Longitudinal Study of Advanced Non-Small Cell Lung Cancer with Initial Durable Clinical Benefit to Immunotherapy: Strategies for Anti-PD-1/PD-L1 Continuation beyond Progression.

BACKGROUND AND AIM: A better understanding of resistance to checkpoint inhibitors is essential to define subsequent treatments in advanced non-small cell lung cancer. By characterizing clinical and radiological features of progression after anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1), we aimed to define therapeutic strategies in patients with initial durable clinical benefit. PATIENTS AND METHODS: This monocentric, retrospective study included patients who presented progressive disease (PD) according to RECIST 1.1 criteria after anti-PD-1/PD-L1 monotherapy. Patients were classified into two groups, "primary resistance" and "Progressive Disease (PD) after Durable Clinical Benefit (DCB)", according to the Society of Immunotherapy of Cancer classification. We compared the post-progression survival (PPS) of both groups and analyzed the patterns of progression. An exploratory analysis was performed using the tumor growth rate (TGR) to assess the global growth kinetics of cancer and the persistent benefit of immunotherapy beyond PD after DCB. RESULTS: A total of 148 patients were included; 105 of them presented "primary resistance" and 43 "PD after DCB". The median PPS was 5.2 months (95% CI: 2.6-6.5) for primary resistance (p < 0.0001) vs. 21.3 months (95% CI: 18.5-36.3) for "PD after DCB", and the multivariable hazard ratio was 0.14 (95% CI: 0.07-0.30). The oligoprogression pattern was frequent in the "PD after DCB" group (76.7%) and occurred mostly in pre-existing lesions (72.1%). TGR deceleration suggested a persistent benefit of PD-1/PD-L1 blockade in 44.2% of cases. CONCLUSIONS: PD after DCB is an independent factor of longer post-progression survival with specific patterns that prompt to contemplate loco-regional treatments. TGR is a promising tool to assess the residual benefit of immunotherapy and justify the continuation of immunotherapy in addition to radiotherapy or surgery.

The Impact of Covid-19 on Diabetes Care in Muscat Governorate: A Retrospective Cohort Study in Primary Care.

BACKGROUND: COVID-19 pandemic has led to health service modification and temporary disruption of the routine care provided to patients with diabetes mellitus (DM) in primary care. This was done to minimize outpatient visits, permit physical distancing, and ensure patients' and healthcare providers safety. There is no evidence that explored or measured the impact of COVID-19 pandemic on diabetes services and patients' glycemic outcome in Oman. AIM AND OBJECTIVES: To explore the accessibility of DM services in primary care after COVID-19 pandemic announcement, and measure patients' glycemic outcome. METHODS: Before and after, retrospective cohort study using Al-Shifa healthcare database in primary care. One thousand adult patients with diabetes who attended DM clinic before pandemic announcement in 2019 were randomly selected and followed up until end of 2020. Patients aged ≥18 years and had at least 2 visits in 2019 were included. Access to DM services was identified by number of patients received care, frequency of consultations, mode of consultation, and type of intervention given to patients. Patients' glycated hemoglobin (HbA1c), and other glycemic parameters after pandemic announcement in 2020 were determined and compared with the same parameters before pandemic in 2019. Association between patients' HbA1c and mode of consultation was measured using multivariable regression analysis. RESULTS: A total of 937 patients continued to follow and received DM care after pandemic announcement. Median number of consultations was 2 with interquartile range (IQR): 3-2. 57.4% had face-to-face alone, 32.4% had combined face to face and telephone consultation, and 10% had telephone consultation alone. Mean difference in HbA1c (%) before and after pandemic announcement was 0.2 ± 1.4 (95% CI: 0.1 to 0.3), P = .002. With multivariable linear regression, the mean difference in HbA1c was -0.3 (-2.3 to 1.5), P = .734 for telephone consultation alone, -0.5 (-2.4 to 1.4), P = .613 for face-to-face alone, and -0.5 (-2.4 to 1.3), P = .636 for combined consultations, compared to those who did not receive any formal consultation. CONCLUSION: Despite service modification and disruption of comprehensive care in primary care after COVID-19 pandemic announcement, DM services were accessible as majority of patients maintained follow up. There was an overall increase in mean glycated hemoglobin, however, it was a less than 1 unit increase. After adjusting for multivariable, glycated hemoglobin was reduced among those who received consultation including telephone consultation compared to those who did not, however evidence was unconvincing.

Unilateral Condylar Hyperplasia: Two Case Reports and a Literature Review.

Condylar hyperplasia (CH) is a rare idiopathic condition affecting the mandibular condyle where the growth of the condylar head and/or neck continues beyond the normal growth period. The disorder presents clinically as facial asymmetry and occlusal discrepancy. Here, we present two cases of CH managed at our centers between 2012 and 2017 with a successful outcome. We highlight the clinical presentation, investigation, and surgical management and give a brief literature review.

Safe removal of epidural catheter--a dilemma, in patients who are started on dual anti platelet therapy postoperatively for acute coronary syndrome--a case report.

Epidural catheter insertion or removal in patients receiving antiplatelet therapy for acute coronary syndrome poses a high risk for epidural hematoma. Though practice guidelines suggest stopping clopidogrel for at least 7 days before such intervention. Withholding anti-platelet drugs for such a long duration represents a great risk to these patients. We present a case of a 53 year old male patient who underwent an exploratory laparotomy. He had an epidural catheter inserted for analgesia. He developed acute myocardial infarction on the first postoperative day, which was treated with dual antiplatelet therapy and percutaneous coronary angioplasty. The removal of epidural catheter in this patient required a clinical decision, balancing the risk of epidural hematoma with continuation of antiplatelet therapy against the risk of coronary re-thrombosis with discontinuation of the medication. We followed a strategy that combined a short duration of discontinuation of therapy, assessment of platelet functions by laboratory test, transfusion of platelets and removal of catheter, followed by restart of anticoagulation, which proved safe for the patient.

Anthracycline and concurrent radiotherapy as adjuvant treatment of operable breast cancer: a retrospective cohort study in a single institution.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) after breast surgery was investigated by few authors and remains controversial, because of concerns of toxicity with taxanes/anthracyclines and radiation. This treatment is not standard and is more commonly used for locally advanced breast cancer. The aim of our study was to evaluate the efficacy and safety of the concomitant use of anthracycline with radiotherapy (RT). FINDINGS: Four hundred women having operable breast cancer, treated by adjuvant chemotherapy (CT) and RT in concomitant way between January 2001 and December 2003, were included in this retrospective cohort study. The study compares 2 adjuvant treatments using CCRT, the first with anthracycline (group A) and the second with CMF (group B). The CT treatment was repeated every 21 days for 6 courses and the total delivered dose of RT was 50 Gy, divided as 2 Gy daily fractions. Locoregional recurrence free (LRFS), event free (EFS), and overall survivals (OS) were estimated by the Kaplan-Meier method. The log-rank test was used to compare survival events. Multivariate Cox-regression was used to evaluate the relationship between patient characteristics, treatment and survival.In the 2 groups (A+B) (n = 400; 249 in group A and 151 in group B), the median follow-up period was 74.5 months. At 5 years, the isolated LRFS was significantly higher in group A compared to group B (98.7% vs 95.3%; hazard ratio [HR] = 0.258; 95% CI, 0.067 to 0.997; log-rank P = .034). In addition, the use of anthracycline regimens was associated with a higher rate of 5 years EFS (80.4% vs 75.1%; HR = 0.665; 95% CI, 0.455 to 1.016; log-rank P = .057). The 5 years OS was 83.2% and 79.2% in the anthracycline and CMF groups, respectively (HR = 0.708; 95% CI, 0.455 to 1.128; log-rank P = .143). Multivariate analysis confirmed the positive effect of anthracycline regimens on LRFS (HR = 0.347; 95% CI, 0.114 to 1.053; log-rank P = .062), EFS (HR = 0.539; 95% CI, 0.344 to 0.846; P = 0.012), and OS (HR = 0.63; 95% CI, 0.401 to 0.991; P = .046). LRFS, EFS and OS were significantly higher in the anthracycline group where the patients (n = 288) received more than 1 cycle of concurrent CT (P = .038, P = .026 and P = .038, respectively). LRFS and EFS were significantly higher in the anthracycline group within the BCT subgroup (P = .049 and P = .04, respectively). There were more hematologic, and more grade 2/3/4 skin toxicity in the anthracycline group. CONCLUSIONS: After mastectomy or BCT, the adjuvant treatment based on anthracycline and concurrent RT reduced breast cancer relapse rate, and significantly improved LRFS, EFS and OS in the patients receiving more than 1 cycle of concurrent CT. There were more hematologic and non hematologic toxicities in the anthracycline group.

Factors of interrupting chemotherapy in patients with Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Little is known about prognosis of metastatic patients after receiving a first-line treatment and failure. Our group already showed in pre-treated patients enrolled in phase I clinical trials that a performance status (PS) > 2 and an LDH > 600 UI/L were independent prognostic factors. In this prospective study, which included 45 patients, we identified clinical and biological variables as outcome predictors in metastatic Non-Small Cell lung cancer after first line chemotherapy were identified. FINDINGS: Forty-five patients that were previously treated for metastatic disease from 12/2000 to 11/2005 in the comprehensive cancer centre (Centre Léon Bérard). Clinical assessment and blood parameters were recorded and considered. Patient prognostic factors for overall survival (OS) with a 0.05-significance level in univariate analysis were entered in a multivariate Cox model for further analysis.Patients' median age was 58.5 years (range: 37 - 76). Sixty two percent of the patients were PS = 0 or 1. After inclusion, nine patients received second-line (22.5%), and two received third-line chemotherapy (5%). Univariate analysis showed that the factors associated with reduced OS were: PS > 2, weight loss >10%, more than one line of chemotherapy treatment and abnormal blood parameters (hemoglobin (Hb), platelet and neutrophils counts). Multiple regression analysis confirmed that PS > 2 and abnormal hemoglobin were independent predictors for low overall survival. According to the presence of none (33%), 1 (37%) and 2 (30%) prognostic factors, median OS were 12, 5 and 2 months respectively. CONCLUSION: From this prospective study, both PS and anemia were found as independent determinants of survival, we found that both PS and anemia were independent determinants of survival. The combination of poor PS and anemia is an effective strategy to predict survival in the case of patients with metastatic NSCLC receiving further treatment after the first line.

Primary Nasopharyngeal non-Hodgkin lymphomas: a retrospective review of 26 Moroccan patients.

BACKGROUND: Nasopharyngeal non-Hodgkin lymphomas (NNHL) are extremely rare. In this study, we will report the progress achieved in the management of this disease in our institute. METHODS: We retrospectively reviewed the records of 26 patients having primary NNHL who were managed between January 1997 and December 2008, to evaluate and compare their clinical characteristics and treatment outcome. Clinical variables, including age, sex, stage, and treatment modality, were assessed. Disease free survival and overall survival were measured. Survival curves were constructed using the KaplanMeier method. The log-rank test was used to compare them. RESULTS: Median age of our patients was 52.7 years. Nasal obstruction, nasal discharge and epistaxis were the frequent symptoms in NNHL patients. Histology of NNHL were mainly large B-cell and follicular lymphoma. Four patients (15.4%) were at stage I, 15 (57.6%) at stage II, and 7 (27%) were at stage III/IV. The patients were treated with chemotherapy alone (27%) or chemotherapy plus radiotherapy (73%). At early stage (stage I/II), the patients were managed with chemo-radiotherapy. When the whole treatment was completed, 18 patients (69.2%) achieved complete response and remained disease free. After 25.9 months median follow-up, overall survival at 1 year was 87% and disease free survival at 1 year was 71%. The difference in term of overall and disease free survival between stage I, II, III and IV was significant (Log rank test: p = 0.02 for overall survival and p = 0.01 for disease free survival). CONCLUSION: From our study, we conclude that histological characteristics, principle of treatment and outcome of primary NNHL patients are particular and more studies have to be directed.

Outcome of recurrent and metastatic small cell carcinoma of the bladder.

BACKGROUND: Bladder small cell carcinoma is an uncommon tumour. Through a retrospective study we will present the evolution of recurrent and metastatic disease and outcome of patients treated at Léon-Bérard Cancer Centre. METHODS: Only 15 patients having recurrent or metastatic bladder small cell carcinoma were treated at Léon-Bérard Cancer Centre between 1996 and 2007. The patients were divided in two groups: a mixed small cell carcinoma group (9 patients) and a pure small cell carcinoma group (6 patients). All the records and informations related to treatment and outcome of the 15 patients were retrospectively analyzed. Various characteristics of small cell carcinoma were investigated. RESULTS: The median age of the 15 patients having recurrent or metastatic bladder small cell carcinoma and treated at Léon-Bérard Cancer Centre was 63 years and the disease was at stage IV for all cases. Nine patients were treated by chemotherapy. Four patients were treated by local radiotherapy (3 with radiotherapy without previous surgery and 1 with surgery followed by radiotherapy) and chemotherapy. One patient was treated by whole brain radiotherapy. And one patient died before treatment. After 52.4 months median follow up, 12 patients died. Median overall survival was 7.6 months. Survival probability at 1 year was 33%. Median overall survival was 9.9 months in the mixed small cell carcinoma group, and was only 4.6 months in the pure small cell carcinoma group. Survival probability at 1 year in the mixed small cell carcinoma group was 44% as compared to 17% in the pure small cell carcinoma group (Log-rank test: p = 0.228). CONCLUSION: Recurrent and metastatic bladder small cell carcinoma is associated with very poor prognosis. The pure bladder small cell carcinoma appears to have poorer outcome than the mixed bladder small cell carcinoma. Chemotherapy using platinum drugs is a mainstay treatment.

Concurrent chemoradiotherapy in adjuvant treatment of breast cancer.

BACKGROUND: The optimal sequencing of chemotherapy and radiotherapy after breast surgery was largely studied but remains controversial. Concurrent chemo-radiotherapy is a valuable method for adjuvant treatment of breast cancer which is under ongoing research program in our hospital. We are evaluating the feasibility of the concomitant use of chemotherapy retrospectively. METHODS: Two hundred forty four women having breast cancer were investigated in a retrospective study. All patients were either treated by radical surgery or breast conservative surgery. The study compares two adjuvant treatments associating concomitant chemotherapy and radiotherapy. In the first group (group A) the patients were treated by chemotherapy and radiotherapy in concomitant way using anthracycline (n = 110). In the second group (group B) the patients were treated by chemotherapy and radiotherapy in concomitant way using CMF treatment (n = 134). Chemotherapy was administered in six cycles, one each 3 weeks. Radiotherapy delivered a radiation dose of 50 Gy on the whole breast (or on the external wall) and/or on the lymphatic region. The Kaplan-Meier method was used to estimate the rates of disease free survival, loco-regional recurrence-free survival and overall survival. The Pearson Khi2 test was used to analyse the homogeneity between the two groups. The log-rank test was used to evaluate the differences between the two groups A and B. RESULTS: After 76.4 months median follow-up (65.3 months mean follow up), only one patient relapsed to loco-regional breast cancer when the treatment was based on anthracycline. However, 8 patients relapsed to loco-regional breast cancer when the treatment was based on CMF. In the anthracycline group, the disease free survival after 5 years, was 80.4% compared to 76.4% in the CMF group (Log-rank test: p = 0.136). The overall survival after 5 years was 82.5% and 81.1% in the anthracycline and CMF groups respectively (Log-rank test: p = 0.428). The loco-regional free survival at 5 years was equal to 98.6% in group A and 94% in group B (Log-rank test: p = 0,033). The rate of grade II and grade III anaemia was 13.9% and 6.7% in anthracycline group and CMF group respectively (Khi2-test: p = 0.009). The rate of grade II and grade III skin dermatitis toxicity was 4.5% in the group A and 0% in the group B (Khi2-test: p = 0.013). CONCLUSION: From the 5 years retrospective investigation we showed similar disease free survival and overall survival in the two concurrent chemo-radiotherapy treatments based on anthracycline and CMF. However in the loco-regional breast cancer the treatment based on anthracycline was significantly better than that of the treatment based on CMF. There was more haematological and skin dermatitis toxicity in the anthracycline group.

Mechanisms of morphine enhancement of spontaneous seizure activity.

BACKGROUND: High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors. METHODS: Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons. RESULTS: Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 microM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 microM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective mu and kappa opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, delta opioid receptor ligands did not have an effect. CONCLUSIONS: The proseizure effect of morphine is mediated through selective stimulation of mu and kappa opiate receptors but not the activation of the delta receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.