Using Mixture of Normal Distributions to Detect Treatment Effects when the Frequentist Method Fails

Background: Results from a clinical trial can either support the efficacy and safety of a new compound or fail to provide such evidence. One reason for ‘non[1]positive’ result is due to the underlying assumption of normality and homogeneity of variances, which are quite often violated when analyzing data from clinical trials, despite randomization. A question of interest is can we obtain more informative results when using mixture of normal distributions or linear models (MLMs) in such cases. Introduction: MLM can be used when traditional methods fail. MLMs “search” within the variability in data to identify components or subgroups of individuals (also known as latent classes) who have common intercepts and common slopes of change in a variable/endpoint of interest but whose intercepts and slopes are different from other subsets of patients. Thus, MLMs can be used to identify subgroups of patients exhibiting differential response to treatment within each treatment arm. The purpose of our study was to examine the usefulness of using MLM in such circumstances. Methods: Data of 155 subjects taken from a Multicenter, randomized, double blind, placebo controlled trial that evaluated the efficacy of Cpn10, administered twice weekly subcutaneously to treat Rheumatoid Arthritis was taken to evaluate the usefulness of MLM. The primary efficacy measure ACR20 was analyzed using a 3-step process: first, MLM was used to estimate RA duration using a 3-component model. The second step took the results of the first step to inform the logistic model and its analyses. Model was fitted with an intercept, MLM components, treatment arm, RA duration (linear and quadratic), dose response (modeled as an interaction effect), age and baseline weight. LOCF was used to impute for missing data. Data was analyzed using MLM and SAS v 9.0. Results: The model was a good fit to the data with a likelihood ratio significant at p=0.026, and a significant increase in the -2log L. We also observed low p-values for those variables that were non normal. Overall and for the 75 mg dose, Cpn 10 was efficacious relative to placebo, p<0.050. We also observed that dose response was significant at p><0.15 Conclusion: The use of MLM adds value because it can be used to understand the disease experience or the value of treatment when traditional statistical methods cannot. Key words: Mixture of linear models, normality, entropy.

Clinical correlation of plasma amino acid profile of post-surgical gastric cancer patients and metastatic gastric cancer patients for establishing biomarker of metastasis

Objectives: This research is aimed to evaluate plasma free amino acid in gastric cancer patients without metastasis (early gastric cancer post gastrectomy) and with metastasis (advanced gastric cancer). Amino acids level of postoperative gastric cancer (M0) patients are compared with metastatic gastric cancer (M1) patients in search of biomarker which can predict the metastasis of gastric cancer. We have made clinical correlation of patients’ vital signs, respiratory rate, pulse rate, blood pressure, body temperature, disease stages, chief complaints, complications and survival curve within light of metastatic and nonmetastatic domain. Background: Majority of cancer patients are diagnosed after seeding of metastatic cells to adjacent organs and distant sites. At this point, treatment is palliative and supportive. The cellular propagation of cancer cells and tumor micro-environment plays vital role in genesis of gastric cancer. Genetic alteration leading to faulty nucleotides to amino acids, then to protein, and finally formation of tumor is the natural sequence of pathogenesis of gastric cancer. Prediction of metastasis by use of plasma free amino acid profile may be of great significance because it will help to tailor the patient specific cancer treatment. Plasma Amino acids are ideal for being developed as tool for prediction of metastasis as they are affordable, less expensive and convenient. Method: This study includes total 54 patients, among which 27 had metastasis of Gastric cancer and rest 27 had undergone gastric surgery at early stage with no recurrence at the time of the study. Twenty-three amino acids were studied. Student’s t test was performed to find out statistically significant values of amino acids. The p value of ≤ 0.05 was considered statistically significant. Amino acids with significant p values were investigated with multivariate logistic regression. Partial Least Squares Discriminant Analysis (PLS DA) was done using Microsoft SPSS 23 version software®. Variable Importance of Projection (VIP) was estimated, values ≥ 1 was considered statistically significant. Result: Performance Score (PS) (p= 0.004) and Body Mass Index (BMI) (p= 0.035) were statistically significant between M0 and M1 groups. Staging (I, II vs. III, IV) (p< 0.001) was significant. Seven amino acids, Asp, Cys, Hcy, His, Leu, Orn and Ser were significant between M0 and M1 in first month evaluation. Eight amino acids, Cys, Hcy, His, Leu, Met, Thr, Trp and Tyr were significant between M0 and M1 in sixth month evaluation. PLS DA regression analysis, VIP test showed Cys, Ser, Hcy, Thr, His, Met, Tyr, Trp to be more important amino acids of significance. Kaplan Meier Overall Survival (OS) = 34.979 months. Mean survival time in M0 was 43.53± 1.741 months. Mean survival in M1 was 26.29± 2.635 months. Conclusion: We found BMI and PS as most important variables in defining and determining the disease status of gastric cancer patients. Nutrition and physical activity is very much characteristic of disease outcome from a physician’s perspective. This study propounds amino acids can be valuable biomarkers of predictive and prognostic importance in metastasis in gastric cancer patients.

Retrospective analysis of postmenopausal patients with hyperthyroidism and possible association with lung cancer in a Primary Health Care Setting in Western Greece

The role of thyroid hormones when circulating at high levels has been shown to have an estrogen-like effect. Estrogens play an important role in lung carcinogenesis. The aim of this study was the retrospective analysis of the laboratory results of postmenopausal women with hyperthyroidism and simultaneous measurement of the tumor marker carcinoembryonic antigen (CEA) and the possible correlation of the findings with lung cancer. The data of the patients who met the above criteria were collected retrospectively from the Microbiological Department of a Primary Health Care Setting in Western Greece for the years 2018, 2019, 2020. Nine patients met the study criteria, and of them one was diagnosed with lung cancer. This study does not indicate direct cause-effect correlation. However, increased vigilance for lung neoplasm in postmenopausal female patients with hyperthyroidism may be an additional auxiliary tool in the assessment and early diagnosis of these patients especially in a Primary Health Care Setting.

The Lavender Way – Lavender Procedure - A Way to Defeat Breast Cancer Without Surgery, Chemotherapy or Radiation A Clarion Call for Radical Change

Background Despite advances in metabolic pathways, exosomes, ct-DNA, biomarkers, and imaging technology, breast cancer is still with us. It is a global curse with incidence set to double in the U.S. by 2030. Increasingly, researchers blame this debacle on our persistent use of unreliable preclinical testing with mouse models. Further, while basic science understanding has exploded, we know each daughter cell is genetically different, with likely increased resistance to therapy - and increased aggressiveness. Nonetheless, our current approach requires killing every one of these daughters to the last. The authors have devised a new game plan; the new goal is to kill the very first cells, not the last ones. This can be implemented globally - with dramatic cost reduction, and more lives saved while leaving the breast intact. Methods The authors have created The Lavender Way, which employs multiple non-radiation diagnostic modalities. This allows us to predict within ten years in a person's lifetime when breast cancer will likely manifest. Then imaging is accelerated with modified military Infrared, ultrasound, and others to locate ultra-small breast cancers (5-8mm). Tumor analysis can determine each tumor’s aggressiveness. Via a 20-minute office procedure under local anesthesia (i.e., Cryoablation, aka The Lavender Procedure), the tumor can be killed with the patients resuming normal activity immediately. It is both a dramatic change in treatment and, just as significant, a dramatic change in lifting the psychological burden of this dreaded disease. Results Group I - Ideal Patients Group II – Less than Ideal Group III – Strictly Palliative All in Group I are alive after seven years except one. That one died of a fall, cancer-free, and one is alive with a local recurrence successfully treated with repeat cryoablation. Group II had one local recurrence, and one had a second primary tumor in a different location in the breast. Group III refused any other treatment and had metastatic disease. They were treated to prevent tumors from eroding through the skin. Most have died. The Lavender Way paves the way for The Lavender Procedure Conclusion Ultra-small breast cancers with optimal bio-markers are ideal candidates for The Lavender Procedure (i.e., Cryoablation). All patients resumed normal activity immediately – without sutures. All patients in Group I and II patients have avoided surgery, chemotherapy, and radiation.

Will Your Breast Cancer Patient’s Mortality Go Up in Smoke?

Dedicated smokers who receive breast radiation may pay an unexpected price[1]in both recurrence risk and in mortality. Smoking during radiation therapy (RT) noticeably increases (and accelerates) the recurrence risk, but it also increases long-term risks of lung and heart mortality. The recurrence risk probably derives from (temporary) smoking - caused hypoxia. On the other hand, concurrent RT and smoking produces synergistic and permanent heart and lung damage. Tumor cell hypoxia can be exogenous (via smoking) or endogenous (inadequate capillary perfusion) or possibly even environmental (at high altitudes). However it occurs, though, it is a major contributor to treatment failure. Techniques for addressing hypoxia - both currently in the clinic, and on the technological horizon - are briefly reviewed here. These include photoacoustics, FLASH radiotherapy, and Cherenkov - Excited Luminescence Imaging (CELI).

Epidural tumor pseudoprogression after spine SBRT: A case report and a mini review of the literature

Introduction: Stereotactic body radiotherapy (SBRT) to the spine is becoming a more common form of treatment. Response assessment is challenging because pseudoprogression (PP) is difficult to distinguish from true tumor progression (TTP). Methods: We report the case of a patient with anaplastic thyroid carcinoma and a bony metastasis to T-7. The MRI 22 months after the first SBRT to this location showed radiological tumor progression to the epidural space resulting in a re-SBRT. The three and six months MRI after re-SBRT showed again progressive epidural growth. After T-7 vertebrectomy, obtained tissue specimens were histopathologically evaluated. Results: Although the MRI sequences after second SBRT were highly suspicious of tumor progression into epidural space, only a small cluster of carcinoma cells of 1mm diameter was found within the bony structure near the disc, not belonging to the radiologically highly suspicious epidural mass. Conclusion: To our knowledge, we report the first case of a radiographic tumor progression to the epidural space following primary SBRT and re-SBRT, which histopathologically revealed a PP after spine surgery. Based on the “epidural progression criterion” from the SPINO-consensus, the first and the second progression after SBRT should have been classified as TTP. Due to the challenge in distinguishing TTP from PP, reporting of such cases are essential to share experiences and thereby improve the understanding of PP after spine SBRT.

A Note on the Exact Relation Between Mixture Likelihood and Entropy

It is interesting to note that the expected value of the log likelihood function is entropy. This note shows that there is an exact relationship between the mixture log likelihood function (ln LM) and the sum of the mixing distribution entropy (HM) and the mixture density entropy (HD). Ln LM is seen as a function exactly of four Shannon entropies, each a unique measure of uncertainty. This method, known as mixtures of linear models (MLM), is a form of empirical Bayes which uses a non-informative uniform prior and generates both confidence intervals and p-values which clinicians and regulatory agencies can use to evaluate scientific evidence. An example based on allergic rhinitis symptoms scores are given and show how easy it is to assess the fit of the model and evaluate the results of the trial.

Evaluation Of Some Coagulation Profile (PT, APTT) In Sudanese Pregnant Women With Sickle Cell Anemia

Background: Sickle cell disease refers to group of genetic disorder characterized by the predominance of hemoglobin S. Changes in the coagulation system seem to play an important role in the clinical manifestations of this disorder. Objective: This study aimed to determine the change in PT and APTT test in Sudanese pregnant women with sickle cell anemia. Material and methods: Fifty pregnant women with SCA with different age and different trimester, admitted to Mohammed Alamin Hamid hospital for children, were included case control study. Eleven healthy and pregnant women without SCA. Blood sample from three group were collected and investigated for PT and APTT. Results: The study revealed that in comparison with control mean PT (P=0.000) and APTT (p=0.000) high significant , in comparison with pregnant without SCA mean PT (P=0.000) and APTT (p=0.000) high significant ,no significant in comparison between all trimester mean PT (P=0.168) APTT (P=0.757) ,high significant in comparison with treatment mean PT(P=0,0000) APTT (P=0.000) ,in comparison with duration of disease and age mean PT(P=0.043) low significant with age APTT (P=0.558) no significant. Conclusion: The study concluded that these is hypercoagulable state in pregnant women with SCA indicated by prolongation in PT and APTT.

Evaluation of Serum Tumor Markers Variation, Following The Radioactive Iodine Therapy in Patients with Differentiated Thyroid Cancer

Introduction: Radioactive iodine is the effective therapy in thyroid cancer. The aim of this study is to evaluate the serum tumor markers in patients under the therapy with radioactive iodine 131. Material and Methods: 45 cases of female patients aged 16-60 years with thyroid cancer surgery referred to the nuclear medicine department of Nemazi hospital for (iodine treatment after surgery) were selected. The selection was on the basis of interviewing and information of patients is consent forms. Only patients with thyroid cancer and referred for the first time without any other diseases were chosen for this study. The selected patients were prescribed a dose of 150 m Ci of I-131. From each patient, 4 mL of chelated serum for serological studies on tumor markers and 2 mL of oxalated serum for spectrophotometry studies on cell death were used in three stages. The first stage before the iodine therapy, the second stage, after 48 hours, and the third stage, 30 days after radioiodine therapy were studied and the results were evaluated by the one-way repeated measures ANOVA test. Results: According to the results of dependent paired T-Test, AFP, in the periods before, 48 hours and 1 month after radioiodine therapy, respectively were 3.46 ± 1.21 and 3.74 ± 1.37 and 3.76 ± 1.25 (p <0.0005). About CA 19-9 in the periods before, 48 hours and one month after radioiodine therapy, the results were 9.30 ± 6.32, 9.95 ± 6.92 (p = 0.040) and 11.26 ± 7.49 (p <0.0005) respectively. About CEA, the results were 1.60 ± 0.60, 1.47 ± 0.55 and 2.23 ± 0.69 (p <0.0005), respectively. In the case of tumor marker CA 15-3 results were 15.53 ± 6.48 and 1.60 ± 0.60 and 15.68 ± 6.52 (p = 0.014), respectively and in the case of ALP, results were 124.22 ± 5 and 122.2 ± 6 and 116.7 ± 7 (p <0.0005), respectively. Conclusion: According to the same studies and the acquired results, it can be concluded that the tumor markers CEA and CA19-9 are more acceptable and sustainable for monitoring the malignancy and progressive disease in patients with thyroid cancer. The decreasing ALP is normal and transient. The increase of AFP and CA15-3 is not even statistically reliable. It is recommended that the period of iodine therapy and falsely elevated tumor markers can be informed to the doctor, during the gastrointestinal studies in patients with thyroid cancer, in order to prevent wrong decisions on the treatment process.

The role of Radiation Therapy in Treatment of COVID-19 induced Pneumonia

Background: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infected people can develop severe inflammatory reactions, which can lead to pneumonia, acute respiratory distress syndrome, and death. The use of radiation in the treatment of COVID-19 induced pneumonia sounds unusual, but is currently being investigated in clinical trials. Some early results have been already published. This study aims to review existing information about the role of radiation therapy in the Treatment of COVID-19 induced pneumonia. Methods and Materials: An electronic search of the PubMed database and additional resources ware used to obtain key literature. The following search terms were used: “Radiation therapy” and “COVID-19”. Results: Search resulted in 137 citations. The first phase of screening identified 13 articles, from which nine articles were identified to be relevant for the second phase of screening. Six articles were included in the review. Conclusion: Low-dose radiotherapy has been considered as a potential treatment for COVID-19 induced pneumonia. The benefits of LDRT for pneumonia have been reported since the early 20th. However knowledge is lacking, hence further investigation of the pros and cons of this method is strongly recommended. LDRT as a prospective cure of COVID-19 induced pneumonia is worthy of research in a clinical setting.