Immune checkpoint inhibitors in clinical trials

Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibodybased therapies targeting cytotoxic T-lymphocyte antigen 4(CTLA4), programmed cell death 1(PD-1), and programmed cell death ligand 1(PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.

Unexplained liver laceration after metastasis radiofrequency ablation

Many studies have established the role of radiofrequency (RF) ablation as a minimally invasive treatment for liver metastases. Although relatively safe, several complications have been reported with the increased use of RF ablation. We describe here a case of unexplained liver laceration after a RF procedure. A woman who presented a solitary metachronous liver metastasis underwent RF ablation treatment for this lesion. Six hours later the patient displayed fatigue and pallor. Emergency blood tests showed a haemoglobin level of < 7 g/dL and markedly elevated transaminase levels. A computed tomography examination revealed two areas of liver laceration with haematoma, one of them following the path of the needle and the other leading away from the f irst. Following a blood transfusion, the patient was haemodynamically stable and completely recovered 24 h later. The patient remained in bed for 1 wk. No surgical intervention was required, and she was discharged 1 wk later.

Non-pulmonary allergic diseases and inflammatory bowel disease: A qualitative review

While the etiological underpinnings of inflammatory bowel disease(IBD) are highly complex, it has been not-ed that both clinical and pathophysiological similarities exist between IBD and both asthma and non-pulmonary allergic phenomena. In this review, several key points on common biomarkers, pathophysiology, clinical manifesta-tions and nutritional and probiotic interventions for both IBD and non-pulmonary allergic diseases are discussed.Histamine and mast cell activity show common behav-iors in both IBD and in certain allergic disorders. IgE also represents a key immunoglobulin involved in both IBD and in certain allergic pathologies, though these links require further study. Probiotics remain a critically important intervention for both IBD subtypes as well as multiple allergic phenomena. Linked clinical phenomena, especially sinonasal disease and IBD, are discussed. In addition, nutritional interventions remain an underuti-lized and promising therapy for modification of both al-lergic disorders and IBD. Recommending new mothers breastfeed their infants, and increasing the duration of breastfeeding may also help prevent both IBD and al-lergic diseases, but requires more investigation. While much remains to be discovered, it is clear that non-pulmonary allergic phenomena are connected to IBD in a myriad number of ways and that the discovery of com-mon immunological pathways may usher in an era of vastly improved treatments for patients.

The challenge of drug resistance in pancreatic ductal adenocarcinoma:a current overview

Pancreatic ductal adenocarcinoma(PDAC)has one of the highest mortality rates among all cancer types.Its delayed diagnosis precludes curative resection,thus most of the current therapies against PDAC are based on chemo-and radiotherapy.Unfortunately,these strategies are insufficient to improve its poor prognosis.Despite the advances made in chemotherapy(e.g.nab-paclitaxel and gemcitabine),many patients with PDAC are unable to benefit from them due to the rapid development of drug resistance.Currently,more than 165 genes have been found to be implicated in drug resistance of pancreatic tumors,including different integrins,mucins,NF-κB,RAS and CXCR4.Moreover,drug resistance in PDAC is thought to be mediated by the modulation of miRNAs(e.g.miRNA-21,miRNA-145 and miRNA-155),which regulate genes that participate in cell proliferation,invasion and metastasis.Finally,cancer stem cells are intimately related to drug resistance in PDAC due to their ability to overexpress ABC genes-involved in drug transport-,and enzymes such as aldehyde dehydrogenases-implicated in cellular drug metabolism-and poly(ADP-ribose)polymerases-involved in drug-induced DNA damage repair.Understanding the mechanisms involved in drug resistance will contribute to the development of efficient therapeutic strategies and to improve the prognosis of patients with PDAC.

Microangiopathic Hemolytic Anemia and Diffuse Bone Metastasis by Signet Ring Cell Adenocarcinoma

Microangiopathic hemolytic anemia (MAHA) is a rare paraneoplastic syndrome and is typically associated with gastric adenocarcinoma. We report a 47-year-old woman who presented with asthenia, lower back pain and bleeding. Twelve years ago the patient underwent total gastrectomy due to gastric adenocarcinoma and achieved complete remission. The patient was diagnosed with MAHA and diffuses bone metastasis of signet ring cell adenocarcinoma of unknown origin and was treated successfully with polichemotherapy based on cisplatin and 5-fluorouracil.

What is the purpose of launching World Journal of Respirology?

Congratulations to the publisher,members of the editorial board of the journal,and all the authors and readers for launching the World Journal of Respirology(WJR).The WJR is a peer-reviewed journal that will report novel theories,methods and techniques for the prevention,diagnosis,treatment,rehabilitation and nursing of patients with respiratory disease.Some of the topics that will be covered in the journal include diagnostic imaging,respiratory physiology,respiratory endoscopy,respiratory system tumors,chronic obstructive pulmonary disease,bronchial asthma,respiratory infections,critical respiratory illness,sleep-related respiratory disorders,interstitial lung disease,pulmonary vascular diseases,pulmonary embolism,traditional medicine,integrated Chinese and Western medicine,evidencebased medicine,epidemiology and nursing.Importantly,the WJR is an online,open-access journal,which will enable it to reach both experts and the general public without the need for registration or payment.If you want to share your work and findings,you will find the WJR an excellent journal for your publications!

Gastric Adenocarcinoma at the Joliot Curie Institute in Dakar: Epidemiological, Diagnostic and Therapeutic Aspects about 54 Cases

Objectives: To study the epidemiological, diagnostic, therapeutic and prognostic aspects of gastric adenocarcinoma at the Joliot Curie Institute in Dakar. Materials and Methods: We conducted a retrospective study over a seven-year period from January 2010 to December 2017 at the Joliot Curie Institute in Dakar. All cases of gastric adenocarcinoma proven by fibroscopy followed by histology or proven on the histological analysis of a surgical specimen were taken into account. The parameters studied were age, risk factors, stages of the disease, treatment and prognosis. Results: There were 54 cases of gastric adenocarcinoma over a period of 7 years. The average age was 54.74 years with extremes of 25 and 84 years. A male predominance was noted (35/54). The main risk factors found were alcohol (5/54), tobacco (13/54), Helicobacter pilori (4/54), gastric ulcer (12/54). Epigastralgia was the most frequent clinical manifestation. FOGD was carried out in 77.8% of patients. Histology was obtained before surgery in 40 patients (74.1% of cases) and on the operating room in 14 patients (25.9%). Patients were classified as stage II in 2/54 cases, stage III in 5/54 cases and stage IV in 47/54 cases. Gastro-entero-anastomosis was the main surgical procedure performed. External radiotherapy was performed in 1/54 patients. Chemotherapy was done in 52/54 patients, 96.3% of the cases. It was palliative in 66.7% of cases, neoadjuvant in 1.9% of cases, adjuvant in 24.1% of cases, perioperative in 3.7% of cases. Mortality was 79.6%. Patient survival times were relatively short: in less than 6 months 24/54 cases, 13/54 cases between 6 - 12 months, 5/54 cases between 13 - 24 months and 6/54 cases beyond 24 months. 6/54 patients were lost from view. Conclusion: Gastric adenocarcinoma is diagnosed lately in our conditions. It is responsible for a high mortality rate. Palliative treatment is often the only option because of the delay in diagnosis.

Management of Phylloid Sarcomas: A Retrospective Study of 12 Cases

Background: Phylloid sarcomas are rare. There is not enough data to codify the management. Objectives: The objective was to study the clinical and therapeutic aspects and the fate of patients after a follow-up of at least 4 years. Thus contributing to the limited body of knowledge on these tumors. Methods: a retrospective analysis of the files from 2013 to 2017 was carried out and patients were followed up until 2021at Hassan II Hospital. Epidemiological, clinical and therapeutic aspects were studied. Survival was calculated using the Kaplan-Meier method. Results: We collected 12 charts of patients treated for phyllodeal sarcoma from 2013 to 2017. The median age was 43 years. The circumstance of discovery was marked by the presence of nodule in all patients. The coupled echo-mammography examination classified the nodules, ACR 4 in 7 patients and ACR 3 in 3 and ACR 5 in 2 patients. Histological examination revealed a phylloid sarcoma in 11 patients and a borderline phylloid tumor in 1 patient. All patients had radical surgery with positive margins in 2 patients, 16.66%. One patient had revision surgery. Histological examination of the surgical specimens showed phylloid sarcoma on all specimens. All patients had adjuvant radiotherapy with doses of 50 Gy in 25 fractions of 2 Gy and a boost of 10 Gy was done in one patient. The median spread of radiotherapy was 37 days. Grade 1 and 2 skin toxicities were noted in 5 and 3 patients respectively. The median time from surgery to radiotherapy was 2.95 months. 3 patients relapsed after 13.6 months of follow-up. The recurrence-free survival at 1 and 3 years was 83% and 75% respectively. Overall survival at 3 and 5 years was 83% and 75% respectively. Conclusion: This is a rare entity which requires randomized trials to codify its management. It would seem that the multidisciplinary approach, associating surgery ± radiotherapy, is a good option.

Pregnancy with Gastric Stromal Tumor

Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. GIST are rare during pregnancy. We report here the case of a patient who was admitted in our university hospital for GIST discovered during the second trimester of pregnancy. She was 42 years old, in the fifth months of pregnancy. She was admitted for biliary colic pain with vomiting. On abdominal examination, we objectified a distended abdomen with uterine height of 18 cm and epigastric mass of 10 cm. Abdominal ultrasound and magnetic resonance imaging (MRI) showed a hepatic, tissue and cystic mass, developing at the expense of the left liver. Endoscopy objectified an aspect of extrinsic compression at the front of the stomach. A cesarean was scheduled at the 35th month of pregnancy for fetal extraction and rescue. Exploration of the peritoneal cavity during surgery has objectified a hepatic highly vascularised mass reaching up to the umbilicus. This mass was unresectable. A postoperative CT scan revealed a large bilobed epigastric mass adhering to the stomach and the left liver. Histological and immunohistochemical study of hepatic process showed a gastrointestinal stromal tumor of high risk of malignancy. Conclusion: few cases have been reported in the literature on GIST during pregnancy showing the rarity of the condition that requires multidisciplinary care.

每周1次紫杉醇联合卡铂及脱氧胞嘧啶核苷用于晚期卵巢癌一线治疗的Ⅰ/Ⅱ期研究:病理学完全有效及对认知功能影响的纵向评估

Background.:To determine the pathologic complete response rate of advanced ovarian cancer to weekly paclitaxel plus gemcitabine and carboplatin with filgrastim,and assess the longitudinal impact of this regimen on quality-of-life and cognitive functioning. Methods.:Fourteen patients with advanced ovarian,peritoneal,or fallopian tube cancer were treated in the phase I portion of the study. Initial doses were paclitaxel:60 mg/m2 days 1,8,and 15; gemcitabine:800 mg/m2 days 1 and 8; and carboplatin:area under the curve (AUC) 5 day 1,every 21 days for 6 cycles with filgrastim. Twenty-seven patients were treated at the phase II dose. Pathologic response was assessed by second-look laparoscopy in patients with complete response. Patients completed longitudinal assess- ments of quality-of-life and cognitive functioning. Results.:Maximally tolerated doses were paclitaxel:80 mg/m2 days 1 and 8; gemcitabine:800 mg/m2 days 1 and 8; and carboplatin:AUC 5 day 1,every 21 days. Forty-eight percent of patients (13/27) experienced at least 1 grade 3 nonhematologic toxicity. Fifty percent (95%confidence interval CI ,31-69%) of assessable patients achieved pathologic complete response. Median progression-free survival was 27.3 months (95%CI,17.7 months to not reached),and overall survival 43.6 months (95%CI,42 months to not reached). Cognitive functioning did not decline during or after chemotherapy. More highly educated women reported a perceived decline in concentration and memory while on chemotherapy. Quality-of-life scores were maintained during therapy. Conclusions.:Fifty percent of patients with advanced stage ovarian cancer achieved pathologic complete response to weekly paclitaxel plus gemcitabine and carboplatin. Cognitive functioning did not decline by objective measures,although highly educated women reported subjective impairment.

The change of paradigm in the treatment of HER2-positive breast cancer with the development of newgeneration antibody-drug conjugates

HER2-positive breast cancer is an aggressive disease.As a result of the development of specific HER2-targeted therapies,such as trastuzumab,more than 20 years ago,the prognosis of these patients has improved.Metastatic HER2-positive breast cancer patients are achieving better survival rates upon treatment with anti-HER2 therapies than patients with HER2-negative disease.Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients.Trastuzumab emtansine,the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy.Despite the progress in treatment development,most patients develop resistance and eventually relapse.Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties,such as trastuzumab deruxtecan and trastuzumab duocarmazine,which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer.