MULTIMODALITY THERAPY INCLUDING SURGICAL RESEC-TION FOR LIMITED SMALL CELL LUNG CANCER

From 1975 through 1990, 199 patients with limited small cell lung cancer (LSCLC) were subjected to multimodality treatment including surgical resection combined with chemotherapy or chemoradiotherapy in our department. The median postoperative survival time of the 199 patients was 39 months, and the 5-year survival rate was 26%, which was decreased with increase of tumor-stage. In comparison of the survival time of patients in Stage Ⅰ and those in Stage Ⅲa, there was a significant difference (P<0.01). There were no significant differences in survival rate of 3 and 5 years between the patients receiving chemotherapy prior to or after surgical resection. The improvement in survival was documented by surgical resection combined with chemotherapy or chemoradiotherapy for LSCLC. The effect of multimodality treatment is correlated with tumor P-TNM staging, the involvement of lymph node, especially that of the mediastinal lymph node, is a negative factor influencing the prognosis. Surgical resection as an initial management, followed by chemotherapy or chemoradiotherapy may be indicated in LSCLC patients of Stage Ⅰ, Stage Ⅱ and some Stage Ⅲa as the cancer can be resected completely.

Multimodal therapy strategies based on hydrogels for the repair of spinal cord injury

Spinal cord injury(SCI)is a serious traumatic disease of the central nervous system,which can give rise to the loss of motor and sensory function.Due to its complex pathological mechanism,the treatment of this disease still faces a huge challenge.Hydrogels with good biocompatibility and biodegradability can well imitate the extracellular matrix in the microenvironment of spinal cord.Hydrogels have been regarded as promising SCI repair material in recent years and continuous studies have confirmed that hydrogel-based therapy can effectively eliminate inflammation and promote spinal cord repair and regeneration to improve SCI.In this review,hydrogel-based multimodal therapeutic strategies to repair SCI are provided,and a combination of hydrogel scaffolds and other therapeutic modalities are discussed,with particular emphasis on the repair mechanism of SCI.

Laparoscopic duodenojejunostomy for malignant stenosis as a part of multimodal therapy:A case report

BACKGROUND Laparoscopic duodenojejunostomy(LDJ) has become the standard surgical procedure for superior mesenteric artery syndrome due to its sufficient outcome in terms of safety and symptom relief. However, there are only a few reports about LDJ for malignant stenosis and its indication remains uncertain.CASE SUMMARY A 77-year-old woman with a history of pancreatic cancer(PC) treated with distal pancreatectomy with en bloc resection of the transverse colon 7 mo ago was admitted for recurrent vomiting. Imaging upon admission revealed marked distention of the duodenum and a tumor around the duodenojejunal flexure. She was diagnosed with malignant stenosis caused by local recurrence of PC. LDJ was performed with an uneventful postoperative course, followed by chemotherapy which gave her 10 mo overall survival.CONCLUSION We think that LDJ is a valuable method for unresectable malignant stenosis around the duodenojejunal flexure as a part of multimodal therapy.

Nanomedicine-based multimodal therapies:Recent progress and perspectives in colon cancer

Colon cancer has attracted much attention due to its annually increasing incidence.Conventional chemotherapeutic drugs are unsatisfactory in clinical application because of their lack of targeting and severe toxic side effects.In the past decade,nanomedicines with multimodal therapeutic strategies have shown potential for colon cancer because of their enhanced permeability and retention,high accumulation at tumor sites,co-loading with different drugs,and combination of various therapies.This review summarizes the advances in research on various nanomedicine-based therapeutic strategies including chemotherapy,radiotherapy,phototherapy(photothermal therapy and photodynamic therapy),chemodynamic therapy,gas therapy,and immunotherapy.Additionally,the therapeutic mechanisms,limitations,improvements,and future of the above therapies are discussed.

Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies.However,the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression.Here,we propose a self-amplifying logic-gated gene editing strategy for gene/H_(2)O_(2)-mediated/starvation multimodal cancer therapy.In this approach,a hypoxia-degradable covalent-organic framework(COF) is synthesized to coat a-ZIF-8 in which glucose oxidase(GOx) and CRISPR system are packaged.To intensify intracellular redox dyshomeostasis,DNAzymes which can cleave catalase mRNA are loaded as well.When the nano system gets into the tumor,the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx,which amplifies intracellular H^(+)and hypoxia,accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells.These tandem reactions deplete glucose and oxygen,leading to logic-gated-triggered gene editing as well as synergistic gene/H_(2)O_(2)-mediated/starvation therapy.Overall,this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

Prognostic factors of recurrent intrahepatic cholangiocarcinoma after hepatectomy:A retrospective study

BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is a highly malignant tumour.Hepatectomy is an effective treatment for early ICC,but postoperative recurrence greatly affects patient survival.Studies on recurrent ICC after hepatectomy are lacking.AIM To investigate the clinical characteristics of patients with recurrent ICC after hepatectomy,analyse prognostic factors and explore diagnosis and treatment strategies.METHODS A retrospective analysis was performed on all ICC patients undergoing hepatectomy from January 2013 to August 2021.Patients with postoperative recurrence were selected according to the inclusion and exclusion criteria.Cumulative overall survival was plotted by the Kaplan-Meier method,and differences were assessed by univariate survival analysis using the log-rank test.Multivariate analysis of cumulative survival was performed using the Cox proportional risk model.RESULTS During the 8-year study period,103 patients underwent ICC-related hepatectomy,and 54 exhibited postoperative recurrence.The median disease-free survival(DFS)was 6 mo,the median overall survival(OS)was 9 mo,and the cumulative OS rates at 1,2 and 3 years after the operation were 40.7%,14.8%and 7.4%,respectively.The median OS after recurrence was 4 mo,and the cumulative OS rates at 1,2 and 3 years after recurrence were 16.1%,6.7%and 3.4%,respectively.Multivariate analysis showed that alcohol consumption[hazard ratio(HR)=4.64,95%confidence interval(CI):1.53-14.04,P=0.007]and DFS<6 mo(HR=3.47,95%CI:1.59-7.60,P=0.002)were independent risk factors for the cumulative survival of patients with recurrence,while treatment after recurrence(HR=0.21,95%CI:0.08-0.55,P=0.001)was an independent protective factor.The median OS time of patients receiving multimodality therapy after recurrence of ICC was 7 mo,which was significantly higher than that of patients receiving only local therapy(3 mo),patients receiving systematic therapy(4 mo)and patients receiving the best supportive therapy(1 mo).Patients with recurrent ICC who received multimodality therapy had a significantly better long-term survival after recurrence than those who did not(P=0.026).CONCLUSION The prognosis of patients with recurrence after ICC-related hepatectomy is poor.Alcohol consumption and DFS<6 mo are independent risk factors in terms of the cumulative survival of patients with recurrence,while treatment after recurrence is an independent protective factor.Multimodality therapy can effectively improve the prognosis of patients.

Further understanding of an uncommon disease of combined small cell lung cancer： clinical features and prognostic factors of 114 cases

Objective： Combined small cell lung cancer （C-SCLC） is an uncommon subgroup of small cell lung cancer （SCLC） and few clinical data can be referred. Our study is to investigate the clinical features and prognostic factors of C-SCLC, as well as the role of multimodality treatment.Methods： Between January 2004 and December 2012, patients with histologically diagnosed C-SCLC were retrospectively analyzed. The survivals were evaluated with the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors.Results： One hundred and fourteen patients were enrolled, with a median age of 59 （range： 20-79） years old. The most common combined component was squamous cell carcinoma （52.6%）. Among these patients, the disease was stage I, II, III and IV in 9.6%, 19.3%, 46.5% and 24.6% of the patients, respectively. Eighty patients （70.2%） received at least two of the three modalities containing chemotherapy, radiotherapy and surgery. The median follow-up was 32.5 months. The median time of overall survival （OS） was 26.2 months. On univariate analysis, smoking （P=0.029）, Karnofsky performance score （KPS） 〈80 （P=0.000）, advanced TNM stage （P=0.000）, no surgery （P=0.010）, positive resection margin （P=0.000）, positive lymph nodes ≥4 （P=0.000）, positive lymph node ratio 〉10% （P=0.000） and non-multimodality treatment （P=0.004） were associated with poor OS. Multivariate analysis confirmed that smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio 〉 10% were poor prognostic features. Conclusions： C-SCLC has a relatively early stage and good prognosis, which may due to the underestimated diagnosis in non-surgical patients. Multimodality therapy is recommended, especially for limited disease. Smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio 〉10% are poor prognostic factors.

Brain Metastases in Patients with Gynecologic Cancers: A Single Institution Experience and Review of the Literature

Objective: Brain Metastasis (BM) from primary gynecologic cancers is a rare entity. The advances and successes in the treatment of primary gynecologic malignancies, have led to prolonged survival and, a higher incidence of BM. This study aims to report the experience at our institution in managing these patients, and provide possible data points that may be essential to note as prognostic factors, and see if our findings are consistent with the literature in this subject. We also aim to provide a brief literature review of patients with gynecologic cancers and BM. Methods: This is a small single institution retrospective study of 23 patients with a gynecologic malignancy and BM, identified between the years 2007-2015. Data were collected on variables including patient demographics, disease and treatment. Results: The median overall survival from the primary diagnosis was 28 months. Median time from diagnosis of BM to death was 9 months. Conclusion: The outcomes in our study are similar to what is stated in the current literature with regard to BM from gynecologic malignancies. Our literature search also revealed that the molecular analysis and treatment of the primary tumor remain important to prevent BMs. The tendency of tumors to metastasize varies for one tumor type to another for the same type of tumor. The tendency to develop BM may not only depend on risk factors such as stage, grade, and histology, but also on the genetic profile of the primary tumor. The study suggests that multimodal treatment of BM has better outcomes in managing BM from gynecologic cancers.

Advantages and issues of concern regarding approaches to peripheral nerve block for total hip arthroplasty

In older patients with comorbidities,hip fractures are both an important and debilitating condition.Since multimodal and multidisciplinary perioperative strategies can hasten functional recovery after surgery improving clinical outcomes,the choice of the most effective and safest pathway represents a great challenge.A key point of concern is the anesthetic approach and above all the choice of the locoregional anesthesia combined with general or neuraxial anesthesia.

Long-term complete response in metastatic poorly-differentiated neuroendocrine rectal carcinoma with a multimodal approach: A case report

BACKGROUND Neuroendocrine gastrointestinal tumors(NETs)are rare and have different natural behaviors.Surgery is the gold standard treatment for local disease while radiotherapy has been demonstrated to be ineffective.Poorly differentiated neuroendocrine carcinomas(NECs)represent only 5%-10%of digestive NETS.Due to aggressive growth and rapid metastatic diffusion,early diagnosis and a multidisciplinary approach are mandatory.The role of surgery and radiotherapy in this setting is still debated,and chemotherapy remains the treatment of choice.CASE SUMMARY A 42-year-old male with an ulcerated bleeding rectal lesion was diagnosed with a NEC G3(Ki67 index>90%)on May 2015 and initially treated with 3 cycles of first-line chemotherapy,but showed early local progressive disease at 3 mo and underwent sphincter-sparing open anterior low rectal resection.In September 2015,the first post-surgery total-body computed tomography(CT)scan showed an early pelvic disease relapse.Therefore,systemic chemotherapy with FOLFIRI was started and the patient obtained only a partial response.This was followed by pelvic radiotherapy(50 Gy).On April 2016,a CT scan and 18F-fluorodeoxy-glucose positron emission tomography imaging showed a complete response(CR)of the pelvic lesion,but pathological abdominal inter-aortocaval lymph nodes were observed.Due to disease progression of abdominal malignant nodes,the patient received radiotherapy at 45 Gy,and finally obtained a CR.As of January 2021,the patient has no symptoms of relapse and no late toxicity after chemotherapy or radiotherapy.CONCLUSION This case demonstrates how a multimodal approach can be successful in obtaining long-term CR in metastatic sites in patients with high grade digestive NECs.

Observations from the Working Group Peritoneal Carcinosis

The aim of this report was to describe the feasibility, overall survival and quality of life of combining multimodal therapy with a complementary therapy concept called LOTUS Care Cure program. The peritoneal carcinomatosis (PC) working group described their observations on the combination of multimodal therapy with a complementary therapy concept based on 132 patients with different cancer entities with suspected PC. PC was not confirmed by laparoscopy in 32.5% of the patients included in the working group of patients with suspected PC. Patient compliance and the feasibility were high. For Ki67, there is a cut-off at 45% with a slower progression at <45% and a faster progression of the disease at >45%. The higher the Karnofsky index, the more improved the therapy and tolerability, with a cut-off of 80%. Overall, 72.0% of patients died. The median survival time in the overall population was 3.74 years (95% CI, 2.57 to 4.91) with a sharp decline in the first 16 weeks. The quality of life of patients can be improved with the implementation of the complementary LOTUS Care Cure Project. Overall, the therapy of PC requires a multi-professional team of therapists and a multimodal therapy concept. The multimodal concept together with the Lotus Care Cure project shows very good feasibility with high compliance and ultimately leads to better and low-risk patient care.

Doxorubicin-Ioaded Fe3O4@MoS2-PEG-2DG nanocubes as a theranostic platform for magnetic resonance imaging- guided chemo-photothermal therapy of breast cancer

Molybdenum disulfide （MoS2）, a typical transition-metal dichalcogenide, has attracted increasing attention in the field of nanomedicine because of its preeminent properties. In this study, magnetic resonance imaging （MRI）-guided chemo-photothermal therapy of human breast cancer xenograft in nude mice was demonstrated using a novel core/shell structure of Fe3O4@MoS2 nanocubes （IOMS NCs） via the integration of MoS2 （MS） film onto iron oxide （IO） nanocubes through a facile hydrothermal method. After the necessary PEGylation modification of the NCs for long-circulation purposes, such PEGylated NCs were further capped by 2-deoxy-D-glucose （2-DG）, a non-metabolizable glucose analogue to increase the accumulation of the as-prepared NCs at the tumor site, as 2-DG molecules could be particularly attractive to resource-hungry cancer cells. Such 2-DG- modified PEGylated NCs （IOMS-PEG-2DG NCs） acted as drug-carriers for doxorubicin （DOX）, which could be easily loaded within the NCs. The obtained IOMS-PEG（DOX）-2DG NCs exhibited a 3？2 relaxivity coefficient of 48.86 （mM）^-1·s^-1 and excellent photothermal performance. 24 h after intravenous injection of IOMS-PEG（DOX）-2DG NCs, the tumor site was clearly detected by enhanced T2-weighted MRI signal. Upon exposure to an NIR 808-nm laser for 5 rain at a low power density of 0.5 W·cm^-2 a marked temperature increase was noticed within the tumor site, and the tumor growth was efficiently inhibited by the chemo-photothermal effect. Therefore, our study highlights an excellent theranostic platform with great potential for targeted MRI-guided precise chemo-photothermal therapy of breast cancer.

Precisely engineering a dual-drug cooperative nanoassembly for proteasome inhibition-potentiated photodynamic therapy

Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evidence that the ubiquitin-proteasome pathway(UPP) significantly impedes PDT by preventing the enrichment of ROS-damaged proteins in tumor cells. To tackle this challenge, we report a facile dual-drug nanoassembly based on the discovery of an interesting co-assembly of bortezomib(BTZ, a proteasome inhibitor) and pyropheophorbide a(PPa) for proteasome inhibition-mediated PDT sensitization.The precisely engineered nanoassembly with the optimal dose ratio of BTZ and PPa demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment,good colloidal stability, long systemic circulation, favorable tumor-specific accumulation, as well as significant enrichment of ROS-damaged proteins in tumor cells. As a result, the cooperative nanoassembly exhibits potent synergistic antitumor activity in vivo. This study provides a novel dual-drug engineering modality for multimodal cancer treatment.

Multifunctional Reduced Graphene Oxide Hydrogel as Drug Carrier for Localized and Synergic Photothermal/Photodynamics/Chemo Therapy

To combine localized drug release with multimodal therapy for malignant tumor, a composite hydrogel as an integrative drug delivery system was facilely prepared. The system contains spinach extract （SE）, reduced graphene oxide （rGO） and gold nanocages （AuNCs）. SE conduces to the formation of hydrogel, and also serves as a green material for improving the biocompatibility of hydrogel, and a natural pho- tosensitizer for killing tumor cells under laser radiation （fi60 nm）. AuNts show obvious photothermy and can enhance the generation of cytotoxic singlet oxygen （102）. The composite hydrogel shell on tumor cells exhibits several competitive advantages including enhanced antitumor effect by retaining the high con- centration of drugs around cancer cell, excellent PDT/FFr compatibility as well as high loading and controllable release of fluorouracil （5-FU） for synergetic multimodal treatment. The survival rate of HeLa cells incubated with 5-FU loaded hydrogel under NIR radiation for 10 min sharply decreases to 1.2%, in- dicating remarkably improved antitumor effects. These results demonstrate that the hydrogel is an excellent delivery carrier for localizable, NIR-responsive and combined PTT/PDT/Chemo synergetic antitumor.

DNA Nanotechnology for Multimodal Synergistic Theranostics

Over the past decade,DNA nanotechnology has developed rapidly due to its unique characteristics,such as excellent biocompatibility,high programmability,good predictability,automatically chemical synthesis,and so on.So far,a variety of DNA-based nanostructures,from small to large and simple to complex,have been designed and synthesized with controllable size and shape in one,two,or three dimensions.Therefore,DNA has become a kind of competitive materials for biosensing,bioimaging and biomedicine.In particular,the integration of DNA nanotechnology with multimodal synergistic theranostics can not only achieve accurate cancer diagnosis by the sensitive and accurate detection of cancer biomarkers,but also achieve enhanced anti-cancer therapeutic efficacy,which promote the development of DNA nanotechnology and nanomedicine.In this review,we first give a comprehensive introduction of DNA nanotechnology,and then summarize the DNA self-assembly and amplification strategies for the construction of functional nanoplatforms for multimodal synergistic theranostics.Finally,the challenges and opportunities faced by DNA nanotechnology in biomedicine are discussed.

An Exceptional Broad-Spectrum Nanobiocide for Multimodal and Synergistic Inactivation of Drug-Resistant Bacteria

This study reports the fabrication of a novel photothermal material formed via the physical blending of excess lauric acid(LA)and cupric acetate,followed by efficient ligand exchange.Surprisingly,the copper–LA complex exhibited a 12-fold enhancement of the molar extinction coefficient in the nearinfrared(NIR)region relative to aqueous cupric acetate.Inspired by this interesting finding,we formulated these photothermal materials into colloidally dispersed nanoparticles via a technique that combined nanoprecipitation and in situ surface polymerization for antibacterial studies.The resultant nanoparticles exhibited rapid and stable photothermal responses to NIR irradiation,with a 4-fold enhanced photothermal conversion efficiency relative to aqueous cupric acetate.Since a positively charged monomer was incorporated during in situ surface polymerization,these positively charged nanoparticles were ingested efficiently and subsequently digested by drug-resistant bacteria.By combining the LA-mediated membrane-damaging effect,copper-mediated Fenton-like reaction,as well as the photothermal effect of the copper–LA complex,a broad-spectrum,multimodal,and synergistic antibacterial effect was achieved both in vitro and in vivo,with the killing efficiency up to 99.99%for ampicillin-resistant Escherichia coli(Ampr E.coli)and 99.9999%for methicillinresistant Staphylococcus aureus(MRSA).Our newly developed nanobiocide represents a class of exceptional broad-spectrum antibacterial materials,holding great potential for treating drug-resistant infections in clinical settings.

Robust and Tumor-Environment-Activated DNA Cross-Linker Driving Nanoparticle Accumulation for Enhanced Therapeutics

Agglomeration of therapeutic nanoparticles in response to tumor microenvironments is a promising approach to enhance drug accumulation and improve therapeutic efficacy.Cytosine-rich DNA sequences show potential as ideal cross-linkers to drive nanoparticle agglomeration because they can sensitively respond to weak acidity and form interchain folding.However,the in vivo application of DNA is generally limited by its poor biostability;as a consequence,modifications with unprotected DNA cross-linkers can enhance the accumulation of nanoparticles twofold at the tumor site.Facing this challenge,we have designed and developed a protection and tumor-environment activation strategy to enable the in vivo application of a DNA cross-linker.Specifically,reactive oxygen species(ROS)-responsive polyethylene glycol(PEG)was modified on the nanoparticle surface together with the DNA crosslinker,which protects DNA from degradation during the blood circulation;meanwhile,when arriving at the tumor site,the nanoparticles shed the PEG shell as a response to ROS to uncover and activate the DNA cross-linkers.Using this strategy,a sevenfold enhancement in tumor accumulation was achieved owing to both superior pH sensitivity and improved stability of DNA cross-linkers.Finally,significantly improved therapeutic efficacy in in vivo anticancer treatment was realized by using this agglomeration strategy driven by protected and stimuli-activated DNA cross-linkers.