Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma:A case report

BACKGROUND Neoadjuvant or perioperative chemotherapy combined with surgery can reduce postoperative recurrence and improve the long-term survival rate of patients with locally advanced resectable gastric carcinoma.Nivolumab combined with chemotherapy has been recommended by the National Comprehensive Cancer Network guidelines as a first-line therapy for advanced gastric carcinoma/adenocarcinoma of the gastroesophageal junction and serves as the basis for immunotherapy combined with chemotherapy to become a neoadjuvant therapy.Herein,we report a case in which pathologic complete response was achieved by neoadjuvant administration of toripalimab,Herceptin,and docetaxel,oxaliplatin,calcium folinate,and fluorouracil(FLOT)chemotherapy followed by surgery for human epidermal growth factor receptor 2(HER2)-and programmed deathligand 1(PD-L1)-positive locally advanced gastric carcinoma.We hope that this case will shed some light on neoadjuvant therapy for gastric carcinoma.CASE SUMMARY The patient was diagnosed with locally advanced adenocarcinoma of the cardia.Immunohistochemistry of the baseline tissues suggested that the tissues were HER2-(fluorescent in situ hybridization)and PD-L1-positive(combined positive score=1).The patient underwent surgery following a four-cycle neoadjuvant therapy comprising Herceptin,toripalimab,and FLOT chemotherapy.The postoperative pathological findings showed mild atypical hyperplasia of the local glands with chronic mucosal inflammation(proximal stomach),no clear residual tumor(tumor regression grade 0),no regional lymph node metastasis,and negative upper and lower cut ends.The levels of tumor markers were reduced to normal levels after re-examination.With good postoperative recovery,the four-cycle preoperative chemotherapy was continued at the same dosage as that previously administered.After the treatment,the patient was monitored every 3 mo with a follow-up of 12 mo(4 times).As of February 27,2022,he was in a good condition without disease progression.The clinical trial registration number is E2019401.CONCLUSION There are many ongoing studies on neoadjuvant immunotherapy combined with chemotherapy or radiotherapy;however,most of these studies are phase II studies with small cohorts.According to the results of some current studies,these combined regimens have shown promising results in terms of efficacy and safety.However,the clinical efficacy and safety of the neoadjuvant therapies used in these combined regimens need to be confirmed by additional prospective phase III clinical trials,and further exploration of molecular markers for effective populations is required.

Combining of chemotherapy with targeted therapy for advanced biliary tract cancer:A systematic review and meta-analysis

BACKGROUND Targeted therapy(TT)has resulted in controversial efficacy as first-line treatment for biliary tract cancer(BTC).More efficacy comparisons are required to clarify the overall effects of chemotherapy(CT)combined with TT and CT alone on advanced BTC.AIM To conduct a meta-analysis of the available evidence on the efficacy of CT combined with TT for advanced BTC.METHODS The PubMed,EMBASE,ClinicalTrials,Scopus and Cochrane Library databases were systematically searched for relevant studies published from inception to August 2022.Only randomized clinical trials(RCTs)including comparisons between the combination of gemcitabine-based CT with TT and CT alone as firstline treatment for advanced BTC were eligible(PROSPERO-CRD42022313001).The odds ratios(ORs)for the objective response rate(ORR)and hazard ratios(HRs)for both progression-free survival(PFS)and overall survival(OS)were calculated and analyzed.Subgroup analyses based on different targeted agents,CT regimens and tumor locations were prespecified.RESULTS Nine RCTs with a total of 1361 individuals were included and analyzed.The overall analysis showed a significant improvement in ORR in patients treated with CT+TT compared to those treated with CT alone(OR=1.43,95%CI:1.11-1.86,P=0.007)but no difference in PFS or OS.Similar trends were observed in the subgroup treated with agents targeting epidermal growth factor receptor(OR=1.67,95%CI:1.17-2.37,P=0.004)but not in the subgroups treated with agents targeting vascular endothelial growth factor receptor or mesenchymal-epithelial transition factor.Notably,patients who received a CT regimen of gemcitabine+oxaliplatin in the CT+TT arm had both a higher ORR(OR=1.75,95%CI:1.20-2.56,P=0.004)and longer PFS(HR=0.83,95%CI:0.70-0.99,P=0.03)than those in the CT-only arm.Moreover,patients with cholangiocarcinoma treated with CT+TT had significantly increased ORR and PFS(ORR,OR=2.06,95%CI:1.27-3.35,PFS,HR=0.79,95%CI:0.66-0.94).CONCLUSION CT+TT is a potential first-line treatment for advanced BTC that leads to improved tumor control and survival outcomes,and highlighting the importance of CT regimens and tumor types in the application of TT.

Efficacy and Safety of Chemotherapy with or without Targeted Therapy in Biliary Tract Cancer:A Meta-analysis of 7 Randomized Controlled Trials

The systematic treatment based on gemcitabine plus cisplatin is recommended as the current standard chemotherapy for unresectable or metastatic biliary tract cancers.However,the exact benefits from the recognized regime are still dismal.We thus elicit this study in an attempt to analyze whether targeted therapy coupled with various chemotherapy could produce improvement of survival benefits.The clinical trials were searched electronically from databases till July 2016 published in English and Chinese.Nine hundred and sixty-four patients from 7 trials were identified in our analysis.The overall analysis achieved a significantly higher overall response rate（ORR） among the patients treated with targeted drugs plus chemotherapy than chemotherapy alone（OR=1.87;95% CI：1.37–2.57;P=0.000）,but failed in the overall progression-free survival（PFS） [mean difference（MD）=0.63;95% CI：–0.45–1.72;P=0.26] and overall survival（OS）（MD=–0.67;95% CI：–2.54–1.20;P=0.49）.In the sub analysis,better ORR was obtained with the addition of EGFR（OR=1.75;95% CI：1.20–2.56;P=0.004） and VEGFR（OR=2.5;95% CI：1.28–4.87;P=0.007） targeted therapy.Furthermore,the sub analysis of EGFR target showed an significant improvement on PFS（MD=1.36;95% CI：0.29–2.43;P=0.01）.No significant differences were observed in the incidences of neutropenia（OR=1.37;95% CI：0.89–2.12）,thrombocytopenia（OR=1.40;95% CI：0.83–2.39）,anemia（OR=1.21;95% CI：0.62–2.38）,peripheral neuropathy（OR=1.52;95% CI：0.81–2.88）,increased AST/ALT（OR=1.40;95% CI：0.82–2.39） as well as fatigue（OR=1.65;95% CI：0.96–2.84） in either of the treatment groups.In conclusion,better ORR associated with chemotherapy combined with targeted therapy（both targeting EGFR and VEGF） is found in the present meta-analysis without the cost of increased unacceptable toxicities,but regretfully not for the OS.The sub-analysis of targeting EGFR instead of VEGF obtains a superior PFS.Otherwise,there is no statistically significant difference in the overall PFS between the combination regime and chemotherapy alone.Given the paucity of favorable data,we need further studies to characterize optimal targeted agents to confirm the potential value to biliary tract cancer.

The Clinical Study of Multigene Combination Test to Guide Chemotherapy Combined with Targeted Therapy in Patients with Advanced Gastrointestinal Tumors

Objective:To study the clinical effects of multigene combination test to guide chemotherapy combined with targeted therapy in patients with advanced gastrointestinal tumors.Methods:The samples were selected from 60 patients with advanced gastrointestinal tumors admitted to our hospital from March 2019 to July 2020,and were divided into a study group and a control group using a random number table model;patients in the control group did not undergo genetic testing and FOLLOX4+PD-1 chemotherapy,while patients in the study group underwent TYMS,ERCC1,EGFR,and KRAS and VEGF gene expression levels test,and the sensitive treatment plan was determined based on the test results,and the clinical indexes were compared between the two groups.Results:By comparing the total effective rate,survival time,and time to disease progression of chemotherapy in the two groups,the study group has a significant advantage(P<0.05).Conclusion:The combination of chemotherapy and targeted therapy for advanced gastrointestinal tumor patients can improve the efficiency of chemotherapy and prolong the time of disease progression and survival,which is worthy of comprehensive promotion.

c-Met targeted therapy of cholangiocarcinoma

Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

Ovarian cancer stem cells: Can targeted therapy lead to improved progression-free survival?

Despite significant effort and research funds, epithelial ovarian cancer remains a very deadly disease. There are no effective screening methods that discover early stage disease; the majority of patients are diagnosed with advanced disease. Treatment modalities consist primarily of radical debulking surgery followed by taxane and platinum-based chemotherapy. Newer therapies including limited targeted agents and intraperitoneal delivery of chemotherapeutic drugs have improved disease-free intervals, but failed to yield longlasting cures in most patients. Chemotherapeutic resistance, particularly in the recurrent setting, plagues the disease. Targeting the pathways and mechanisms behind the development of chemoresistance in ovarian cancer could lead to significant improvement in patient outcomes. In many malignancies, including blood and other solid tumors, there is a subgroup of tumor cells, separate from the bulk population, called cancer stem cells(CSCs). These CSCs are thought to be the cause of metastasis, recurrence and resistance. However, todate, ovarian CSCs have been difficult to identify, isolate, and target. It is felt by many investigators that finding a putative ovarian CSC and a chemotherapeutic agent to target it could be the key to a cure for this deadly disease. This review will focus on recent advances in this arena and discuss some of the controversies surrounding the concept.

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

The “predictive molecule targeted chemotherapy” for relapsed ovarian cancer—a pilot study

Objective: How to choose chemotherapy regimen is a often-encountered and formidable problem in the setting of relapsed ovarian cancer. So far, it was usually according to the clinical trials and doctors’ experience and the response rate was very low. In the present study, we proposed a new treatment strategy–the “predictive molecule targeted chemotherapy, PMTC” to choose supposedly sensitive protocols and void supposedly resistant protocols based on the specific predictive molecule expression of individual tumor tissue. Methods: Retrospectively analysis of 16 cases of relapsed ovarian cancer patients from January 2002 to December 2003, as the experience-directed chemotherapy group (control group), to calculate the response rate. Prospectively recruit 9 cases of relapsed ovarian cancer patients after January 2004, whose chemotherapy drug choice was based on the expression of 6 predictive molecules (p53, et al) by means of immunohistochemistry, as the PMTC group, to calculate the response rate. χ2 test was used for the statistical analysis. Results: The response rate of control group was 26%, including 31% for second line and 14% for third line respectively. The response rate of PMTC group was 78%, in which 5 cases of early relapse all responded. The difference was significant (P=0.011). Conclusions: PMTC is a new effective method to treat the relapsed ovarian cancer.

Anti-EGFR and anti-VEGF agents:Important targeted therapies of colorectal liver metastases

Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, &#x0201c;new&#x0201d; RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The results of the FIRE-III trial showed that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, P = 0.017) for evaluable population. With the balanced allocation of second-line treatment, the FIRE-III trial was expected to provide evidence for selecting following regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combination therapy with more than one targeted agent has been proven to provide no benefit, and even was reported to be harmful as first-line treatment by four large clinical trials. However, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents.

Discussion on gemcitabine combined with targeted drugs in the treatment of pancreatic cancer

Pancreatic cancer is a malignant tumor with poor prognosis.The treatment of pancreatic cancer depends on the tumor stage and type,and includes local treatment(surgery,radiotherapy and ablation intervention)and systemic therapy(chemotherapy,targeted therapy and immunotherapy).We read with great interest the review“Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment”published on World J Gastroenterol and intended to share some of our perspectives in pancreatic cancer treatment.This review presents the therapeutic effects of the combination of gemcitabine and targeted drugs,which gives us a deeper insight into the combination treatments for pancreatic cancer.

Ex vivo liver resection and auto-transplantation and special systemic therapy in perihilar cholangiocarcinoma treatment

This editorial contains comments on the article“Systematic sequential therapy for ex vivo liver resection and autotransplantation:A case report and review of li-terature”in the recent issue of World Journal of Gastrointestinal Surgery.It points out the actuality and importance of the article and focuses primarily on the role and place of ex vivo liver resection and autotransplantation(ELRAT)and systemic therapy,underlying molecular mechanisms for targeted therapy in perihilar cho-langiocarcinoma(pCCA)management.pCCA is a tough malignancy with a high proportion of advanced disease at the time of diagnosis.The only curative option is radical surgery.Surgical excision and reconstruction become extremely com-plicated and not always could be performed even in localized disease.On the other hand,ELRAT takes its place among surgical options for carefully selected pCCA patients.In advanced disease,systemic therapy becomes a viable option to prolong survival.This editorial describes current possibilities in chemotherapy and reveals underlying mechanisms and projections in targeted therapy with ki-nase inhibitors and immunotherapy in both palliative and adjuvant settings.Fi-broblast grow factor and fibroblast grow factor receptor,human epidermal grow-th factor receptor 2,isocitrate dehydrogenase,and protein kinase cAMP activated catalytic subunit alpha(PRKACA)and beta(PRKACB)pathways have been ac-tively investigated in CCA in last years.Several agents were introduced and approved by the Food and Drug Administration.They all demonstrated mean-ingful activity in CCA patients with no global change in outcomes.That is why every successfully treated patient counts,especially those with advanced disease.In conclusion,pCCA is still hard to treat due to late diagnosis and extremely complicated surgical options.ELRAT also brings some hope,but it could be performed in very carefully selected patients.Advanced disease requires systemic anticancer treatment,which is supposed to be individualized according to the genetic and molecular features of cancer cells.Targeted therapy in combination with chemo-immunotherapy could be effective in susceptible patients.

Advances in Conversion Therapy for Primary Unresectable Hepatocellular Carcinoma

Primary liver cancer is one of the most common malignant tumours in the world, and according to statistics, about half of liver cancers occur in China, which seriously threatens the lives and health of people around the world, especially in China. Hepatocellular carcinoma is the most common type, accounting for about 90 per cent of primary liver cancers. Most patients are asymptomatic in the early stage and fail to pay attention to it. Most of the patients are in the middle or late stage when they are first diagnosed, and only 20% - 30% of them can receive radical hepatectomy. Patients are through the treatment to make the tumour shrinkage and downstaging, to achieve the condition of resectable, that is, the conversion treatment. Conversion therapy has great potential for development and has now become an indispensable treatment for intermediate and advanced hepatocellular carcinoma. However, there are various treatment options for conversion therapy, no uniform guidelines to guide clinical selection, and the overall conversion rate is still low, so it is particularly important to explore appropriate conversion therapy options. This article mainly describes the existing conversion therapies, hoping to provide help and ideas for exploring the best conversion therapies in the future.

Chemotherapy and molecular targeting therapy for recurrent cervical cancer

For patients with primary stage IVB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords： ＂uterine cervical cancer＂, ＂chemotherapy＂, and ＂targeted therapies＂. Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase III trials. To examine the best agent to combine with cisplatin, several landmark phase III clinical trials were conducted by Gynecologic Oncology Group （GOG） and Japan Clinical Oncology Group （JCOG）. Through, GOG204 and JCOG0505, paclitaxel/cisplatin （TP） and paclitaxel/carboplatin （TC） are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival （OS）. Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only modest gains in OS, particularly for patients with multiple poor prognostic factors. Therefore, it is crucial to consider not only the survival benefit, but also the minimization of treatment toxicity, and maximization of quality of life （QOL）.

Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation:Where do we stand?

Liver transplantation (LT) for hepatocellular carcinoma (HCC) within Milan criteria is a widely accepted optimal therapy. Neo-adjuvant therapy before transplantation has been used as a bridging therapy to prevent dropout during the waiting period and as a down-staging method for the patient with intermediate HCC to qualify for liver transplantation. Transarterial chemoembolization and radiofrequency ablation are the most commonly used method for locoregional therapy. The data associated with newer modalities including drug-eluting beads, radioembolization with Y90, stereotactic radiation therapy and sorafenib will be discussed as a tool for converting advanced HCC to LT candidates. The concept &#x0201c;ablate and wait&#x0201d; has gained the popularity where mandated observation period after neo-adjuvant therapy allows for tumor biology to become apparent, thus has been recommended after down-staging. The role of neo-adjuvant therapy with conjunction of &#x0201c;ablate and wait&#x0201d; in living donor liver transplantation for intermediate stage HCC is also discussed in the paper.

Cathepsin B-responsive prodrugs for cancer-targeted therapy:Recent advances and progress for clinical translation

The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin B in targeted cancer cells.However,clinical translation of such therapeutic approaches has been restricted by low antitumor efficacy that is mainly attributable to undesirable pharmacokinetic profiles and inefficient tumor-targeting of cathepsin B-responsive prodrugs,due to their small-molecule structure.In recent decades,many researchers have widely investigated the drug delivery system(DDS)to improve the in vivo pharmacokinetic profiles and tumor-targeting efficiency of cathepsin B-responsive prodrugs via the application of polymers,dendrimers,antibodies,lipids,and inorganic nanoparticles as drug carriers.In addition,the potential therapeutic efficacy of DDS for cathepsin B-responsive prodrugs is demonstrated in multiple studies and combinatorial treatment with typical therapeutic modalities can effectively overcome the challenges of tumor heterogeneity and multidrug resistance.In this review,recent advances and progress of new DDS for cathepsin B-responsive prodrugs are outlined,and their clinical trials are discussed.Besides,potential challenges and the outlooks for clinical translation of cathepsin B-responsive prodrugs are highlighted.

Neoadjuvant chemotherapy for metastatic colorectal cancer to the liver: from chemotherapy to targeting therapy

Despite the advances in surgical techniques, adjuvant chemotherapy and targeted therapy, approximately 40%-70% of patients with progressive colorectal cancer will develop liver metastases, of whom one-third are found at the time of diagnosis.[1] Surgical resection is now the standard treatment and also the only potentially curative treatment for resectable lesions.

New advances in targeted gastric cancer treatment

Despite a decrease in incidence over past decades,gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.

Chemotherapy for hepatocellular carcinoma:The present and the future

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia

Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.