Impact of the COVID-19 Pandemic on Cancer Patients: Experience of the medical oncology department of CHU HASSAN II Fez.

Introduction: In December 2019, COVID 19 spread worldwide, but did not officially start in MOROCCO until March 02, 2020. Since then, this pandemic has significantly impacted the health status of patients in general and cancer patients in particular. The main objective of our study is to evaluate the prognosis of patients treated for cancer and infected with COVID-19. Material and method: A descriptive study with prospective collection was carried out at the medical oncology department of CHU Hassan II in FEZ over a period of two years, from March 2020 to March 2022. Data was carried out on the software SPSS. Results: One hundred cancer patients tested positive for COVID-19 infection and were collected within our department. The average age was 56 years [22-91]. The sex ratio was 1.2. Patients with breast cancer were the most affected by this infection (34%). The clinical symptomatology was dominated by the respiratory syndrome (45%).The diagnosis was made through thoracic CT scan in 62% of cases. 76% of patients were in a metastatic stage. 96% of patients were undergoing oncological treatment. For symptomatique patients, the standard treatment approach involved using antibiotics in 76% of cases. Evolution was marked by recovery in 79% of patients, with a death rate of 12% in this cancer patient population. Conclusion: COVID-19 infection is particularly severe in cancer patients. Mortality among these patients remains high and is associated with overall patient characteristics. However, anticancer treatments have not shown deleterious effects on the course of COVID-19.

Comparison of Clinicopathological and Survival Features of Right and Left Colon Cancers: Experience of the Medical Oncology Department of Fez

Right-sided colon cancers (RCC) and left-sided colon cancers (LCC) have different epidemiological, physiological, pathological, genetic, and clinical characteristics, which result in differences in the course, prognosis, and outcome of disease. The objective of our study is to compare right-sided colon cancers and left-sided colon cancers regarding clinicopathological and survival characteristics. This is a retrospective study of 664 patients with colon cancer treated at the medical oncology department of Fez over a period from December 2009 to September 2020. Rectosigmoid, descending colon, and splenic flexure tumors were considered left-sided colon cancers, whereas ascending colon tumors were considered right-sided colon cancers. The Kaplan Meier method was used to estimate median survival. The study included 664 patients (female, 47%) having colon cancer with a median age of 60 years (23 - 83). Of the patients, 78.5% (n = 519) had LCC and 19.36 % (n = 128) had RCC. The rate of patients aged ≥ 65 years and the rate of patients with a family history of colon cancer was higher in the LCC patients. The proportion of poorly differentiated adenocarcinomas represented 3%, of which 63% had cancer of the right colon. There was a significantly higher proportion of higher T stage (T3-4: 62% vs 38%) in right sided tumors as compared to left sided tumors. The rate of metastatic patients was 64.1% in the RCC group and 43% in the LCC group. The median follow-up period was 14 months in the RCC group and 19 months in the LCC group with higher median overall survival in the LCC group (32 vs 21 months). We found histopathological differences between right and left sided colon cancer. Tumors on the right colon were found to be more aggressive, as expressed by poorer differentiation, higher T stage associated with a median overall survival better in left colon cancer.

Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases

Colorectal cancer metastasizes predictably, with liver predominance in most cases. Because liver involvement has been shown to be a major determinant of survival in this population, liver-directed therapies are increasingly considered even in cases where there is(limited) extrahepatic disease. Unfortunately, these patients carry a known risk of recurrence in the liver regardless of initial therapy choice. Therefore, there is a demand for minimally invasive, non-surgical, personalized cancer treatments to preserve quality of life in the induction, consolidation, and maintenance phases of cancer therapy. This report aims to review evidence-based conceptual, pharmacological, and technological paradigm shifts in parenteral and percutaneous treatment strategies as well as forthcoming evidence regarding next-generation systemic, locoregional, and local treatment approaches for this patient population.

Management of Malignants Gliomas: About 20 Cases Treated in the Medical Oncology Department of Fattouma Bourguiba University Hospital-Monastir

Introduction: Malignant gliomas refer to grade III or IV brain tumors defined according to the World Health Organization (WHO) classification. They are a heterogeneous group of pathologies and represent a serious health problem by their frequency, severity and treatment difficulties. The prognosis of malignant gliomas remains poor despite all the medical advances. Materials and Methods: It is a retrospective study included 20 cases of malignant glial tumors treated at the medical oncology department, Fattouma Bourguiba hospital in Monastir between 2012 and 2016, according to the STUPP protocol. Results: These were 12 men and 8 women with a median age of 43. Clinical signs were not very specific, dominated by intracranial hypertension and deficit signs. Imagery referred to the diagnosis of malignant gliomas in 1st intention. Surgery consisted of a macroscopically complete exeresis in (15%) cases, a partial exeresis in (50%), the rest of the patients had a stereotactic biopsy. Histology found GBM in 16 patients (80%), 2 cases of Grade III anaplastic astrocytoma (10%), 1 case of anaplastic oligodendroglioma (5%), and 1 case of Grade III anaplastic eppendymoma (5%). Most of our patients received concurrent radio-chemotherapy and adjuvant TMZ chemotherapy was administered in 15 patients, 7 of whom received the full 6 scheduled cures. A relapse treatment was decided in only one of the 12 patients who relapsed. 6 patients are still alive. The median survival is 11.27 months. In our series, overall survival was related to histological type (p = 0.006) and neurological status assessed at the end of RT-CT (p = 0.001). While age, general condition score, type of surgery, and post-therapeutic development did not show a statistically significant relationship, although survival rates were consistent with the criteria assessed. Conclusion: Malignant gliomas are rare tumors, bad prognosis, aggravated in Tunisia by a diagnostic delay. The creation of a multidisciplinary neuro-oncology group can help to improve management.

Non-Clear Cell Renal Carcinomas: About 23 Cases Experience of the Medical Oncology Department of the Hassan II Hospital in Fez, Morocco

Background: Non-clear cell renal cell carcinomas represent a very rare and heterogeneous variety of kidney cancer. The aim of this study is to describe the main epidemiological, clinical, paraclinical, histological and therapeutic characteristics of these cancers. Methods: A descriptive retrospective study was conducted in the Medical Oncology Department of the Hassan II Hospital in Fez, collecting 23 patients with these tumors during the period from January 2008 to January 2020. The statistical analysis is made by the SPSS software version 23. Survival was calculated by the Kaplan-Meier method. Results: The average age of the patients was 57.4 years. The sex ratio M/F was 1.3. The main risk factor was smoking (n = 10). The most common symptom was low back pain (n = 23). 17 patients were metastatic, while 6 patients had localized disease. The most common histological type was papillary carcinoma (n = 12). Patients with localized disease have undergone an extended total nephrectomy. After a median follow-up of 145 months, the median of recurrence-free survival was 48 months and that of overall survival was 150 months. In a metastatic situation, 16 patients had received systemic treatment, of which 13 patients had received sunitinib, 2 patients pazaopanib and only one patient received everolimus. After a median follow-up of 20 months, the median of progression-free survival was 5 months and that of overall survival was 9 months. Conclusion: At the present time, there is no therapeutic standard for the management of patients with these tumors. Surgery for people with localized or locally advanced disease remains the initial and most important approach. For patients with advanced disease, a clinical trial should be considered.

Lung cancer management during the COVID-19 pandemic:experience of a medical oncology unit at a tertiary hospital in Singapore

Coronavirus disease 2019(COVID-19),caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),was declared a pandemic by the World Health Organisation(WHO)on 11 March 2020.The pandemic has had profound effects on healthcare systems across the world,and also poses unique challenges for oncology services.Singapore saw its first imported case of COVID-19 on 23 January 2020,and there has since been 52,000 confirmed cases and 27 deaths as of early August 2020 locally.Oncologists have a special duty to our patients to ensure patient safety and provide optimum care without undue disruption which may compromise long-term cancer-specific outcomes.We herein examine the impact that the COVID-19 pandemic has had on our clinical services,and share our experience with regards to manpower reconfiguration,infection control measures,diagnostic evaluation of patients with suspected COVID-19,oncological management of lung cancer patients,as well as changes in the education and training of juniors,from our unique position as a Medical Oncology department in Tan Tock Seng Hospital,a tertiary hospital affiliated with the National Centre of Infectious Diseases in Singapore.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

TM9SF1 promotes bladder cancer cell growth and infiltration

BACKGROUND Bladder cancer(BC)is the most common urological tumor.It has a high recur-rence rate,displays tutor heterogeneity,and resists chemotherapy.Furthermore,the long-term survival rate of BC patients has remained unchanged for decades,which seriously affects the quality of patient survival.To improve the survival rate and prognosis of BC patients,it is necessary to explore the molecular mechanisms of BC development and progression and identify targets for treatment and intervention.Transmembrane 9 superfamily member 1(TM9SF1),also known as MP70 and HMP70,is a member of a family of nine transmembrane superfamily proteins,which was first identified in 1997.TM9SF1 can be expressed in BC,but its biological function and mechanism in BC are not clear.AIM To investigate the biological function and mechanism of TM9SF1 in BC.Overexpression of TM9SF1 increased the in vitro proliferation,migration,and invasion of BC cells by promoting the entry of BC cells into the G2/M phase.Silencing of TM9SF1 inhibited in vitro proliferation,migration,and invasion of BC cells and blocked BC cells in the G1 phase.CONCLUSION TM9SF1 may be an oncogene in BC.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract

Mixed neuroendocrine non-neuroendocrine neoplasms(MiNENs)are a hetero-geneous group of malignant neoplasms that can settle in the gastroenteropan-creatic tract.They are composed of a neuroendocrine(NE)and a non-NE compo-nent in at least 30%of each tumour.The non-NE component can include different histological combinations of glandular,squamous,mucinous and sarcomatoid phenotypes,and one or both of the components can be low-or high grade malignant.Recent changes in the nomenclature of these neoplasms might lead to great deal of confusion,and the lack of specific clinical trials is the main reason why their management is difficult.The review aims to clarify the definition of MiNEN and analyze available evidence about their diagnosis and treatment options according to their location and extension through careful analysis of the available data.It would be important to reach a general consensus on their diagnosis in order to construct a classification that remains stable over time and facilitates the design of clinical trials that,due to their low incidence,will require long recruitment periods.

Systemic Inflammation Response Index and weight loss as prognostic factors in metastatic pancreatic cancer: A concept study from the PANTHEIA-SEOM trial

BACKGROUND The prognostic value of the Systemic Inflammation Response Index(SIRI)in advanced pancreatic cancer is recognized,but its correlation with patients´nutritional status and outcomes remains unexplored.AIM To study the prognostic significance of SIRI and weight loss in metastatic pancreatic cancer.METHODS The PANTHEIA-Spanish Society of Medical Oncology(SEOM)study is a multicentric(16 Spanish hospitals),observational,longitudinal,non-interventional initiative,promoted by the SEOM Real World-Evidence work group.This pilot study sought to analyze the association between weight loss and inflammatory status as defined by SIRI.The cohort stems from a proof-of-concept pilot study conducted at one of the coordinating centers.Patients with pathologically confirmed metastatic pancreatic adenocarcinoma,treated from January 2020 to January 2023,were included.The index was calculated using the product of neutrophil and monocyte counts,divided by lymphocyte counts,obtained within 15 days before initiation chemotherapy.This study evaluated associations between overall survival(OS),SIRI and weight loss.RESULTS A total of 50 patients were included.66%of these patients were male and the median age was 66 years.Metastasis sites:36%liver,12%peritoneal carcinomatosis,10%lung,and 42%multiple locations.Regarding the first line palliative chemotherapy treatments:50%received gemcitabine plus nab-paclitaxel;28%,modified fluorouracil,leucovorin,irinotecan and oxaliplatin,and 16%were administered gemcitabine.42%had a weight loss>5%in the three months(mo)preceding diagnosis.21 patients with a SIRI≥2.3×10^(3)/L exhibited a trend towards a lower median OS compared to those with a SIRI<2.3×10^(3)/L(4 vs 18 mo;P<0.000).Among 21 patients with>5%weight loss before diagnosis,the median OS was 6 mo,in contrast to 19 mo for those who did not experience such weight loss(P=0.003).Patients with a weight loss>5%showed higher SIRI levels.This difference was statistically significant(P<0.000).For patients with a SIRI<2.3×10^(3)/L,those who did not lose>5%of their weight had an OS of 20 mo,compared to 11 mo for those who did(P<0.001).No association was found between carbohydrate antigen 19-9 levels≥1000 U/mL and weight loss.CONCLUSION A higher SIRI was correlated with decreased survival rates in patients with metastatic pancreatic cancer and associated with weight loss.An elevated SIRI is suggested as a predictor of survival,emphasizing the need for prospective validation in the upcoming PANTHEIA-SEOM study.

Is sarcopenia effective on survival in patients with metastatic gastric cancer?

BACKGROUND Sarcopenia is a progressively diminishing state characterized by the reduction of muscle mass and density,which is frequently observed in malignancies of solid organs.AIM To assess how sarcopenia affects the overall survival of individuals who have been diagnosed with metastatic gastric cancer.METHODS The study retrospectively included individuals who had been diagnosed with metastatic gastric cancer between January 2008 and December 2020.Sarcopenia was identified through the calculation of the average Hounsfield units(HUAC)using computed tomography(CT)images taken at the time of diagnosis in patients.RESULTS A total of 118 patients with metastatic gastric cancer were evaluated.Sarcopenia was detected in 29 patients(24.6%).The median survival of all patients was 8(1-43)mo.The median survival of patients with sarcopenia was 2 mo,while it was 10 mo for those without sarcopenia(P<0.001).A significant relationship was found between sarcopenia and survival.CONCLUSION Sarcopenia has been observed to impact survival outcomes in various types of solid tumor cancers.Sarcopenic patients can be identified in a short time,easily and inexpensively,by HUAC measurements from CT images used for diagnosis,and survival could be promoted with nutritional support.

Current and Potential Roles of Ferroptosis in Bladder Cancer

Ferroptosis,a type of regulated cell death driven by iron-dependent lipid peroxidation,is mainly initiated by extramitochondrial lipid peroxidation due to the accumulation of iron-dependent reactive oxygen species.Ferroptosis is a prevalent and primitive form of cell death.Numerous cellular metabolic processes regulate ferroptosis,including redox homeostasis,iron regulation,mitochondrial activity,amino acid metabolism,lipid metabolism,and various disease-related signaling pathways.Ferroptosis plays a pivotal role in cancer therapy,particularly in the eradication of aggressive malignancies resistant to conventional treatments.Multiple studies have explored the connection between ferroptosis and bladder cancer,focusing on its incidence and treatment outcomes.Several biomolecules and tumor-associated signaling pathways,such as p53,heat shock protein 1,nuclear receptor coactivator 4,RAS-RAF-MEK,phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin,and the Hippo-tafazzin signaling system,exert a moderating influence on ferroptosis in bladder cancer.Ferroptosis inducers,including erastin,artemisinin,conjugated polymer nanoparticles,and quinazolinyl-arylurea derivatives,hold promise for enhancing the effectiveness of conventional anticancer medications in bladder cancer treatment.Combining conventional therapeutic drugs and treatment methods related to ferroptosis offers a promising approach for the treatment of bladder cancer.In this review,we analyze the research on ferroptosis to augment the efficacy of bladder cancer treatment.

Metastatic clear cell sarcoma of the pancreas:A sporadic cancer

Primary or secondary clear cell sarcoma of the pancreas is an exceedingly rare and aggressive disease.In addition to pathology,molecular analysis is pivotal in differential diagnosis,especially with malignant melanoma.A key aspect in identifying clear cell sarcoma is specific genetic alterations,notably the translocation of t(12;22)(q13;q13),a diagnostic hallmark of this sarcoma subtype,which is absent in malignant melanoma.Treatment of primary clear cell sarcoma of the pancreas is the same as that for adenocarcinoma.

IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Erratum to Treatment strategies for patients with HER2-positive gastric cancer

For the affiliation information,the affiliation for author Feixue Wang should be Department of GI Medical Oncology,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Tianjin's Clinical Research Center for Cancer,Tianjin Key Laboratory of Digestive Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin Medical University,Tianjin 300060,China.

Emerging role of liquid biopsy in rat sarcoma virus mutated metastatic colorectal cancer:A case report

BACKGROUND In patients with metastatic colorectal cancer(mCRC),the treatment options are limited and have been proved to be affected by rat sarcoma virus(RAS)mutational status.In RAS wild-type(wt)patients,the combination of antiepidermal growth factor receptor(EGFR)monoclonal antibodies with chemotherapy(CT)is more effective than CT alone.On the other hand,RAS-mutated patients are not eligible for treatment with anti-EGFR antibodies.CASE SUMMARY Eleven patients with initially RAS-mutated mCRC were followed from diagnosis to May 2022.At the time of cell-free DNA determination,five patients had undergone one CT line,five patients had undergone two CT lines,and one patient had undergone three CT lines(all in combination with bevacizumab).At the second and third treatment lines[second line(2L),third line(3L)],patients with neo-RAS wt received a combination of CT and cetuximab.In neo-RAS wt patients treated with anti-EGFR,our findings indicated an increase in progression-free survival for both 2L and 3L(14.5 mo,P=0.119 and 3.9 mo,P=0.882,respectively).Regarding 2L overall survival,we registered a slight increase in neo-RAS wt patients treated with anti-EGFR(33.6 mo vs 32.4 mo,P=0.385).At data cut-off,two patients were still alive:A RAS-mutated patient undergoing 3L treatment and a neo-RAS wt patient who received 2L treatment with anti-EGFR(ongoing).CONCLUSION Our case series demonstrated that monitoring RAS mutations in mCRC by liquid biopsy may provide an additional treatment line for neo-RAS wt patients.

Anti-EGFR antibody monotherapy for colorectal cancer with severe hyperbilirubinemia: A case report

BACKGROUND Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer(CRC).Effective drainage is often im-possible before initiating systemic chemotherapy,owing to the liver’s diffuse metastatic involvement.Moreover,an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable.CASE SUMMARY The patient,a man in his 50s,presented with progressive fatigue and severe jaundice.Computed tomography revealed multiple hepatic masses with thick-ened walls in the sigmoid colon,which was pathologically confirmed as a well-differentiated adenocarcinoma.No RAS or BRAF mutations were detected.The Eastern Cooperative Oncology Group(ECOG)performance status(PS)score was 2.Biliary drainage was impossible due to the absence of a dilated bile duct,and panitumumab monotherapy was promptly initiated.Subsequently,the bilirubin level decreased and then normalized,and the patient’s PS improved to zero ECOG score after four cycles of therapy without significant adverse events.CONCLUSION Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.

A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell death.Apatinib is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis pathway.However,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported yet.Tumor.secreted exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered.Here,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of Apatinib.In conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.