<0.05). In conclusion, KRAS is the most commonly mutated gene, and KRAS mutations may be a poor prognostic factor for patients with CRC. KRAS wild-type patient resistance may be related to PIK3CA gene mutations, although this needs further verification in larger cohorts. BRAF mutations may be associated with RNF215 expression in patients with CRC.

The occurrence and development of radiation-induced lung injury after interstitial brachytherapy and stereotactic radiotherapy in SD rats.

BACKGROUND: To compare the severity of radiation-induced lung injury (RILI) after the right lung of SD rats received interstitial brachytherapy and stereotactic radiotherapy (SBRT). METHODS: RILI rat model was established using interstitial brachytherapy and SBRT methods, respectively. CT scan was performed to analyze the lung volume and the CT value difference between the left and right lungs in rats. Then the lung tissues were analyzed through H&E staining, peripheral blood was extracted to detect the expression levels of serum inflammatory cytokines, pro-fibrotic cytokines, and fibrotic-inhibiting cytokines by ELISA. RESULTS: The difference between right and left lung CT values was significantly elevated in the SBRT group when compared with the control group and the interstitial brachytherapy group (P < 0.05). The IFN-γ expression in the interstitial brachytherapy group was significantly different from that in the SBRT group at week 1, 4, 8 and 16. Besides, the expressions of IL-2, IL-6 and IL-10 in SBRT group were significantly higher than that of interstitial brachytherapy group (P < 0.05). The TGF-ß expression in interstitial brachytherapy group reached its peak with the increase of time from week 1 to week 16, and it was significantly lower than SBRT group (P < 0.05). The mortality rate in the SBRT group was 16.7%, which was significantly higher than that in the interstitial brachytherapy group. CONCLUSION: The treatment method of interstitial brachytherapy is considered as an effective and safe tool by reducing the side effects of radiotherapy and increasing the radiation dose of radiotherapy.

Ring finger protein 215 is a potential prognostic biomarker involved in immune infiltration and angiogenesis in colorectal cancer.

The prognostic value of ring finger protein 215 (RNF215) in colorectal cancer (CRC) is unclear. Herein, the present study aimed to investigate the precise value of RNF215 based on CRC datasets from The Cancer Genome Atlas (TCGA) and clinical cases. CRC patient data was collected from TCGA and clinical samples from the Department of Pathology, Shanghai Fifth People's Hospital, Fudan University (Shanghai, China). Logistic regression analysis was used to investigate the correlations between RNF215 and clinicopathological characteristics. The predictive value of RNF215 for the clinical outcome of CRC was determined using Kaplan-Meier curves and Cox regression. Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), and angiogenesis analysis were also conducted to investigate the biological role of RNF215. Immunohistochemistry was conducted to validate the results. The results of the present study confirmed that RNF215 protein expression was significantly associated with age, lymphatic invasion, and overall survival (OS). Univariate analysis showed that upregulation of RNF215 in CRC was significantly associated with age and lymphatic invasion. Kaplan-Meier survival analysis revealed that high RNF215 expression predicted poorer OS and disease-specific survival. A total of nine experimentally detected RNF215-binding proteins were identified with the STRING tool and Cytoscape software. GSEA suggested that RNF215 was associated with several important pathways involved in tumor occurrence, including the Kyoto Encyclopedia of Genes and Genomes MAPK signaling pathway and the WikiPathway RAS signaling pathway. ssGSEA confirmed that RNF215 was significantly expressed in natural killer cells, CD8 T cells and T helper cells. Angiogenesis analysis revealed that numerous angiogenesis-related genes had the same expression trend as RNF215 in CRC. The immunostaining results indicated that RNF215 expression was significantly higher in CRC tissues than in corresponding normal tissues. In conclusion, increased RNF215 expression may be a potential molecular marker predictive of poor survival and a treatment target in CRC. In addition, RNF215 may participate in the formation of CRC through a variety of signaling pathways.

Freestanding narrowband terahertz filters based on aluminum foil.

Terahertz (THz) filters with high transmission coefficient (T) in the passband and frequency selectivity are critical in numerous applications such as astronomical detection and next-generation wireless communication. Freestanding bandpass filters eliminate the Fabry-Pérot effect of substrate, thus providing a promising choice for cascaded THz metasurfaces. However, the freestanding bandpass filters (BPFs) using the traditional fabrication process are costly and fragile. Here, we demonstrate a methodology to fabricate THz BPFs using aluminum (Al) foils. We designed a series of filters with center frequencies below 2 THz and manufacture them on 2-inch Al foils with various thicknesses. By optimizing the geometry, T of the filter at the center frequency is over 92%, and the relative full-width half maxima (FWHM) is as narrow as 9%. The responses of BPFs show that "cross-shaped" structures are insensitive to the polarization direction. The simple and low-cost fabrication process of the freestanding BPFs promise their widespread applications in THz systems.

Low-dose total body irradiation enhances systemic anti-tumor immunity induced by local cryotherapy.

BACKGROUND: Strategies that restore the immune system's ability to recognize malignant cells have yielded clinical benefits but only in some patients. Tumor cells survive cryotherapy and produce a vast amount of antigens to trigger innate and adaptive responses. However, because tumor cells have developed immune escape mechanisms, cryotherapy alone may not be enough to induce a significant immune response. METHODS: The mice were randomly divided into four groups: Group A: low-dose total body irradiation combined with cryotherapy (L-TBI+cryo); Group B: cryotherapy (cryo); Group C: low-dose total body irradiation(L-TBI); Group D: control group (Control). The tumor growth, recurrence, and survival time of mice in each group were compared and the effects of different treatments on systemic anti-tumor immunity were explored. RESULTS: L-TBI in conjunction with cryotherapy can effectively control tumor regrowth, inhibit tumor lung metastasis, extend the survival time of mice, and stimulate a long-term protective anti-tumor immune response to resist the re-challenge of tumor cells. The anti-tumor mechanism of this combination therapy may be related to the stimulation of inflammatory factors IFN-γ and IL-2, as well as an increase in immune effector cells (CD8+ T cells) and a decrease in immunosuppressive cells (MDSC, Treg cells) in the spleen or tumor tissue. CONCLUSIONS: We present unique treatment options for enhancing the immune response caused by cryotherapy, pointing to the way forward for cancer treatment.

Reducing Target Volumes of Intensity Modulated Radiation Therapy After Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: Long-Term Results of a Prospective, Multicenter, Randomized Trial.

PURPOSE: The objective of this study was to estimate the long-term survival, late toxicity profile, and quality of life of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with combined induction chemotherapy (IC) and concurrent chemoradiotherapy from a clinical trial focused on reducing the target volume of intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: This prospective, randomized clinical trial was conducted across 6 Chinese hospitals and included 212 patients with stage III-IVB NPC who were randomly allocated to a pre-IC or post-IC group. Eligible patients were treated with 2 cycles of IC + CCRT. All patients underwent radical IMRT. Gross tumor volumes of the nasopharynx were delineated according to pre-IC and post-IC tumor extent in the pre-IC and post-IC groups, respectively. RESULTS: After a median follow-up of 98.4 months, 32 of 97 (32.9%) and 33 of 115 (28.7%) patients experienced treatment failure or died in the pre-IC and post-IC groups, respectively. None of the patients developed grade 4 late toxicity. Late radiation-induced toxicity predominantly manifested as grade 1 to 2 subcutaneous fibrosis, hearing loss, tinnitus, and xerostomia, whereas grade 3 late toxicity included xerostomia and hearing loss. The 5-year estimated overall, progression-free, locoregional recurrence-free, and distant metastasis-free survival rates in the pre-IC and post-IC groups were 78.2% versus 83.3%, 72.0% versus 78.1%, 90.2% versus 93.5%, and 78.1% versus 82.1%, respectively. The pre-IC group had a significantly higher incidence of xerostomia and hearing damage than the post-IC group. In terms of quality of life, compared with the pre-IC group, the post-IC group showed significant improvement in cognitive function (P = .045) and symptoms including dry mouth (P = .004), sticky saliva (P = .047), and feeling ill (P = .041). CONCLUSIONS: After long-term follow-up, we confirmed that reducing the target volumes of IMRT after IC in locoregionally advanced NPC showed no inferiority in terms of the risk of locoregional relapse and potentially improved quality of life and alleviated late toxicity.

Screening of linear B-cell epitopes and its proinflammatory activities of Haemophilus parasuis outer membrane protein P2.

Haemophilus parasuis is a commensal organism of the upper respiratory tract of pigs, but virulent strains can cause Glässer's disease, resulting in significant economic losses to the swine industry. OmpP2 is an outer membrane protein of this organism that shows considerable heterogeneity between virulent and non-virulent strains, with classification into genotypes I and II. It also acts as a dominant antigen and is involved in the inflammatory response. In this study, 32 monoclonal antibodies (mAbs) against recombinant OmpP2 (rOmpP2) of different genotypes were tested for reactivity to a panel of OmpP2 peptides. Nine linear B cell epitopes were screened, including five common genotype epitopes (Pt1a, Pt7/Pt7a, Pt9a, Pt17, and Pt19/Pt19a) and two groups of genotype-specific epitopes (Pt5 and Pt5-II, Pt11/Pt11a, and Pt11a-II). In addition, we used positive sera from mice and pigs to screen for five linear B-cell epitopes (Pt4, Pt14, Pt15, Pt21, and Pt22). After porcine alveolar macrophages (PAMs) were stimulated with overlapping OmpP2 peptides, we found that the epitope peptides Pt1 and Pt9, and the loop peptide Pt20 which was adjacent epitopes could all significantly upregulated the mRNA expression levels of IL-1α, IL-1ß, IL-6, IL-8, and TNF-α. Additionally, we identified epitope peptides Pt7, Pt11/Pt11a, Pt17, Pt19, and Pt21 and loop peptides Pt13 and Pt18 which adjacent epitopes could also upregulate the mRNA expression levels of most proinflammatory cytokines. This suggested that these peptides may be the virulence-related sites of the OmpP2 protein, with proinflammatory activity. Further study revealed differences in the mRNA expression levels of proinflammatory cytokines, including IL-1ß and IL-6, between genotype-specific epitopes, which may be responsible for pathogenic differences between different genotype strains. Here, we profiled a linear B-cell epitope map of the OmpP2 protein and preliminarily analyzed the proinflammatory activities and effects of these epitopes on bacterial virulence, providing a reliable theoretical basis for establishing a method to distinguish strain pathogenicity and to screen candidate peptides for subunit vaccines.

Risk Factors for Operation Complications of High Dose Rate 3-Dimensional Interstitial Brachytherapy for Lung Cancer.

BACKGROUND: The risk factors for operation complications of high-dose-rate dimensional (3D) interstitial brachytherapy for lung malignant tumors are still unclear. We aimed to provide a reliable reference for the preoperative safety assessment of interstitial brachytherapy. PATIENTS AND METHODS: We analyzed the degree and incidence of operational complications in 120 eligible patients with lung carcinoma who underwent computed tomography (CT)-guided HDR interstitial brachytherapy. Univariate and multivariate analyses were used to study the relationships between patient-related factors, tumor-related factors, operation-related factors, and operational complications. RESULTS: The most frequent complications of CT-guided HDR interstitial brachytherapy were pneumothorax and hemorrhage. In univariate analysis, smoking, emphysema, distance of implanted needles through the normal lung tissue, number of implanted needle adjustments, and distance of the lesion from the pleura were the risk factors for pneumothorax; the tumor size, distance of the tumor from the pleura, number of implanted needle adjustments, and distance of the implanted needle through the normal lung tissue were risk factors for hemorrhage. In multivariate analysis, the depth of the implanted needle through the normal lung tissue and distance of the lesion from the pleura were independent risk factors for pneumothorax. Tumor size, number of implanted needle adjustments, and distance through normal lung tissue were independent risk factors for hemorrhage. CONCLUSION: This study provides a reference for the clinical treatment of lung cancer by analyzing the risk factors for complications of interstitial brachytherapy.

Albumin-Modified Gold Nanoparticles as Novel Radiosensitizers for Enhancing Lung Cancer Radiotherapy.

Background: Considering the strong attenuation of photons and the potential to increase the deposition of radiation, high-atomic number nanomaterials are often used as radiosensitizers in cancer radiotherapy, of which gold nanoparticles (GNPs) are widely used. Materials and Methods: We prepared albumin-modified GNPs (Alb-GNPs) and observed their radiosensitizing effects and biotoxicity in human non-small-cell lung carcinoma tumor-bearing mice models. Results: The prepared nanoparticles (Alb-GNPs) demonstrated excellent colloidal stability and biocompatibility at the mean size of 205.06 ± 1.03 nm. Furthermore, clone formation experiments revealed that Alb-GNPs exerted excellent radiosensitization, with a sensitization enhancement ratio (SER) of 1.432, which is higher than X-ray alone. Our in vitro and in vivo data suggested that Alb-GNPs enabled favorable accumulation in tumors, and the combination of Alb-GNPs and radiotherapy exhibited a relatively greater radiosensitizing effect and anti-tumor activity. In addition, no toxicity or abnormal irritating response resulted from the application of Alb-GNPs. Conclusion: Alb-GNPs can be used as an effective radiosensitizer to improve the efficacy of radiotherapy with minimal damage to healthy tissues.

Effect of triple therapy with low-dose total body irradiation and hypo-fractionated radiation plus anti-programmed cell death protein 1 blockade on abscopal antitumor immune responses in breast cancer.

Immunostimulatory effects of radiotherapy can be synergistically augmented with immune checkpoint blockade to act both on irradiated tumor lesions and distant, non-irradiated tumor sites. Our hypothesis was that low-dose total body irradiation (L-TBI) combined with hypo-fractionated radiotherapy (H-RT) and anti-programmed cell death protein 1 (aPD-1) checkpoint blockade would enhance the systemic immune response. We tested the efficacy of this triple therapy (L-TBI + H-RT + aPD-1) in BALB/c mice with bilateral breast cancer xenografts. The L-TBI dose was 0.1 Gy. The primary tumor was treated with H-RT (8 Gy × 3). The PD-1 monoclonal antibody was injected intraperitoneally, and the secondary tumors not receiving H-RT were monitored for response. The triple therapy significantly delayed both primary and secondary tumor growths, improved survival rates, and reduced the number of lung metastasis lesions. It increased the activated dendritic and CD8+ T cell populations and reduced the infiltration of myeloid-derived suppressor cells in the secondary tumor microenvironment relative to other groups. Thus, L-TBI could be a potential therapeutic modality, and when combined with H-RT and aPD-1, the therapeutic effect could be enhanced significantly.

The Application of Nanotechnology in Immunotherapy based Combinations for Cancer Treatment.

There has been a great amount of advancement in the early field of nano-immunotherapy and combination therapy. Persistent consideration regarding the clinical challenges and therapeutic hindrance should be tended to achieve therapeutic efficacy and potential. In this review, we will address how nanotechnology could defeat the difficulties resulting from cancer immunotherapy, how nanoparticles' utilization can enhance the efficacy of immune checkpoint blockers, and reconstituting the tumor microenvironment can promote antitumor responses. Moreover, this review discusses how nanoparticles mediate therapeutic modalities like chemotherapy, photodynamic therapy, photothermal therapy, and radiotherapy, which are used to target and destroy cancerous cells, initiate the release of tumor antigens, and can trigger anti-tumor immunity reactions. Furthermore, we analyzed the potential benefits of immunotherapy combinatorial using the nanoparticle delivery system to prevent tumor recurrence, hinder metastases, and decrease systemic toxicity of major organs and healthy cells common with uncontrolled targeting.

Effect of 3-Dimensional Interstitial High-Dose-Rate Brachytherapy With Regional Metastatic Lymph Node Intensity-Modulated Radiation Therapy in Locally Advanced Peripheral Non-Small Cell Lung Cancer: 5-Year Follow-up of a Phase 2 Clinical Trial.

PURPOSE: We aimed to reveal the 5-year clinical outcomes of 3-dimensional (3D) interstitial high-dose-rate (HDR) brachytherapy with regional metastatic lymph node intensity modulated radiation therapy (IMRT) for locally advanced peripheral non-small cell lung cancer (NSCLC), which has been shown to have low toxicity and improved 2-year survival rates in patients with this disease. METHODS AND MATERIALS: In this phase 2, single-arm, open-label clinical trial, 83 patients with locally advanced peripheral NSCLC were enrolled (median follow-up [range], 53.7 [4.3-120.4] months). All eligible patients received 3D interstitial HDR brachytherapy with regional metastatic lymph node IMRT. The primary endpoint was overall survival (OS). Secondary endpoints were local recurrence-free survival, regional recurrence-free survival, progression-free survival, distant metastasis-free survival, toxicities, and quality of life. RESULTS: The final analysis included 75 patients (19 [25.3%] females, 56 [74.7%] males; median [range] age, 64 [44-80] years; stage IIIA, 34 [45.3%]; stage IIIB, 41 [54.7%]). At the latest follow-up, 32 (42.7%) patients had survived. The median OS was 38.0 months (5-year OS, 44.5%; 95% confidence interval [CI], 33.8%-58.6%). Local recurrence-free survival, recurrence-free survival, and distant metastasis-free survival at 5 years were 79.2% (95% CI, 68.5%-91.5%), 73.6% (95% CI, 61.5%-88.1%), and 50.3% (95% CI, 38.3%-66.1%), respectively. The dominant failure pattern was distant disease, corresponding to 40% (30 of 75) of patients and 65.2% (30 of 46) of all failures. Two (2.7%) patients developed grade 1 acute pneumonitis. Grade 2 and 3 acute esophagitis occurred in 11 (14.7%) and 4 (5.3%) patients, respectively. No late radiation-related grade ≥2 late adverse events were observed. CONCLUSIONS: 3D interstitial HDR brachytherapy with regional metastatic lymph node IMRT for locally advanced peripheral NSCLC shows significant OS and has a low toxicity rate. Additional evaluation in a phase 3 trial is recommended to substantiate these findings.

5-Fluorouracil combined with cisplatin via arterial induction for advanced T-stage nasopharyngeal carcinoma: A 10-year outcome of a phase I/II study.

Background and Purpose: Currently, there is no optimal dose recommendation for a 120-h continuous infusion of 5-fluorouracil via arterial cannulation for advanced T-stage nasopharyngeal carcinoma (NPC). Thus, the aim of this study was to determine the maximum tolerated dose (MDT), along with the efficacy, late adverse events, and 10-year survival outcome of 5-fluorouracil administered continuously for 120 h combined with cisplatin via the superficial temporal artery in patients with advanced T-stage NPC. Materials and Methods: Fifty-one patients with histologically confirmed advanced T-stage NPC were eligible for inclusion in this clinical trial. The patients received induction chemotherapy consisting of cisplatin (20 mg/m2/d for 1-5 d) and 5-fluorouracil, administered continuously for 120 h at different dose gradients via a superficial temporal artery. To identify the MTD of 5-fluorouracil infused arterially, we employed a 3 + 3 design during study phase I. The initial dose administered was 200 mg/m2/d, which then was gradually escalated by 50 mg/m2/d until the MTD was reached. Following two cycles of induction chemotherapy, current radical chemoradiotherapy commenced. We assessed the efficacy, survival, toxicity, and quality of life of patients following treatment. Results: The overall response (complete response + partial response) rates following induction chemotherapy in the primary mass and lymph nodes were 100% and 100%, respectively. All 51 (100%) patients achieved T-category down-staging after intra-arterial chemotherapy. The MTD was 450 mg/m2/d for 120 h. No late neurological toxicities, such as brain stem injury, temporal lobe necrosis, and spinal cord injury, were observed. The 5- and 10-year overall survival (OS) rates were 78.0% and 71.7%, respectively, with a median OS of 131 months. Conclusion: Continuous infusion of 5-fluorouracil combined with cisplatin via the superficial temporal artery showed promising survival benefits and few toxicities in patients with advanced T-stage NPC.

Treatment of malignant pleural effusion in non-small cell lung cancer with VEGF-directed therapy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a critical regulator of malignant pleural effusion (MPE) in non-small-cell lung cancer (NSCLC). Bevacizumab (BEV) and apatinib (APA) are novel VEGF blockers that inhibit lung cancer cell proliferation and the development of pleural effusion. METHODS: In this study, we established Lewis lung cancer (LLC) xenograft mouse models to compare the therapeutic effect of APA and BEV in combination with cisplatin (CDDP) against MPE. The anti-tumour and anti-angiogenic effects of this combination therapy were evaluated by 18F-FDG PET/CT imaging, TUNEL assay and Immunohistochemistry. RESULTS: The triple drug combination significantly prolonged the overall survival of the tumour-bearing mice by reducing MPE and glucose metabolism and was more effective in lowering VEGF/soluble VEGFR-2 levels in the serum and pleural exudates compared to either of the monotherapies. Furthermore, CDDP + APA + BEV promoted in vivo apoptosis and decreased microvessel density. CONCLUSIONS: Mechanistically, LLC-induced MPE was inhibited by targeting the VEGF-MEK/ERK pathways. Further studies are needed to establish the synergistic therapeutic effect of these drugs in NSCLC patients with MPE.KEY MESSAGESCombined treatment of MPE with apatinib, bevacizumab and cisplatin can prolong the survival time of mice, reduce the content of MPE, decrease the SUVmax of thoracic tumour tissue, down-regulate the content of VEGF and sVEGFR-2 in serum and pleural fluid, and promote the apoptosis of tumour cells. Angiogenesis and MPE formation can be inhibited by down-regulation of HIF-1α, VEGF, VEGFR-2, MEK1 and MMP-2 molecular signalling pathway proteins.

Therapeutic Plasma Exchange: For Cancer Patients.

Therapeutic plasma exchange is used as a trial method for the treatment of cancer patients. Therapeutic plasma exchange uses in vitro technology to remove pathogenic factors in the plasma, returning the replacement and remaining components to the patient to facilitate cure. In the effort to explore new methods of cancer treatment, the introduction of therapeutic plasma exchange brings new hope for cancer treatment; however, the current evidence supporting therapeutic plasma exchange is controversial, and most of the evidence comes from observational studies, lacking large prospective randomized trials. Therefore, this review attempts to focus on the main indications of therapeutic plasma exchange for the treatment of tumors and their complications, including hematological tumors (multiple myeloma cast nephropathy and hyperviscosity syndrome), nervous system tumors (myasthenia gravis associated with thymoma, paraneoplastic neurological syndrome, Lambert-Eaton myasthenia syndrome, and anti-N-methyl-D-aspartate receptor encephalitis), overdose of chemotherapy drugs. In addition, the issues of side-effects and safety in the use of therapeutic plasma exchange are also discussed. However, well-designed prospective trials are needed to better define the role of therapeutic plasma exchange in cancer.

Patient-Derived Organoids Can Guide Personalized-Therapies for Patients with Advanced Breast Cancer.

Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.

Imaging of Tumor Hypoxia With Radionuclide-Labeled Tracers for PET.

The hypoxic state in a solid tumor refers to the internal hypoxic environment that appears as the tumor volume increases (the maximum radius exceeds 180-200 microns). This state can promote angiogenesis, destroy the balance of the cell's internal environment, and lead to resistance to radiotherapy and chemotherapy, as well as poor prognostic factors such as metastasis and recurrence. Therefore, accurate quantification, mapping, and monitoring of hypoxia, targeted therapy, and improvement of tumor hypoxia are of great significance for tumor treatment and improving patient survival. Despite many years of development, PET-based hypoxia imaging is still the most widely used evaluation method. This article provides a comprehensive overview of tumor hypoxia imaging using radionuclide-labeled PET tracers. We introduced the mechanism of tumor hypoxia and the reasons leading to the poor prognosis, and more comprehensively included the past, recent and ongoing studies of PET radiotracers for tumor hypoxia imaging. At the same time, the advantages and disadvantages of mainstream methods for detecting tumor hypoxia are summarized.