Survival Statistics For Patients Research Articles

True-T – Improving T-cell response quantification with holistic artificial intelligence based prediction in immunohistochemistry images

The immune response associated with oncogenesis and potential oncological therapeutic interventions has dominated the field of cancer research over the last decade. T-cell lymphocytes in the tumor microenvironment are a crucial aspect of cancer’s adaptive immunity, and the quantification of T-cells in specific cancer types has been suggested as a potential diagnostic aid. However, this is currently not part of routine diagnostics. To address this challenge, we present a new method called True-T, which employs artificial intelligence-based techniques to quantify T-cells in colorectal cancer (CRC) using immunohistochemistry (IHC) images. True-T analyses the chromogenic tissue hybridization signal of three widely recognized T-cell markers (CD3, CD4, and CD8). Our method employs a pipeline consisting of three stages: T-cell segmentation, density estimation from the segmented mask, and prediction of individual five-year survival rates. In the first stage, we utilize the U-Net method, where a pre-trained ResNet-34 is employed as an encoder to extract clinically relevant T-cell features. The segmentation model is trained and evaluated individually, demonstrating its generalization in detecting the CD3, CD4, and CD8 biomarkers in IHC images. In the second stage, the density of T-cells is estimated using the predicted mask, which serves as a crucial indicator for patient survival statistics in the third stage. This approach was developed and tested in 1041 patients from four reference diagnostic institutions, ensuring broad applicability. The clinical effectiveness of True-T is demonstrated in stages II-IV CRC by offering valuable prognostic information that surpasses previous quantitative gold standards, opening possibilities for potential clinical applications. Finally, to evaluate the robustness and broader applicability of our approach without additional training, we assessed the universal accuracy of the CD3 component of the True-T algorithm across 13 distinct solid tumors.

Abstract PO027: Glioma cells within high functional connectivity network hubs exhibit a proliferative and infiltrative tumor phenotype

Abstract BACKGROUND: There is emerging preclinical evidence that neuronal activity influences glioma proliferation. In humans however it remains unknown how dynamic physiological interactions between glioma cells and neurons influence tumor growth and cognition. We therefore studied the mechanisms underpinning why some glioma cells maintain functional connections with neurons and the causal relationship of these connections to tumor growth and associated cognitive impairments. METHODS: We employed magnetoencephalography in newly diagnosed IDH-wild-type glioblastoma (GBM) patients to identify intratumoral regions with high (HFC) and low (LFC) brain functional connectivity. Site-directed patient tumor biopsies from HFC and LFC regions were used to perform immunohistochemistry experiments and generate patient-derived xenografts. Primary patient-derived neurosphere cultures were generated from HFC and LFC regions and spheroid invasion and EdU proliferation assays were performed to characterize their invasive and proliferative phenotypes, respectively. The morphology and size of HFC and LFC neurospheres was also evaluated to determine the clonogenicity profile. Secreted proteins from patient serum was measured using ELISA. Cognitive assessments and survival statistics of patients were performed to correlate with functional connectivity measures. RESULTS: Compared to LFC, primary patient samples from HFC regions showed increased expression of pre- and post-synaptic markers. Primary patient HFC cultures co-cultured with hippocampal neurons and induced neuron organoids again demonstrated increased synaptogenesis markers. IDH-wt GBM HFC cultures demonstrated little clonogenicitiy and low proliferation however when co-cultured with neurons markedly increased their proliferative potential both in vitro and in vivo. Similarly, when compared to HFC alone and LFC conditions, the degree of cell invasion, measured by the spheroid invasion area and microtube length, was significantly increased by the addition of conditioned media from hippocampal neuronal culture. HFC IDH-wt patient derived xenografts survived a shorter time compared to LFC. Importantly, compared to patients without intratumoral high functional connectivity regions, GBM patients with intratumoral HFC showed shorter overall survival and worse cognitive task performance. CONCLUSION: Synaptogenic glioma cells are enriched within high connectivity intratumoral regions maintains their affinity for neurons primarily through TSP-1 mediated paracrine signaling. This distinct HFC tumor sub-population exhibits an aggressive invasive and proliferative tumor phenotype, which in turn contributes to the observed adverse cognitive and survival outcomes. Citation Format: Saritha Krishna, Abrar Choudhury, Michelle Monje, Shawn Hervey-Jumper. Glioma cells within high functional connectivity network hubs exhibit a proliferative and infiltrative tumor phenotype [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO027.

Cancer metabolomics: A tool of clinical utility for early diagnosis of gynaecological cancers.

Gynaecological cancers are the major cause of cancer-related deaths in Indian women. The poor prognosis and lack of symptoms in the early stages make early cancer diagnosis difficult. The absence of mandatory screening programmes and the lack of awareness pose to be a real challenge in a developing economy as India. Prompt intervention is required to enhance cancer patient survival statistics and to lessen the social and financial burden. Conventional screening and cytological techniques employed currently have helped to reduce the incidence of cancers considerably. However, these tests offer low sensitivity and specificity and are not widely used for risk assessment, leading to inadequate early-stage cancer diagnosis. The accomplishment of Human Genome Project (HGP) has opened doors to exciting ‘omics’ platforms. Promising research in genomics and proteomics has revolutionized cancer detection and screening methodologies by providing more insights in the gene expression, protein function and how specific mutation in specific genes corresponds to a particular phenotype. However, these are incompetent to translate the information into clinical applicability. Various factors such as low sensitivity, diurnal variation in protein, poor reproducibility and analytical variables are prime hurdles. Thus the focus has been shifted to metabolomics, which is a much younger platform compared to genomics and proteomics. Metabolomics focuses on endpoint metabolites, which are final products sustained in the response to genetic or environmental changes by a living system. As a result, the metabolome indicates the cell’s functional condition, which is directly linked to its phenotype. Metabolic profiling aims to study the changes occurred in metabolic pathways. This metabolite profile is capable of differentiating the healthy individuals from those having cancer. The pathways that a cell takes in turning malignant are exceedingly different, owing to the fact that transformation of healthy cells to abnormal cells is linked with significant metabolic abnormalities. This review is aimed to discuss metabolomics and its potential role in early diagnosis of gynaecological cancers, viz. breast, ovarian and cervical cancer.

EXTH-52. GLIOBLASTOMA-TARGETING AUTOLOGOUS INDUCED NEURAL STEM CELL THERAPY: EVALUATING SAFETY, TOXICITY, PERSISTENCE, AND TRANSPLANT METHODS IN A POST-SURGICAL CANINE MODEL

Abstract BACKGROUND Glioblastoma patient survival statistics have remained unchanged for more than three decades. Despite tumor resection and chemoradiotherapy, recurrence is inevitable. Moreover, the invasive behavior of glioblastoma confounds treatment. To improve patient survival statistics, a targeted therapy that can home to distant tumor foci is desperately needed. Induced neural stem cells (iNSCs) armed with cytotoxic payloads have proven efficacious against human xenograft models of glioblastoma. To further propel iNSCs to human clinical trials, we investigated the safety, toxicity, and persistence of iNSCs in a canine model. METHODS Autologous iNSCs generated from the skin of four non-tumor-bearing, purpose-bred, male beagles were engineered to express TRAIL and thymidine kinase (TK). iNSCs were loaded with ferumoxytol to facilitate MRI-tracking. Canines were divided into two cohorts to denote iNSC administration route: scaffold encapsulation or intracerebroventricular (ICV). Two dose levels were investigated: 1′106 iNSCs/kg or 3′106 iNSCs/kg. The scaffold cohort received a single dose of iNSCs while the ICV cohort received three doses of iNSCs via a Rickham reservoir. To activate TK, canines were administered valganciclovir. Canine health was assessed via neurological exams, MRI, and serial blood, urine, and CSF analyses. RESULTS No acute injection reactions were observed. Three of four canines exhibited surgery-induced blindness. Urine and CSF analyses were unremarkable. Unexpectedly, blood analyses showed transient neutropenia. Hypodense signal was observed on all MRI sequences through endpoint. Post-mortem histopathology of the spleen, liver, and lung were unremarkable. As expected, brain tissues exhibited gliosis, fibrous thickening, and inflammation. Spinal cords exhibited acute hemorrhaging, attributed to perimortem CSF draws. Surprisingly, significant testicular degeneration was observed; this was confirmed to be caused by valganciclovir. In conclusion, iNSCs exhibit limited toxicity and warrant further exploration. FUTURE DIRECTIONS Prospective studies will investigate the efficacy of autologous iNSCs in a spontaneous canine glioma model in preparation for human clinical trials.

Cancer survival statistics for patients and healthcare professionals - a tutorial of real-world data analysis.

Monitoring survival of cancer patients using data collected by population-based cancer registries is an important component of cancer control. In this setting, patient survival is often summarized using net survival, that is survival from cancer if there were no other possible causes of death. Although net survival is the gold standard for comparing survival between groups or over time, it is less relevant for understanding the anticipated real-world prognosis of patients. In this review, we explain statistical concepts targeted towards patients, clinicians and healthcare professionals that summarize cancer patient survival under the assumption that other causes of death exist. Specifically, we explain the appropriate use, interpretation and assumptions behind statistical methods for competing risks, loss in life expectancy due to cancer and conditional survival. These concepts are relevant when producing statistics for risk communication between physicians and patients, planning for use of healthcare resources, or other applications when consideration of both cancer outcomes and the competing risks of death is required. To reinforce the concepts, we use Swedish population-based data of patients diagnosed with cancer of the breast, prostate, colon and chronic myeloid leukaemia. We conclude that when choosing between summary measures of survival it is critical to characterize the purpose of the study and to determine the nature of the hypothesis under investigation. The choice of terminology and style of reporting should be carefully adapted to the target audience and may range from summaries for specialist readers of scientific publications to interactive online tools aimed towards lay persons.

SCIDOT-24. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY

Abstract Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.

STEM-12. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY

Abstract Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.

The Differential Diagnosis of Squamous Cells in Pancreatic Aspirates: From Contamination to Adenosquamous Carcinoma

Background: This study was conducted to describe the frequency and significance of squamous cells in fine needle aspiration (FNA) specimens of the pancreas in benign and malignant processes. Methods: A retrospective review was performed of 102 patients with squamous cells in their pancreatic FNA specimens from 1986 to 2012. The malignant cases were classified as adenosquamous carcinoma (ASqC) or metastatic squamous cell carcinoma, and a double institutional review of the ASqC cases was undertaken to characterize the clinical and pathological features and survival statistics of patients who present with unresectable or metastatic ASqC and have no follow-up surgery. Survival analyses were performed. Results: Of the 4,094 pancreas FNA procedures performed in the study, squamous features were found in 102 (2.5%) of all cases, and 48% of these cases represented ASqC. The other cases were contamination (52%) or atypical (<1%). ASqC constituted 4.5% (46/1,025) of all primary pancreatic exocrine malignancies. When compared with conventional adenocarcinoma, ASqC demonstrated a significantly poorer overall median survival (11.0 vs. 6.51 months; p = 0.023), and this difference was also seen in patients presenting with metastatic disease (median survival of 9.1 vs. 4.2 months; p = 0.025). Conclusions: Squamous cells in FNA specimens from the pancreas have a broad differential diagnosis that ranges from contamination to ASqC.

Control Dominating Subclones for Managing Cancer Progression and Posttreatment Recurrence by Subclonal Switchboard Signal: Implication for New Therapies

In contrast to hematological malignancies, meaningful improvements in survival statistics for patients with malignant brain tumors have not been realized in >40 years of clinical research. Clearly, a new medical approach to brain cancers is needed. Recent research has led to a new concept that needs to destroy all cancer subclones to control the cancer progression. However, this new concept fails to distinguish the difference between dominating subclones and dormant subclones. Here, we address the issue of clonal switch and emphasize that there may be one or more than one dominant clones within the tumor mass at any time. Destructing one dominant clone triggers activating other dormant subclones to become dominating subclones, causing cancer progress and post-treatment cancer recurrence. We postulate the concept of subclonal switchboard signaling and the pathway that involved in this process. In the context of stem cell and development, there is a parallel with the concept of quiescent/dormant cancer stem cells (CSC) and their progeny, the differentiated cancer cells; these 2 populations communicate and co-exist. The mechanism with which determines to extend self-renewal and expansion of CSC is needed to elucidate. We suggest eliminating the "dominating subclonal switchboard signals" that shift the dormant subclones to dominating subclones as a new strategy.

Urine Metabolomic Analysis Identifies Potential Biomarkers and Pathogenic Pathways in Kidney Cancer

Kidney cancer is the seventh most common cancer in the Western world, its incidence is increasing, and it is frequently metastatic at presentation, at which stage patient survival statistics are grim. In addition, there are no useful biofluid markers for this disease, such that diagnosis is dependent on imaging techniques that are not generally used for screening. In the present study, we use metabolomics techniques to identify metabolites in kidney cancer patients' urine, which appear at different levels (when normalized to account for urine volume and concentration) from the same metabolites in nonkidney cancer patients. We found that quinolinate, 4-hydroxybenzoate, and gentisate are differentially expressed at a false discovery rate of 0.26, and these metabolites are involved in common pathways of specific amino acid and energetic metabolism, consistent with high tumor protein breakdown and utilization, and the Warburg effect. When added to four different (three kidney cancer-derived and one "normal") cell lines, several of the significantly altered metabolites, quinolinate, α-ketoglutarate, and gentisate, showed increased or unchanged cell proliferation that was cell line-dependent. Further evaluation of the global metabolomics analysis, as well as confirmation of the specific potential biomarkers using a larger sample size, will lead to new avenues of kidney cancer diagnosis and therapy.

Current survival statistics for patients with newly diagnosed glioblastoma treated with radiation and temozolomide on research studies in the United States

2003 Background: Many novel agents are being studied in combination with radiation and temozolomide (RT+TMZ) in newly diagnosed glioblastoma using survival as the primary endpoint. These single arm phase II studies generally plan to compare their results with those reported from the phase III EORTC RT+TMZ study (Stupp, NEJM, 2005). Methods: The NABTT CNS Consortium has completed accrual to three RT+TMZ+ novel agent studies using the same eligibility criteria. A total of 281 patients with newly diagnosed glioblastoma were enrolled. The novel agents included talampanel (72 pts), poly ICLC (97 pts), and cilengitide (112 pts). The survival data emerging from these three single arm phase II studies was compared with the published EORTC data. Results: The median age, KPS, and percent undergoing debulking surgery for EORTC patients was 56, 86% (WHO 0–1), and 84% and for NABTT patients receiving talampanel 60, 90, and 77%, poly ICLC 56, 90, 86%, and cilengitide 55, 90, and 76%. A total of 247 patients (88%) were ages 18–70 making them comparable to the EORTC patient population. Currently available survival data for these NABTT and EORTC studies are provided below. MGMT methylation status and survival based on dose levels are not currently available. Conclusions: Survival of newly diagnosed glioblastoma patients treated with RT+TMZ + novel agents at 9 NABTT institutions accruing from 2005 to 2008 appears increased compared to RT+TMZ at 85 EORTC institutions accruing from 2000 to 2002. These results do not appear related to a specific effective agent. As a result, caution should be exercised when comparing outcomes from recently conducted Phase II studies in this patient population to published EORTC data. [Table: see text] No significant financial relationships to disclose.

Conditional Survival in Anal Cancer: Results from the SEER Dataset 1988-2001

Survival statistics for patients with anal cancer are typically reported in terms of survival from time of initial diagnosis. However, for patients who have survived a given period of time after diagnosis, conditional survival (CS) is a more clinically relevant measure, as it accounts for changes in risk over time. The specific aim of this study was to estimate CS for anal cancer patients through analysis of large-scale cancer registry data.

Initiation of An Intestinal Transplant Program: The Indiana Experience

Establishment of a new intestinal transplant (Itx) program in the United States entails significant programmatic costs and a steep learning curve. We report results of the first 4 years of the program at Indiana University. Forty-six intestinal and multivisceral transplants (MVtx) were performed between 2003 and 2007. All organ procurements were performed by our team. Immunosuppression included an induction protocol combined with maintenance tacrolimus monotherapy. Scheduled rejection surveillance was with magnification endoscopy. Forty-three patients (13 children and 30 adults) received 10 Itx (22%), 5 modified MVtxs (11%), and 31 (MVtx, 67%). Recipient ages ranged from 3 months to 66 years, with median follow-up time of 15 months. Thirty-five patients are currently alive (81%). Patient and graft survival at 30 days was 85%/86% in pediatric and 93%/91% in adult; overall survival was 69%/64% in pediatric and 87%/75% in adult. Thirty patients (69%) experienced episodes of rejection. Multivisceral transplanted patients experienced less episodes of severe rejection (2/31, 6%) when compared with patients with isolated Itx and modified MVtxs. Retransplantation was performed in three patients with nonresponsive severe acute rejection. The Indiana University Intestinal and Multivisceral Transplant program experienced significant early graft loss and mortality among pediatric patients, but not among adults. This discrepancy resolved within 2 years of program initiation. After 4 years, adult and pediatric graft and patient survival statistics are similar to those at other programs.

Conditional survival in ovarian cancer: A SEER database analysis

6620 Background: Survival statistics for patients with ovarian cancer are typically reported in terms of survival from time of diagnosis. For patients who have survived a period of time since diagnosis, however, conditional survival (CS) is a more clinically relevant measure, as it accounts for the changes in risk over time. The purpose of this study was to estimate CS for ovarian cancer patients through analysis of large-scale cancer registry data. Methods: Ovarian cancer cases were extracted from the Surveillance, Epidemiology, and End Results (SEER 17) database from the National Cancer Institute for patients diagnosed between 1988–2001. Five-year relative CS calculations were performed with stratification by age, race, stage, histology, and grade for patients who had already survived up to 5 years from diagnosis. Results: The 5-year overall relative CS improved over time for up to 5 years after diagnosis for ovarian cancer patients. The largest gains in CS over time were seen for patients with advanced...

Conditional survival in ovarian cancer: Results from the SEER dataset 1988–2001

Objectives Survival statistics for patients with ovarian cancer are typically reported in terms of survival from time of diagnosis. For patients who have survived a period of time since diagnosis, however, conditional survival (CS) is a more clinically relevant measure, as it accounts for the changes in risk over time. The purpose of this study was to estimate CS for ovarian cancer patients through analysis of large-scale cancer registry data. Methods Ovarian cancer cases were extracted from the Surveillance, Epidemiology, and End Results (SEER 17) database from the National Cancer Institute (NCI) for patients diagnosed between 1988–2001. Five-year relative CS calculations were performed with stratification by age, race, stage, histology, and grade for patients who had already survived up to 5 years from diagnosis. Results The 5-year overall relative CS improved over time for up to 5 years after diagnosis for ovarian cancer patients. The largest gains in CS over time were seen for patients with advanced stage disease, poor grade, and serous and undifferentiated epithelioid histologies. For patients with stage IV disease, 5-year CS more than tripled over the first 5 years of surveillance (17%–56%). Among histological types, patients with undifferentiated epithelioid histology saw 5-year CS rise from 29% at diagnosis to 84% after 5 years. Conclusions Prognosis improves over time for almost all groups of ovarian cancer patients. For ovarian cancer survivors, CS provides a more relevant measure of prognosis than conventional survival estimates that are made at the time of diagnosis.

Non-Gaussian heart rate as an independent predictor of mortality in patients with chronic heart failure

Morbidity and mortality due to chronic heart failure remain unacceptably high despite effective drug therapies, and the search for a better risk predictor is ongoing. Statistics derived from beat-to-beat fluctuations in heart rate or heart rate variability (HRV) have been used for this purpose, but the current predictability level is low or moderate at best. The purpose of this study was to evaluate whether a recently proposed non-Gaussian index of HRV is a significant and independent mortality predictor in patients with congestive heart failure (CHF). Twenty-four-hour Holter ECGs from 108 CHF patients were evaluated. Thirty-nine (36.1%) of the patients died during the follow-up period of 33 +/- 17 months. Cox proportional hazards regression analysis was performed to determine factors related to all-cause mortality. The factors evaluated derived from clinical information, including plasma brain natriuretic peptide, conventional time- and frequency-domain and fractal HRV measures, and a recently proposed non-Gaussian index lambda of HRV. The short-term (<40 beats) non-Gaussian index lambda(40) (hazard ratio per increment of unit standard deviation 1.64, 95% confidence interval [1.23, 2.18], P <.001) and the long-term (<1,000 beats) index lambda(1000) (hazard ratio 1.42, 95% confidence interval [1.07, 2.18], P <.02), together with brain natriuretic peptide (hazard ratio 2.26, 95% confidence interval [1.45, 3.53], P <.001), are significant univariate risk predictors of mortality. In a multivariate model, lambda(40) (1.49, [1.13, 1.96], P <.005) and brain natriuretic peptide (2.39, [1.53, 3.75], P <.001) are independent predictors of the survival statistics of patients. None of the conventional HRV measures have predicted the mortality of patients in a significant and independent manner. The results of this study indicate the usefulness of the short-term non-Gaussian index of HRV for risk prediction in patients with CHF.

Meta Analysis of Advanced Cancer Survival Data Using Lognormal Parametric Fitting: A Statistical Method to Identify Effective Treatment Protocols

We describe the use of a parametric lognormal model to calculate and compare survival statistics in the clinical treatment of advanced/metastatic pancreatic, breast and colon cancers. The fit using the lognormal model explained greater than 90% (R(2) ranged from 0.917 to 0.998 for a total of the 51 arms from published studies) of the variation in the cumulative survival statistics of patients treated for advanced cancers. A meta-analytic Q-test was performed to test whether there were significant differences between different studies. For all three cancer types, the Q-test showed highly significant differences between the survival arms (p<0.0001 for pancreatic, breast and colon cancers). The z-values expressed the difference of the average of lognormal means relative to each study in terms of deviation expressed in standard errors. The treatments that were most effective ranked with the highest z-value: Doxorubicin plus docetaxel for pancreatic cancer (z-value = 4.1); Capecitabine plus paclitaxel for breast cancer (z-value = 3); irinotecan, fluorouracil and folinate for colon cancer (z-value = 7.4).

Conditional survival in head and neck squamous cell carcinoma

Survival statistics for patients with head and neck squamous cell carcinomas (HNSCC) are commonly calculated from the time of diagnosis. The less commonly employed conditional survival (CS) analyzes survival for patients who have survived a period of time after diagnosis. Useful prognostic information for cancer survivors is provided by CS analysis. Estimated baseline CS parameters for HNSCC were sought using large-scale cancer registry data. HNSCC cases identified from the Surveillance, Epidemiology, and End Results (SEER) Program were accessed to identify those diagnosed between 1973 and 1998. Five-year observed, relative, and cumulative CS calculations were performed, with secondary stratification by site, extent of disease, and age. The overall 5-year observed survival for all sites increased from 47.8% for 76,181 included patients from the time of diagnosis to 64.4% for those 43,985 patients alive at 3 years, and thereafter plateaus. The greatest increase in CS was for oropharyngeal cancers, which more than doubled over the first decade of surveillance (26.5%-60%). Distant disease showed a 10-year increase in CS (17.4%-60.4%), whereas localized disease CS was essentially static, ranging from 66.1% to 68.5%; for those over 65 at diagnosis it ranged from 39.9-52.9%, whereas patients <65 years at diagnosis ranged from 53.8-73.5%. Benchmark CS estimates for domestic HNSCC cohorts were developed from the SEER database. CS is a useful tool to assist clinicians in predicting the probability of demise from HNSCC for patients surviving 1 or more year after diagnosis.

The first 20 years of heart transplantation in Ireland

The first Irish heart transplant was performed on the 10th of September 1985. Over the next 20 years, 229 transplants were performed in 228 recipients. To evaluate the success of the first generation of cardiac transplantation in Ireland. Analysis of clinical outcomes and survival statistics for patients undergoing heart transplantation in Ireland and comparison with international standards. There has been a steady improvement in transplant outcome over this time and survival figures for recipients between 2000 and 2004 show a hospital, 1-year and 5-year survival rate of 85.7%, 84.1% and 76.8% respectively. Thirty-eight of the 99 heart transplants performed between 1985 and 1994 are still alive more than 10 years later and the longest survivor is now 19 years post transplantation. The results compare favourably with international figures. Heart transplantation offers excellent longterm survival and quality of life but remains challenged by a shortage of suitable donor organs.

Defects in Cell Growth Regulation by C18:0-Ceramide and Longevity Assurance Gene 1 in Human Head and Neck Squamous Cell Carcinomas

In this study, endogenous long chain ceramides were measured in 32 human head and neck squamous cell carcinoma (HNSCC) and 10 nonsquamous head and neck carcinoma tumor tissues, as compared with adjacent noncancerous tissues, by liquid chromatography/mass spectroscopy. Interestingly, only one specific ceramide, C(18:0)-ceramide, was selectively down-regulated in the majority of HNSCC tumor tissues. On the other hand, in nonsquamous tumor tissues, this selectivity for C18-ceramide was not detected. These data suggested the hypotheses that decreased levels of C18-ceramide might impart a growth advantage to HNSCC cells and that increased generation of C18-ceramide may be involved in the inhibition of growth. These roles were examined by reconstitution of C18-ceramide at physiologically relevant concentrations in UM-SCC-22A cells (squamous cell carcinoma of hypopharynx) via overexpression of mammalian upstream regulator of growth and differentiation factor 1 (mUOG1), a mouse homologue of longevity assurance gene 1 (mLAG1), which has been shown to specifically induce the generation of C18-ceramide. Liquid chromatography/mass spectroscopy analysis showed that overexpression of the mLAG1/mUOG1 resulted in increased levels of only C(18:0)-ceramide by approximately 2-fold, i.e. concentrations similar to those of normal head and neck tissues. Importantly, increased generation of C18-ceramide by mLAG1/mUOG1 inhibited cell growth (approximately 70-80%), which mechanistically involved the modulation of telomerase activity and induction of apoptotic cell death by mitochondrial dysfunction. In conclusion, this study demonstrates, for the first time, a biological role for LAG1 and C18-ceramide in the regulation of growth of HNSCC.