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.

Simultaneous development of pneumonitis and autoimmune diabetes secondary to immune checkpoint inhibitor treatment with durvalumab in an advanced small cell lung cancer patient: A case report.

RATIONALE: Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of various types of cancers worldwide, which is the most significant breakthrough in cancer therapy in recent years. Despite their excellent benefits in anti-tumor efficacy, a subset of patients will experience various autoimmune toxicities, termed as immune-related adverse events (irAEs), which can affect almost any organ systems, but related to the pulmonary and pancreatic islets simultaneously has rarely been reported and discussed. PATIENT CONCERNS: In this report, we describe a rare case of a 65-year-old man patient with advanced small cell lung cancer (SCLC) who suffered general fatigue, dry cough, chest tightness, shortness of breath and polyuria-polydipsia syndrome after the eighth cycle treatment with programmed cell death ligand-1 (PD-L1) inhibitor durvalumab. DIAGNOSES: According to the results of laboratory tests, chest computed tomography and multidisciplinary discussion, the patient was eventually diagnosed with ICI-related pneumonitis and autoimmune diabetes mellitus. INTERVENTIONS: Multiple daily subcutaneous insulin injections, empirical anti-infection and immunosuppression treatment with corticosteroids were performed. OUTCOMES: After the cessation of durvalumab and comprehensive treatment, the patient's respiratory condition was relieved significantly and his blood glucose was well controlled with insulin therapy. LESSONS: With the widespread use of ICIs, there will be more patients developing these rare but severe irAEs in clinical practice, which should attract great attention of both clinicians and patients.

Extraction, Biochemical Characterization, and Health Effects of Native and Degraded Fucoidans from Sargassum crispifolium.

In the current investigation, a native crude fucoidan (Ex) was extracted from Sargassum crispifolium, pretreated by single-screw extrusion, and two degraded fucoidans, i.e., ExAh (degradation of Ex by ascorbic acid) and ExHp (degradation of Ex by hydrogen peroxide), were obtained. The extrusion pretreatment increased the extraction yield of fucoidan by approximately 1.73-fold as compared to the non-extruded sample. Among Ex, ExAh, and ExHp, their molecular weight and chemical compositions varied, but the structural features were similar. ExHp possessed the greatest antioxidant activities among the extracted fucoidans. According to the outcome, ExAh exhibited the maximum immune promoting effects via enhanced NO, TNF-α, IL-1ß, IL-6, and IL-10 secretion. Thus, both ExHp and ExAh may potentially be used as an effective antioxidant and as immunostimulant agents, which could be of great value in the development of food and nutraceutical products.

Simultaneous and ultra-sensitive SERS detection of SLPI and IL-18 for the assessment of donor kidney quality using black phosphorus/gold nanohybrids.

Due to the global challenge of donor kidney shortage, expanding the pool of deceased donors has been proposed to include expanded criteria donors. However, the lack of methods to precisely measure donor kidney injury and predict the outcome still leads to high discard rates and recipient complications. As such, evaluation of deceased donor kidney quality is critical prior to transplantation. Biomarkers from donor urine or serum provide potential advantages for the precise measure of kidney quality. Herein, simultaneous detection of secretory leukocyte peptidase inhibitor (SLPI) and interleukin 18 (IL-18), two important kidney injury biomarkers, has been achieved, for the first time, with an ultra-high sensitivity using surface enhanced Raman scattering (SERS). Specifically, black phosphorus/gold (BP/Au) nanohybrids synthesized by depositing Au nanoparticles (NPs) onto the BP nanosheets serve as SERS-active substrates, which offer a high-density of inherent and accessible hot-spots. Meanwhile, the nanohybrids possess biocompatible surfaces for the enrichment of target biomarkers through the affinity with BP nanosheets. Quantitative detection of SLPI and IL-18 were then achieved by characterizing SERS signals of these two biomarkers. The results indicate high sensitivity and excellent reproducibility of this method. The limits of detection reach down to 1.53×10-8 mg/mL for SLPI and 0.23×10-8 mg/mL for IL-18. The limits of quantification are 5.10×10-8 mg/mL and 7.67×10-9 mg/mL for SLPI and IL-18. In addition, simultaneous detection of these biomarkers in serum was investigated, which proves the feasibility in biologic environment. More importantly, this method is powerful for detecting multiple analytes inheriting from excellent multiplexing ability of SERS. Giving that the combined assessment of SLPI and IL-18 expression level serves as an indicator of donor kidney quality and can be rapidly and reproducibly conducted, this SERS-based method holds great prospective in clinical practice.

Clinical and Biological Interpretation of Survival Curves of Cancer Patients, Exemplified With Stage IV Non-Small Cell Lung Cancers With Long Follow-up.

Worldwide, 18.1 million new invasive cancers and 9.9 million cancer deaths occurred in 2020. Lung cancer is the second most frequent (11.4%) and, with 1.8 million deaths, remains the leading cause of cancer mortality. About 1.7 million of lung cancers are of the non-small cell lung cancer (NSCLC) subtype, and of these, 60%-70% are in advanced stage IV at the time of diagnosis. Thus, the annual worldwide number of new NSCLC stage IV patients is about 1 million, and they have a very poor prognosis. Indeed, 25%-30% die within 3 months of diagnosis. However, the survival duration of the remaining 700,000 new patients per year surviving >3 months varies enormously. Surprisingly, little research has been done to explain these survival differences, but recently it was found that classical patient, tumour and treatment features cannot accurately distinguish short- and very long-term survivors. What then are the causes of these bewildering survival variations amongst "the same cancers"? Clonality, proliferation differences, neovascularization, intra-tumour heterogeneity, genetic inhomogeneity and other cancer hallmarks play important roles. Considering each of these, single or combined, can greatly improve our understanding. Another technique is analysis of the survival curve of a seemingly homogeneous group of cancer patients. This can give valuable information about the existence of subgroups and their biological characteristics. Different basic survival curves and what their shapes tell about the biological properties of these invasive cancers are discussed. Application of this analysis technique to the survival curve of 690 stage IV NSCLC patients with a 3.2-120.0-month survival suggests that this seemingly homogeneously group of patients probably consists of 4-8 subgroups with a very different survival. A subsequent detailed mathematical analysis shows that a model of 8 subgroups gives a very good match with the original survival curve of the whole group. In conclusion, the survival curve of a seemingly homogeneous group of cancer patients can give valuable information about the existence of subgroups and their biological characteristics. Application of this technique to 690 NSCLC Stage IV patients makes it probable that 8 different subgroups with very different survival rates exist in this group of cancers.

Dual-targeting SERS-encoded graphene oxide nanocarrier for intracellular co-delivery of doxorubicin and 9-aminoacridine with enhanced combination therapy.

A graphene oxide (GO)-based nanocarrier that imparts tumor-selective delivery of dual-drug with enhanced therapeutic index, is introduced. GO is conjugated with Au@Ag and Fe3O4 nanoparticles, which facilitates it with SERS tracking and magnetic targeting abilities, followed by the covalent binding of the anti-HER2 antibody, thus allowing it to both actively and passively target SKBR3 cells, human breast cancer cells expressed with HER2. Intracellular drug delivery behaviors are probed using SERS spectroscopy in a spatiotemporal manner, which demonstrates that nanocarriers are internalized into the lysosomes and release the drug in response to the acidic microenvironment. The nanocarriers loaded with dual-drug possess increased cancer cytotoxicity in comparison to those loaded with a single drug. Attractively, the enhanced cytotoxicity against cancer cells is achieved with relatively low concentrations of the drug, which is demonstrated to be involved in the drug adsorption status. These results may give us the new prospects to design GO-based delivery systems with rational drug dosages, thus achieving optimal therapeutic response of the multi-drug with increased tumor selectivity and reduced side effects.

"How Long Have I Got?" in Stage IV NSCLC Patients With at Least 3 Months Up to 10 Years Survival, Accuracy of Long-, Intermediate-, and Short-Term Survival Prediction Is Not Good Enough to Answer This Question.

BACKGROUND: Most lung cancer patients worldwide [stage IV nonsmall cell lung cancer (NSCLC)] have a poor survival: 25%-30% die <3 months. Yet, of those surviving >3 months, 10%-15% (70,000-105,000 new patients worldwide per year) survive (very) long. Surprisingly, little scientific attention has been paid to the question, which factors cause the good prognosis in these NSCLC stage IV long survivors. Therefore, "How long do I still have?" currently cannot be accurately answered. We evaluated in a large group of 737 stage IV NSCLC patients surviving 3.2-120.0 months, the accuracies of short- and long-term survival predictive values of baseline factors, radiotherapy (RT), platinum-based chemotherapy (PBT), and tyrosine kinase inhibitor targeted therapy (TKI-TT). METHODS: This is a noninterventional study of 998 consecutive first-onset stage IV NSCLC patients. A total of 737 (74%) survived 3.2-120.0 months, 47 refused RT, PBT, and TKI-TT. Single and multivariate survival analysis and receiver operating curve (ROC) analysis were used with dead of disease (DOD) or alive with disease (AWD) as endpoints. RESULTS: The median survival (16.1 months) of 47 patients who refused PBT, RT, and TKI-TT was significantly worse than those with RT, PBT, and/or TKI-TT (23.3 months, HR = 1.60, 95% CI = 1.06-2.42, p = 0.04). Of these latter 690 patients, 42% were females, 58% males, median age 63 years (range 27-85), 1-, 2-, 5-, and 10-year survival rates were 74%, 49%, 16%, and 5%. In total, 16% were alive with disease (AWD) at the last follow-up. Pathology subtype (adenocarcinoma vs. all others), performance score, TNM substage, the number of PBT cycles and TKI-TT had independent predictive value. However, with the multivariate combination of these features, identification results of short-term nonsurvivors and long-term survivors were poor. CONCLUSIONS: In stage IV NSCLC patients with >3 months survival, baseline features, and systemic therapeutic modalities have strong survival predictive value but do not accurately identify short- and long-term survivors. The predictive value of other features and interventions discussed should be investigated in the worldwide very large group of stage IV NSCLC patients with >3 months survival.

Enhancement of Cell Adhesion, Cell Growth, Wound Healing, and Oxidative Protection by Gelatins Extracted from Extrusion-Pretreated Tilapia (Oreochromis sp.) Fish Scale.

Gelatin has been broadly utilized in the food, pharmaceutical, photographic, cosmetic and packaging industries, and there is also huge potential for novel applications of gelatin in the fields of biotechnology and biomedicine. In the present study, we extracted gelatin from fish processing waste, i.e., scale of tilapia, by a combined method of extrusion-pretreatment and hot water extraction. The extrusion-pretreatment process increases the extraction yield of gelatin. Three gelatins (FS2: preconditioning with double-distilled water (ddH2O) before extrusion; FS12: preconditioning with citric acid solution before extrusion; FS14: preconditioning with acetic acid solution before extrusion) were obtained and all of them enhanced cell adhesion, cell growth, and wound healing in HaCaT cells and protected HaCaT cells from H2O2-induced cellular damage. Among FS2, FS12, and FS14, FS12 exhibited the most pronounced enhancement of cell adhesion, cell growth, and wound healing in HaCaT cells, and thus it may have potential as an effective natural raw material in cell therapies for cutaneous wounds and for reducing H2O2-induced oxidative damage of cells. In additional experiments, it was found that phosphorylations of Akt and mTOR are involved in the signaling pathway activated by FS2, FS12, and FS14 in HaCaT cells.

In Metastatic Non-small cell Lung Cancer Platinum-Based Treated Patients, Herbal Treatment Improves the Quality of Life. A Prospective Randomized Controlled Clinical Trial.

Background: According to clinical experience, Traditional Chinese Medicine (TCM) herbs added to platinum-based therapy (PBT) improve the Quality of Life (QOL) in metastatic non-small cell lung cancer (NSCLC) patients, but this must be prospectively validated. Patients and Methods: Based on clinical impressions regarding the effect of adding TCM herbs to platinum-based chemotherapy, we anticipated that 2 × 21 patients would be sufficient to obtain significant results with an α < 0.05 and power (1 - ß) of 90%. To be on the safe side, we enrolled at least 28 patients in each group. In a prospective randomized controlled trial, 61 uniquely defined consecutive patients (PBT+PLACEBO, N = 32; PBT+TCM, N = 29) with stage IIIB-IV, Eastern Cooperative Oncology Group (ECOG) performance scores (PS) = 0-1 and TCM syndrome combined Qi-Yin deficiency were enrolled. These 61 patients were selected from originally 154 consecutive stage IIIB-IV lung cancer patients in the enrollment period. Patients were hospitalized and strictly controlled/surveyed during the entire 2-month treatment period, to guarantee use of or abstinence from TCM herbal and placebo fluids. Occurrence of nausea-vomiting, QOL by Functional Assessment of Cancer Therapy-Lung (FACT-L) scales and changes in ECOG "improved and stable rates" were compared before and after two treatment cycles. Results: Before treatment, the clinico-pathologic and QOL features in PBT+PLACEBO and PBT+TCM patients did not differ (P > 0.10). The only side effects attributed by some of the patients to the TCM herbs were transient, mild gastric/abdominal heaviness in the first 2 weeks, but these also occurred amongst the PBT+PLACEBO patients (17 and 13%, P > 0.10). The incidence rates of nausea during treatment were 17% in PBT+TCM versus 75% in PBT+PLACEBO; vomiting rates were 14 and 56% (P < 0.0001 and 0.002). Moreover, ECOG "improved and stable rates" were 90% in the PBT+TCM versus 69% in the PBT+PLACEBO group (P = 0.04). In PBT+TCM patients, FACT-L social/familial and functional subscales were better after 2 months' treatment (P = 0.02 and 0.03). Contrarily, in PBT+PLACEBO patients, the QOL variables total score, physical and emotional subscales were worse after PBT treatment (P = 0.03, 0.0001, and 0.003). Conclusion: In stage IIIB-IV ECOG-PS = 0-1 NSCLC patients with Qi-Yin deficiency and platinum-based chemotherapy, adding TCM herbal medication improves the QOL. As this category of patients constitutes 40% of all metastatic NSCLCs, these results could have significant clinical impact.

Chemotherapy in conjunction with traditional Chinese medicine for survival of elderly patients with advanced non-small-cell lung cancer: protocol for a randomized double-blind controlled trial.

BACKGROUND: Traditional Chinese medicine (TCM) is considered an important complementary therapy with beneficial effects for cancer patients. Elderly patients with non-small-cell lung cancer (NSCLC) are a complex patient group with increasing co-morbidity and shrinking physiological reserve, and may derive substantial benefit from the supportive aspects of TCM. Researchers from Shanghai Longhua Hospital found that qi and yin deficiency is a common syndrome in patients with stage III or IV lung cancer. This project was designed to study the combination of single-agent chemotherapy with TCM methods of benefiting qi and yin in elderly patients with advanced NSCLC. METHODS AND DESIGN: This is a double-blind controlled, multi-center, and prospective study with randomly selected participants from elderly NSCLC patients in China. Seventy-six patients who meet the inclusion criteria will be allocated into two groups, which will receive treatments of 3-week single-agent chemotherapy with TCM or placebo for four cycles. Progression-free survival (PFS) is the primary end point, and the secondary end points are overall survival, objective response rate, time-to-progression, and quality of life (EORTC QLQ-LC43, and TCM syndrome score). Meanwhile, other end points such as toxicity, side effects and safety of the treatments will be assessed. DISCUSSION: Results from this study may provide evidence on the effectiveness, and parameters for the usage of single-agent chemotherapy combined with or without TCM on PFS of elderly patients with NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov. (Identifier: NCT01780181).

Multi-center randomized double-blind controlled clinical study of chemotherapy combined with or without traditional Chinese medicine on quality of life of postoperative non-small cell lung cancer patients.

BACKGROUND: Traditional Chinese medicine (TCM) is a widely applied complementary therapy for cancer patients. It can reduce the chemical drugs induced toxic effects to improve the quality of life (QOL). This study applies the highest quality of clinical trial methodology to examine the role of TCM in improving QOL of postoperative non-small-cell lung cancer patients. METHODS AND DESIGN: This study is a multi-center, randomized, placebo-controlled, double-blind trial. Four hundred eighty patients will be recruited into seven different research centers in China. These patients that meet the inclusion criteria will be randomized into either a treatment group or a placebo group. Each group will receive treatments of 3-weekly chemotherapy with TCM or placebo for four cycles. The primary outcome will involve the evaluation of QOL and the secondary outcome assessments will include two-year disease-free survival rate and disease-free survival. Other efficacy assessments are changes of TCM symptoms and toxicity. Side effects and safety profile of the therapy would be evaluated at the same time. The investigators expect that TCM therapy combined with chemotherapy is superior to chemotherapy solely in terms of QOL improvement and disease-free survival extension. "Intention-to-treat" analysis will include all randomized participants. DISCUSSION: The results from the clinical trial will provide evidence for the effectiveness of chemotherapy combined with or without TCM in QOL of postoperative NSCLC patients. TRIAL REGISTRATION: Clinical Trials.gov (Identifier: NCT01441752).

Prognostic proof and possible therapeutic mechanisms of herbal medicine in patients with metastatic lung and colon cancer.

Recent studies based on epidemiological models published in this journal and elsewhere have demonstrated encouraging patterns suggesting that herbal treatment may improve prognosis in advanced colon and lung cancer patients. Various problems exist with data from nonrandomized studies of this type, but a strong signal of potential positive effect can be seen. The therapeutic mechanisms of traditional Chinese medicine in metastatic cancer are discussed against a hypothetical, dualistic antiproliferation model and immune-stimulation model of tumor progression and regression. Recommendations are made for a strategy to demonstrate more conclusively the efficacy of adjunct herbal treatment during cancer chemotherapy and for discussions with patients until such time as the efficacy trials are completed.

Is the improvement of prognosis of patients with metastatic pulmonary adenocarcinoma treated with TCM herbal medicine due to lag time to treatment bias?

UNLABELLED: BACKGROUND. Traditional Chinese herbal medicine was associated with improved prognosis in patients with performance score 0-1 at the time of diagnosis of stage IV pulmonary adenocarcinoma (PAC) treated with platinum-based chemotherapy (PBT). OBJECTIVE. The authors investigated the effect of 1- to 4-month lag time to traditional Chinese medicine (TCM) treatment on the median and 1-year survival of PBT-PAC patients. METHODS: The median lag time to treatment was 3 months. In the first 3 months, about 35% of the patients died, but thereafter the survival curve flattened off and the death of the next 35% to 40% of patients took 9 months. Leaving out patients with lag time up to 3 months therefore would be a reasonable choice. To be on the safe side, the effects of leaving out patients up to 4 months were investigated. The Kaplan-Meier survival curves were used. RESULTS: The median and 1-year survival of the PBT-PAC patients was 5.0 months and 27%, respectively. Leaving out patients with 0-1 month follow-up, 0-2, 0-3, and 0-4 months follow-up changed the median and 1-year survival, respectively, to 5.5 months and 32%, 6.5 months and 36%, 9.0 months and 43%, and 10.0 months and 52%. The median survival of PBT + TCM in PAC patients was 22.6 months and 78%. Median lag time to TCM treatment was 3.0 months. With up to 4 months lag time to treatment due to combined patients' and TCM doctor's waiting time, the improved survival of PBT + TCM performance score 0-1 (fully ambulant) patients at the time of diagnosis still is significant (P < .01, hazard ratio = 0.51). Moreover, the survival of patients treated by TCM doctors with little or more months lag time to treatment was not different (P = .79). CONCLUSION: Increasing lag time to treatment up to 4 months improves the median and 1-year survival of PBT patients without TCM but is unlikely to explain the greatly improved prognosis of PBT + TCM treated patients with fully ambulant stage IV PAC.

Traditional Chinese medicine herbal treatment may have a relevant impact on the prognosis of patients with stage IV adenocarcinoma of the lung treated with platinum-based chemotherapy or combined targeted therapy and chemotherapy.

BACKGROUND: Targeted therapy (TT), chemotherapy, and traditional Chinese medicine herbal treatment (TCM) can improve the prognosis of advanced pulmonary adenocarcinoma patients. Their independent prognostic value is unknown. OBJECTIVE: To study whether TCM improves survival in stage IV pulmonary adenocarcinoma patients with platinum-based chemotherapy (PBT), or combined PBT and second-line TT. METHODS: Retrospective analysis of 133 fully ambulant clinical outpatients treated with PBT alone or PBT with/without second-line TT, with/without TCM. Univariate (Kaplan-Meier) and multivariable (Cox model) survival analysis were performed, using disease-specific mortality as an endpoint. RESULTS: Gender (P = .002), TT (P < .0001), and TCM (P < .0001) had univariate prognostic value but not age, radiotherapy, or TCM syndrome differentiation (P > .10). TCM herbal treatment (P < .0001) and TT (P = .03) had multivariable independent prognostic value. TCM-treated patients (n = 103, PBT+TT+TCM+ = 62; PBT+TT-TCM+ =41) had 88% 1-year overall survival rate with median survival time (MST) of 27 months, contrasting 27% 1-year overall survival and MST of 5.0 months for non-TCM-treated (n = 30) patients. Patients with chemotherapy/TT/TCM (PBT+TT+TCM+, n = 62), TCM without TT (PBT+TT-TCM+, n = 41), or chemotherapy only (PBT+TT-TCM-, n = 30), had 1-year survival rates of 94%, 78%, and 27% respectively; for these 3 groups, respectively, MST was not reached (MST of 30.9 months), 22.6, and 5.0 months (P < .0001). CONCLUSIONS: TCM herbal treatment may improve survival of stage IV pulmonary adenocarcinoma patients treated with chemotherapy without or with second-line TT. This warrants formal phase 1 and 2 trials and ultimately properly designed prospective clinical validation trials with adequate methodology developed for data collection.