Treatment of early-stage lung cancer: ...

Senan, S. [Promotor]Slotman, B.J. [Promotor

Necrotizing Soft Tissue Infections Management: A study about the intervention with Long incision fasciiotomies over other Types of traditional management

INTRODUCTION: Necrotizing Soft Tissue Infections (NSTI’S) comprise a spectrum of disease entities that are characterized by extensive rapidly progressive soft tissue necrosis that usually involves the muscular fascia and subcutaneous tissue, but can also affect skin & muscle. NSTI’S classified as cellulitis, fasciitis or myositis, based on the principle soft tissue layer involved with necrosis. These infections can have either an indolent or fulminant presentation and their clinical course is unpredictable. OBJECTIVE: To study the advantage of decompression by single long incision fasciiotomies with over other types of traditional management in the cases of Necroitizing soft tissue infections. MATERIALS & METHODS: This was a descriptive study conducted at Chengalpattu Medical College, Dept. of General Surgery in unit IV. The wards are 9 & 10, & septic ward over a period of one & half years June 2009 to December 2011. This includes the patients diagnosed as cellulitis, necrotizing fasciitis and admitted through surgical OP & Casualty. The patients below 12 years of age, localized abscesses, intra abdominal solid organs involvement, secondary surgical wound infections and Diabetic foot were excluded from the study. After resuscitation in Casualty reception the patients underwent wound debridement where pus was collected for culture & sensitivity test. Septic OT used in all of the cases. In selected cases single or multiple long incisions done. In few cases all necrosed material and slough was removed. Wound was irrigated with Hydrogen peroxide & Normal saline. The post debridement management included correction of fluid and electrolyte balance coagulation profile, intravenous antibiotics, daily dressings & nutritional supplementation. Antibiotics were changed later according to the culture sensitivity results. The patients were kept in isolated septic ward. Few patients had “Matthan thylam” application which was useful in wound granulation & deodorization. Few of them got opinion from plastic surgery department and received SSG. Later the patients followed up to a possible time intervals. Data was connected with special reference to demographics, clinical features, investigations, co morbidities, involved site, surgical intervention, outcome & follow up. CONCLUSION: The following are conclusions that could be inferred from the study on the surgical spectrum and risk factors among the diseased. - The patients more affected are above 50 yrs (56%). - The male: female ratio is 4:1 - Type of insult. Not known 36%, Snake bite 18%, R T A 10%, Throne prick 5%, Minor abrasions 10%, Others 21%. Parts affected: Lower limb 67%, Scrotum & Low Abdomen 20%, Upper Limb 10%, Trunk with limb 3%, Average time of presentation after symptoms: 7.4 days. Comorbid illnesses: Total number of D M patients 39, Freshly diagnosed D M 8%, Recently diagnosed D M 8%, Known I H D pts 8%, Pts on steroids 3%, Old P T pts 5%, Varicose veins pt 3%, Nil 41%, Known DM II 5%, Others 21%. Blood group affected: A1 +ve 20.5%, A1B +ve 2.5%, AB –ve 2.6%, B +ve 28.2%, O +ve 46.2%. Average time taken for intervention: 6.4 hrs. Type of Intervention: Multiple stab & small incisions 36%, Single or paired long fasciiotomy 51%, incisions with minimal debridment, Vigerous debridment of necrosed tissues 10%, Amputaion (B/K) 3%, Average time taken for recovery (from septicemia& negative culture): Unknown insult cases with long incision fasciiotomies require 3 weeks average. Snake bite cases require average 3.8 weeks. The edema & discharge disappear on 4th to 7th day in unkown insult cases. Snake bite cases also. Multiple stab & small incisions required more than five weeks for –ve Culture & recovery from local symptoms. The edema & discharge persisted more than 25 days in these cases

A MASS COMPATIBLE UPLC METHOD FOR THE QUANTIFICATION OF IMPURITIES IN FLUTICASONE PROPIONATE NASAL SPRAY

Objective: The objectives of the present study were to develop and validate a mass compatible ultra-performance liquid chromatography (UPLC) method to quantify the impurities in fluticasone nasal spray, and to establish a suitable container-closure system for the formulation. Methods: A gradient method was optimized with a flow rate of 0.5 ml/min, detector wavelength-240 nm, run time-25 min and 0.1% Trifluoroacetic acid (TFA) in water as solvent A and Methanol as solvent B. Results: The developed method was linear over the range of 0.07-1.10 µg/ml for impurity-I, 0.16-2.47 µg/ml for impurity-II, 0.67-10.0 µg/ml for impurity-III, and 1.29-19.3 µg/ml for impurity-IV. The limit of quantification (LOQ) and limit of detection (LOD) were established as 0.07 and 0.02 µg/ml, 0.14 and 0.05 µg/ml, 0.59 and 0.19 µg/ml, 1.06 and 0.35 µg/ml for impurities I-IV respectively. The percent relative standard deviation (%RSD) of the replicate analysis for impurities I-IV, was within the acceptance criteria (0.4, 0.2, 0.3, and 0.1% respectively) that proved the precision of the method. The accuracy of the method was studied from 50%-150% of test concentration and the results ranged from 100.3% to 109.4%. The container-closure compatibility study revealed that the solution stored in the glass container system did not generate any additional peaks in the chromatogram. Conclusion: Hence, the developed method can be employed by quality testing laboratories to quantify impurities in fluticasone propionate nasal spray. The study also suggests that glass containers could serve as a compatible system for the storage of fluticasone propionate nasal solution

Continuous hyperfractionated accelerated radiotherapy - Escalated dose (CHART-ED): A phase i study

Patients who present with locally advanced inoperable non-small cell lung cancer (NSCLC) may be suitable for radical radiotherapy. A randomised trial of 563 patients compared CHART and conventional radical radiotherapy (60 Gy/30f) given over 6 weeks and suggested that CHART resulted in a 9% improvement in 2-year survival (Saunders et al., 1999). RT dose escalation for both conventional and CHARTWEL (CHART-WeekEndLess) - fractionation schedules is feasible with modern 3-dimensional CT-based planning techniques and we initiated a phase I CHART dose escalation study in 2009. Methods Patients with WHO performance status 0-2 histologically confirmed, inoperable, stage I-III non-small cell lung cancer were recruited into an open phase I dose escalation trial. Three cohorts of six patients were recruited sequentially. Total dose was escalated from standard CHART radiotherapy of 54 Gy/36f/12 days to 57.6 Gy (2 × 1.8 Gy fractions on day 15, Group 1), 61.2 Gy (4 × 1.8 Gy fractions on days 15-16, Group 2) and 64.8 Gy (6 × 1.8 Gy fractions on days 15-17, Group 3). Results Between April 2010 and May 2012, 18 patients were enrolled from 5 UK centres and received escalated dose radiotherapy. 14 were male, 16 squamous cell histology and 12 were stage IIIA or IIIB. The median age was 70 years and baseline characteristics were similar across the three dose cohorts. One patient did not start escalated radiotherapy but all remaining patients completed their planned radiotherapy schedules. Of these 9 patients have died to date with a median survival of 2 years across the three cohorts. Grade 3 or 4 adverse events (fatigue, dysphagia, nausea and anorexia - classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) were reported in 6 patients but the pre-specified dose limiting toxicities (grade 4 early oesophagitis; grade 3 cardiac, spinal cord and pneumonitis) were not observed. Conclusions CHART remains a radiotherapy schedule in routine use across the UK and in this dose escalation study no dose limiting toxicities were observed. We feel the dose of 64.8 Gy/42f/17 days should be taken forward into further clinical trials. The sample size used in this study was small so we plan a randomised phase II study that includes other radiotherapy schedules to confirm safety and select an accelerated sequential chemo-radiotherapy schedule to take into phase III studies

Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): Study protocol for a randomized phase III trial

Background: Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4-10 metastatic cancer lesions. Methods: One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion: This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4-10 oligometastatic lesions. Trial registration: Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018

Is there a role for IGF-1 in the development of second primary cancers?

Cancer survival rates are increasing, and as a result, more cancer survivors are exposed to the risk of developing a second primary cancer (SPC). It has been hypothesized that one of the underlying mechanisms for this risk could be mediated by variations in insulin‐like growth factor‐1 (IGF‐1). This review summarizes the current epidemiological evidence to identify whether IGF‐1 plays a role in the development of SPCs. IGF‐1 is known to promote cancer development by inhibiting apoptosis and stimulating cell proliferation. Epidemiological studies have reported a positive association between circulating IGF‐1 levels and various primary cancers, such as breast, colorectal, and prostate cancer. The role of IGF‐1 in increasing SPC risk has been explored less. Nonetheless, several experimental studies have observed a deregulation of the IGF‐1 pathway, which may explain the association between IGF‐1 and SPCs. Thus, measuring serum IGF‐1 may serve as a useful marker in assessing the risk of SPCs, and therefore, more translational experimental and epidemiological studies are needed to further disentangle the role of IGF‐1 in the development of specific SPCs

Is the combination of immunotherapy and radiotherapy in non-small cell lung cancer a feasible and effective approach?

For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small-cell lung cancer (NSCLC). The recent introduction of immunotherapy (IT) in clinical practice, especially strategies targeting negative regulators of the immune system, so-called immune checkpoint inhibitors, has led to a paradigm shift in lung cancer as in many other solid tumors. Although antibodies against programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) are currently on the forefront of the immuno-oncology field, the first efforts to eradicate cancer by exploiting the host's immune system date back to several decades ago. Even then, researchers aimed to explore the addition of RT to IT strategies in NSCLC patients, attributing its potential benefit to local control of target lesions through direct and indirect DNA damage in cancer cells. However, recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Herein, the authors review the rationale of combining IT and RT across all NSCLC disease stages and summarize both historical and current clinical evidence surrounding these combination strategies. Furthermore, an overview is provided of active clinical trials exploring the IT-RT concept in different settings of NSCLC