Size Of Patient Cohort Research Articles

Plasma growth hormone as a prognostic biomarker to durvalumab and tremelimumab in patients with advanced hepatocellular carcinoma.

e16161 Background: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). Methods: In this study, we included 24 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023. Plasma GH levels were measured from prospectively collected blood samples from 16 of the 24 patients and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 μg/L and ≤0.9 μg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log-rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Results: Twenty-four patients were included in this analysis, four female and twenty male, with a median age of 66.5 years. Of these 24 patients, 16 had GH levels available for analysis. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Conclusions: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Comparing the efficacy of two generations of EGFR-TKIs: An integrated drug-disease mechanistic model approach in EGFR-mutant lung adenocarcinoma.

e20578 Background: The epidermal growth factor receptor (EGFR) is frequently mutated in patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) targeting EGFR have been developed. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. Methods: We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, two EGFR TKIs, to accurately simulate the drugs' distribution within the primary tumor and metastatic sites following administration. These models were integrated with a mechanistic model of EGFR-mutant LUAD, enabling the representation of the mechanism of action of gefitinib and osimertinib. This model outputs the evolutions of the primary tumor and each metastasis, facilitating the evaluation of patient progression following RECIST criteria. Notably, the model encapsulates the heterogeneity within the tumor, representing various subclones defined by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002, FLAURA and AURA3 clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. Results: The model adeptly replicated the time to progression in EGFR-mutant LUAD patients receiving gefitinib or osimertinib, whether as first-line or second-line therapy. Furthermore, it accurately mirrored the progression causes as per the RECIST criteria, including the emergence of new metastases in the lung, brain, liver, and bone. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. Conclusions: The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a promising tool for deriving pertinent insights and informing treatment strategies. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the requisite patient cohort size in such trials, optimizing resource utilization.

#2435 Calciphylaxis: patient demographics, risk factors and outcomes in a single regional centre in New Zealand

Abstract Background and Aims Calciphylaxis, a condition associated with microvascular calcification and subsequent formation of non-healing tender skin lesions, has previously been estimated to affect only approximately 1% of patients with ESRD each year. However, clinicians practicing in a regional renal unit in the North Island of New Zealand have noted an increase in the frequency of clinical diagnoses of this condition over recent years. The aim of this review was to analyze patient demographics and risk factors and attempt to identify any correlation with subsequent outcomes. Method A cross sectional retrospective review of dialysis patients from Palmerston North Hospital's Renal Unit who were found to have diagnoses of calciphylaxis, was performed. The following factors were assessed: gender, ethnicity, smoking status, diabetes, obesity, hypertension, dialysis modality, prescription of phosphate binders, vitamin D analogues, and sodium thiosulphate (STS). We included patients with both histologically proven calciphylaxis and clinical diagnosis only. Levels of serum PTH, calcium and phosphate at the time of diagnosis were reviewed, though only PTH levels were included in the final analysis. Results A total of nineteen patients were identified having calciphylaxis as a diagnosis in the period studied. Findings were limited due to the small patient cohort size, but of those identified and reviewed some commonalities were found. Included were 9 NZ European people and 8 NZ Māori people. There were 8 females. One patient was a current smoker at time of diagnosis and five were documented as ex-smokers. Fourteen patients (74%) had type 2 diabetes mellitus and hypertension. Twelve patients (63%) were obese. Eighteen patients (95%) had hyperparathyroidism. Warfarin use was seen in 10 of the patients studied (52%) and twelve (63%) had used phosphate binders. Nine patients (47%) were diagnosed in the period between 2011 and 2021, with the remaining ten (53%) diagnoses occurring in 2022 or 2023. The majority (90%) were treated with STS, however 84% died. Dialysis modality at time of diagnosis and throughout disease span was also reviewed. Eight patients (42%) used only haemodialysis (HD), six patients (32%) used both modalities and five patients (26%) used only peritoneal dialysis. The majority (63%) of patients were on haemodialysis at time of diagnosis. Conclusion Calciphylaxis appears to be increasing dramatically in the single center studied in this review. Positive correlations were identified between high levels of PTH, obesity, hypertension, type 2 diabetes, and use of warfarin. Unfortunately, due to small case numbers, and poor historical documentation, further conclusions could not be drawn easily. A further RCT would be required to investigate the efficacy of STS as a treatment for calciphylaxis.

Outcomes Following Extracellular Matrix Cartilage Allograft for the Management of Osteochondral Lesions of the Talus: A Systematic Review

Introduction/Purpose: The purpose of this systematic review was to evaluate the clinical and radiographic outcomes in patients who received extracellular matrix cartilage allograft (EMCA) during surgical intervention for osteochondral lesions of the talus (OLT). Methods: During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies evaluating outcomes in patients who received EMCA during surgical intervention for osteochondral lesions of the talus. Data regarding lesion characteristics, surgical characteristics, subjective clinical outcomes, radiographic outcomes, complication rates, failure rates and secondary surgical procedure rates were extracted and analysed. In total, 5 clinical studies were included in this review. Results: In total, 162 patients received EMCA during surgical intervention for OLT at a weighted mean follow-up of 23.8 ± 4.2 months. The weighted mean lesion area was 77.9 ± 42.6 mm2. Overall, 111 (68.5%) of OLTs were located medially, 45 (27.8%) of OLTs were located laterally and 6 (3.7%) OLTs were located centrally. Four studies performed arthroscopic debridement and bone marrow stimulation with ECMA, 3 studies utilized concentrated bone marrow aspirate and 1 study performed autologous osteochondral transplantation. Improvements were noted in AOFAS, FAOS and VAS scores following surgical intervention. The weighted mean post-operative MOCART score was 76.3 ± 2.9. In total, 17 (10.5%) complications were reported across the 5 studies. Twelve failures (7.4%) were recorded, all of which required further surgical intervention. Conclusion: This systematic review demonstrated improvements in subjective clinical outcomes and radiological outcomes at short-term follow-up following surgical intervention for OLTs augmented with ECMA. A low failure rate and moderate complication rate was noted. However, there was marked heterogeneity between the included studies with regards to surgical technique utilized, lesion size and patient cohort size. Further research is warranted to determine the optimal role of ECMA in the management of OLT.

Plasma Growth Hormone as a Prognostic Biomarker to Durvalumab and Tremelimumab in Patients with Advanced Hepatocellular Carcinoma.

In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). In this study, we included 16 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023 and had plasma GH measurements recorded before treatment. Plasma GH levels were measured from prospectively collected blood samples and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 μg/L and ≤0.9 μg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Sixteen patients were included in this analysis, two female and fourteen male, with a median age of 65.5 years. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Abstract A021: Cancer disparities among Muslim women: Population identification by name

Abstract Background: A total of 3.5 million American Muslims live in the United States (US), representing 1% of the total population. Over 50% of American Muslims are foreign-born [1]. Racially, American Muslims are very diverse religious groups in the US with no majority race, split as 25% Black, 24% White, 18% Arab, 18% Asian, 7% mixed race, and 5% Hispanic [2]. In terms of origin, Middle Eastern Countries represent 41% of the entire Muslim community in the US [3]. In the last two decades, the population growth trajectory of the American Muslim community has been doubling; the projection was 2.6 million (0.8 %) in 2010 and is expected to be 6.2 million (1.7%) in 2030 [4]. Virginia has the second-largest Muslim population in the US by the percentage of the population, with an estimated 2.7% [2]. Much of that population is concentrated in Northern Virginia and the Richmond Area [5]. Our previous work showed that Muslim women seek cancer care at an advanced stage. However, we had a limitation in identifying Muslim women in the VCU health system as most Muslims do not share their religion at registration [6]. We created an algorithm to identify Muslim patients by name to address this issue. Methods: Identifying patient populations by name has been done by the North American Association of Central Cancer Registries (NAACCR) to better identify Hispanic populations. Their algorithm uses family names and county of residence information [7]. Our algorithm uses Names only at this time. We used a collection of Middle-Eastern names from a publicly available database [8]. We excluded names frequently used in the United States; examples include Maria, Sarah, and Daniel. Then we used the Names in the database to heuristically identify patients with Middle-Eastern origin. Results: We identified 165 female Muslim cancer patients between 2012 and 2021 at VCU Health System, a 260% improvement compared to our previous work without the new identification algorithm. Similar to our previous work, the extended cohort shows that Muslim women are diagnosed with late-stage breast cancer more frequently than non-Muslim women (20% vs. 14%, p-value = 0.04). Conclusion: Our algorithm to identify Muslim patients made a difference in the patient cohort size, making it possible to do a more robust analysis and draw statistically significant conclusions. Future work: Our algorithm needs further improvement. Currently, we are focusing on Middle-Eastern names, we plan to be more inclusive with additional Muslim majority areas. Citation Format: Tamas S. Gal, NourEldin Abosamak, Fariha Tariq, Nevena Skoro, Rana Ramadan, Asmaa Namoos. Cancer disparities among Muslim women: Population identification by name [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A021.

Post-Traumatic Stress Disorder: Identifying Potential Differences in Participant Response to CAPS-5 Life Events Checklist Questionnaire Based on Gender

Introduction: Post-traumatic stress disorder (PTSD) is a complicated and debilitating psychiatric condition that affects 1 in 3 people who have been exposed to, witnessed, or learned about a traumatic event. Females are almost 2-fold as likely to meet the criteria for PTSD and almost 4-fold as likely than males to develop chronic PTSD. In this pilot study, we examined Life Events Checklist Questionnaire responses from participants who were clinically diagnosed with PTSD to identify if there was a difference in response to checklist questions based on gender. Materials and methods: Study participants (N = 39; n = 17 (43.6%) males; n = 22 (56.4%) females), with a PTSD diagnosis, were recruited in the US between January and June 2019 by PrecisionMed, California, USA. Study participants were matched for age, gender, and ethnicity. A CAPS-5 Life Events Checklist Questionnaire was applied at interview and symptom severity was calculated based on the sum of the participant responses. Results: In total, N = 33 questions from the CAPS-5 Life Events Checklist Questionnaire were addressed to each of the study participants. All but one question was significantly different between males and females; namely, the inability to recall certain aspects of the traumatic event (p < 0.05) (chi square χ2). However, as the patient cohort size was limited (N = 39), we applied a post hoc Bonferroni (α = 0.05/33 = 0.0015) to account for any potential bias in the results. Based on the post hoc analysis, we did not observe any differences in the participant response based on gender. Conclusions: Although the literature identifies gender as a significant risk for PTSD, in this participant cohort, we failed to observe any differences in the subject response to the CAPS-5 Life Events Checklist Questionnaire. The only finding that was significant was that females were 3-times more likely to experience sexual abuse than males. However, it is likely that males are more resistant to report sexual abuse, as was noted in the case report forms.

Abstract TP106: Diagnostic Capability Of An Emerging Portable Stroke Detection Device In Clinical Practice

Introduction: Portable stroke detection devices may serve as important tools in stroke triage. With the capacity to differentiate stroke type and severity, these devices may allow for reductions in time-to-treatment, leading to improved patient outcomes in time sensitive neurologic diseases. One such device is the Cerebrotech Visor, an FDA-approved technology that aims to identify severe stroke by detecting bioimpedance asymmetry in brain tissue across a wide range of electromagnetic wavelengths. This study aims to evaluate the ability of this device to detect stroke types in a pilot set of patients presenting as acute stroke codes. Methods: Trained operators performed scans using the Visor during stroke codes from November 2020 to July 2021 on eligible patients. Clinical and radiologic characteristics as well as the Visor output, an algorithmically derived asymmetry score, were prospectively entered into a quality assurance database. CT findings and subsequent physician notes were used to classify patient stroke type and severity. T-tests were performed to assess the ability of the Visor score to detect various types of CT-confirmed stroke. Results: Seventy-eight patients were included and scanned. Using CT results, patients were classified into categories: ischemic stroke (IS) (16), intracerebral hemorrhage (ICH) (12), subdural hematoma (2), brain tumor (0), prior neurosurgical procedure (0), intraventricular hemorrhage (2), hydrocephalus (1), and no findings (49), with 3 patients experiencing a combination of these neurological findings. Visor scores for IS and ICH were individually compared to the cohort without IS and ICH, respectively. A t-test comparing patients with IS to the rest of the cohort showed significantly higher Visor scores (9.66 vs 7.13, p = 0.014). Although patients with ICH also had higher Visor scores, the difference was not statistically significant (8.16 vs 7.55, p = 0.30). Conclusion: The Cerebrotech Visor was able to differentiate between IS and non-IS with the current bioimpedance asymmetry-based device algorithm. Future studies aim to increase patient cohort size and use this patient-centered data to develop a machine learning algorithm to better differentiate other stroke types with this bioimpedance technology.

Identification of Adverse Risk Factors for Survival in Acquired Pure Red Cell Aplasia Receiving Immunosuppressive Therapy By the Japan PRCA2004/2006 Study and Introduction to the New Cohort Study PRCA2016

Pure red cell aplasia (PRCA) is characterized by normocytic normochromic anemia associated with reticulocytopenia and erythroid hypoplasia in otherwise normal bone marrow. The acquired chronic PRCA may present as a primary hematological disorder in the absence of any other diseases or develop associated with certain conditions such as thymoma, lymphoproliferative disorders, infections, collagen vascular diseases, or after exposure to a wide variety of drugs. Idiopathic PRCA and secondary PRCA not responding to the treatment of the underlying diseases are generally treated by immunosuppressive therapy and the most patients require long-term treatment. Glucocorticoids, cyclosporine and cyclophosphamide are commonly used for initial treatment as monotherapy or combination therapy and majority of the patients respond to immunosuppression. However, most patients treated with these medications relapse during tapering of the treatment. Because of the extreme rarity of this disease, the long-term outcome of chronic PRCA following immunosuppression remains unclear and the adverse risk factors for survival have to be elucidated.In order to identify the adverse risk factors for survival in acquired chronic PRCA following immunosuppression and improve the prognosis, we have conducted nationwide surveys for adult acquired chronic PRCA in Japan. We conducted the first study for adult chronic PRCA in japan in 2004 and 2006 that had been diagnosed between 1990 and 2006 across 109 institutions, and collected the data on a total of 185 patients (PRCA2004/2006 study). We have also started another cohort study in 2016 in collaboration with the Japanese Society of Hematology (JSH) (PRCA2016 study) that was approved by the institutional review board and the ethical committee of the JSH.In PRCA2004/2006 study 73 patients (39%) were classified as having idiopathic PRCA and 112 patients (61%) as having secondary PRCA, including 42 thymoma- and 14 large granular lymphocyte leukemia (LGL)-associated PRCA. The details on idiopathic, thymoma-associated and LGL-leukemia-associated PRCA have been previously reported (Sawada K, et al. Haematologica 2007;92:1021; Hirokawa M, et al. Haematologica 2008;93:27; Fujishima N, et al. Haematologica 2008;93:1555). The last questionnaires for the patients with these three subtypes of PRCA were sent to the institutions in 2012 for collecting the data on relapse, subsequent treatment and efficacy and outcome.The PRCA2004/2006 study revealed that the median overall survival (OS) has not yet been reached in idiopathic PRCA following immunosuppression and the estimated median OS times in thymoma-associated and LGL leukemia-associated PRCA were 142 and 148 months, respectively. Twenty-two deaths were reported and the major causes of death were infection and organ failure (Hirokawa M, et al. Brit J Haematol 2015;169:879). Poor response to induction therapy and relapse of anemia were demonstrated to be associated with death and this was also confirmed by the Mantel-Byar analysis (p<0.001) (Fig. 1). The efficacy of re-induction therapy for relapsing PRCA was inferior to the initial inductive therapy (p<0.001) (Fig. 2).With the results of this study, we have proposed the clinical guidelines for management of PRCA in 2011 and we conducted another cohort study in 2016 in collaboration with the Japanese Society of Hematology (JSH) (PRCA2016 study). The primary endpoint of this study is the OS in chronic PRCA following immunosuppression and the principal aim is to learn whether or not the prognosis would be improved. Between 2006 and 2014, 554 PRCA patients were registered in the JSH hematological disorder registry and we asked the physicians to participate in this study (Fig. 3). The potential size of patient cohort is 181, including 116 idiopathic and 65 secondary PRCA and these patients will be followed up during the next ten years. The PRCA2016 cohort study is expected to reveal the unbiased results regarding the long-term survival and quality of life in PRCA following immunosuppression. [Display omitted] DisclosuresFujisawa:Bristol myers Squibb: Honoraria; Beckman Coulter: Honoraria; Eisai: Honoraria; Janssen Pharmaceutical: Honoraria; Novartis: Honoraria; Astellas: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; SHIONOGI CO, LTD: Honoraria, Research Funding; Shire plc: Honoraria; Alexion Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; MSD: Research Funding. Yonemura:Alexion Pharma GK: Honoraria, Research Funding. Kurokawa:Pfizer Inc.: Research Funding; Celgene Corporation: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Other: Scholarship donations for the laboratory, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding.

Global assessment of the integrated stress response in CF patient-derived airway and intestinal tissues

BackgroundChronic inflammation is a hallmark among patients with cystic fibrosis (CF). We explored whether mutation-induced (F508del) misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR), and/or secondary colonization with opportunistic pathogens, activate tissue remodeling and innate immune response drivers. MethodsUsing RNA-seq to interrogate global gene expression profiles, we analyzed stress response signaling cascades in primary human bronchial epithelia (HBE) and intestinal organoids. ResultsPrimary HBE acquired from CF patients with advanced disease and prolonged exposure to pathogenic microorganisms display a clear molecular signature of activated tissue remodeling pathways, unfolded protein response (UPR), and chronic inflammation. Furthermore, CFTR misfolding induces inflammatory signaling cascades in F508del patient-derived organoids from both the distal small intestine and colon. ConclusionDespite the small patient cohort size, this proof-of-principle study supports the use of RNA-seq as a means to both identify CF-specific signaling profiles in various tissues and evaluate disease heterogeneity. Our global transcriptomic data is a useful resource for the CF research community for analyzing other gene expression sets influencing CF disease signature but also transcriptionally contributing to CF heterogeneity.

Closing the gap: actualising shared decision-making through effective medication abortion patient follow-up care

BackgroundEffective care dearth in USA healthcare systems can be augmented by patient engagement and shared decision-making (SDM). These effective care strategies can facilitate medical abortion follow-up care (ensuring patients are...

Comparison of salvage therapies for isolated para-aortic lymph node recurrence in patients with uterine cervical cancer after definitive treatment

BackgroundSome studies have demonstrated that concurrent chemo-radiotherapy is an effective salvage treatment for isolated para-aortic lymph node (PALN) recurrence.However, no studies have compared multi-treatment modalities, such as radiation therapy (RT), concurrent chemoradiotherapy (CCRT), surgery, chemotherapy, and best supportive care (BSC), across a sufficient number of patients with PALN recurrence. We thus aimed to evaluate the clinical outcomes of multi-treatment modalities for isolated PALN recurrence in uterine cervical cancer.MethodsRecords of 50 patients who were first diagnosed with isolated PALN recurrence after definitive cervical cancer treatment from 2002 to 2016 at our institution were reviewed retrospectively. The initial definitive cervical cancer therapies included RT alone, CCRT, or surgery with or without post-operative RT. The median follow-up time was 33 months. The median age at recurrence diagnosis was 57 years (range, 26–84 years). The median duration between the end of initial treatment and recurrence was 10 months (range, 1–91 months). The median maximum metastatic lesion size was 17 mm (range, 8–60 mm). Twenty-four patients had one or two PALN metastases, while 26 had 3 or more. Eighteen patients were treated for recurrence with RT alone, seven with CCRT, three with surgery, 17 with chemotherapy, and five with BSC. Potential prognostic factors included histopathology, initial FIGO stage, initial treatment, age at recurrence, tumor markers (serum SCC-Ag and CEA) at recurrence, time to recurrence, maximum size of the metastatic lesion, number of metastases, and the recurrence treatment method.ResultsThe 3-year overall survival (OS) rates of all patients were 47.0%. The 3-year OS rate of patients who underwent CCRT for recurrence was 85.7%; surgery, 66.7%; chemotherapy, 48.8%; RT, 41.3%; and BSC, 0% (p = 0.014). Univariate analysis revealed that only the recurrence treatment method was significantly associated with OS. The 3-year local control rate (LCR) and progression free survival (PFS) rate for CCRT were 100 and 71.4%; for surgery, 100 and 66.7%; for chemotherapy, 33.6 and 13.7%; and for RT, 55.5 and 14.1%, respectively (LCR: p = 0.028, PFS: p = 0.059). The number of metastatic lesions, SCC-Ag levels and recurrence treatment method were significantly associated with LCR. Age at recurrence, SCC-Ag levels, and number of metastatic lesions were significantly associated with PFS.ConclusionsAlthough our patient cohort size was small, our results suggest that CCRT may be effective in preventing local disease recurrence in the PALN and may improve OS.

Functional Annotation of Genetic Loci Associated With Sepsis Prioritizes Immune and Endothelial Cell Pathways.

Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated by three genome-wide association studies. However, genes from such suggestive loci may also provide crucial information to unravel genetic mechanisms that determine sepsis heterogeneity. Therefore, in this study, we made use of integrative approaches to prioritize genes and pathways affected by sepsis associated genetic variants. By integrating expression quantitative trait loci (eQTL) results from the largest whole-blood eQTL database, cytokine QTLs from pathogen-stimulated peripheral blood mononuclear cells (PBMCs), publicly available blood transcriptome data from pneumoniae-derived sepsis patients, and transcriptome data from pathogen-stimulated PBMCs, we identified 55 potential genes affected by 39 independent loci. By performing pathway enrichment analysis at these loci we found enrichment of genes for adherences-junction pathway. Finally, we investigated the functional role of the only one GWAS significant SNP rs4957796 on sepsis survival in altering transcription factor binding affinity in monocytes and endothelial cells. We also found that transient deficiency of FER and MAN2A1 affect endothelial response to stimulation, indicating that both FER and MAN2A1 could be the causal genes at this locus. Taken together, our study suggests that in addition to immune pathways, genetic variants may also affect non-immune related pathways.

Abstract P5-03-03: Cytotoxic t-lymphocyte density increased within the tumor immune microenvironment of patients with breast cancer following treatment with Akt inhibitor MK-2206

Abstract Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Tumor infiltrating lymphocytes (TILs) found within the tumor immune microenvironment (TME) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. Our aim is to characterize the TME in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor as part of a presurgical, window of opportunity, trial. In our presurgical trial (clinicaltrials.gov #: NCT01319539), patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: Quantitative multiplex immunofluorescence (qmIF) was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 patient treated with MK-2206, and 5 prospectively collected untreated controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. Student T- test was used to compare biomarker changes before and after MK-2206. Results: Preliminary analysis demonstrates that patients treated with MK-2206 exhibited a significantly increased median cytotoxic T-cells (CD3CD8+) density, as compared to the matched control cohort (87% vs.0.2%, p &amp;lt; 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. Proximity comparison, using nearest neighbor analysis was used to assess for potential impact of therapy on interactions between CD3CD8+ cells and BC cells. The median distance from CD3+CD8+ cells to nearest neighboring tumor cell was determined in both the pre and post tissues specimens for both groups. In patients treated with MK-2206, a 12.5% reduction in median distance was observed between CD3+CD8+ cells and tumor cells following treatment, suggestive that the increased effector T cells are not relegated to the periphery. This observation was not seen in the pre and post samples of the control cohort. Conclusions: In our study, we found that presurgical Akt inhibition lead to a significant increase in the cytotoxic T-cell population which was in similar proximity, if not closer, to tumor cells as compared to matched controls. Limitations of this exploratory study include a small patient cohort size and use of a single pathology evaluation technique. We are currently expanding our characterization of the TME with a more comprehensive myeloid panel as well as performing additional tissue analysis to validate our findings. At present, there are currently FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavor to understand the impact of these therapies on the TME may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited by future immunotherapy therapeutics. Citation Format: Marks DK, Gartrell RD, Asmar ME, Hart TD, Lu Y, Esancy CL, Hibshoosh H, Connolly EP, Kalinsky KM, Saenger YM. Cytotoxic t-lymphocyte density increased within the tumor immune microenvironment of patients with breast cancer following treatment with Akt inhibitor MK-2206 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-03-03.

Effect of design specifications in dose-finding trials for combination therapies in oncology.

Model-based dose-finding methods for a combination therapy involving two agents in phase I oncology trials typically include four design aspects namely, size of the patient cohort, three-parameter dose-toxicity model, choice of start-up rule, and whether or not to include a restriction on dose-level skipping. The effect of each design aspect on the operating characteristics of the dose-finding method has not been adequately studied. However, some studies compared the performance of rival dose-finding methods using design aspects outlined by the original studies. In this study, we featured the well-known four design aspects and evaluated the impact of each independent effect on the operating characteristics of the dose-finding method including these aspects. We performed simulation studies to examine the effect of these design aspects on the determination of the true maximum tolerated dose combinations as well as exposure to unacceptable toxic dose combinations. The results demonstrated that the selection rates of maximum tolerated dose combinations and UTDCs vary depending on the patient cohort size and restrictions on dose-level skipping However, the three-parameter dose-toxicity models and start-up rules did not affect these parameters. Copyright © 2016 John Wiley & Sons, Ltd.

Decision-tree model for health economic comparison of two long-acting somatostatin receptor ligand devices in France, Germany, and the UK.

BackgroundLong-acting somatostatin receptor ligands (SRL) with product-specific formulation and means of administration are injected periodically in patients with acromegaly and neuroendocrine tumors. A simple decision-tree model aimed at comparing cost savings with ready-to-use Somatuline Autogel® (lanreotide) and Sandostatin LAR® (octreotide) for the UK, France, and Germany. The drivers of cost savings studied were the reduction of time to administer as well as a reduced baseline risk of clogging during product administration reported for Somatuline Autogel®.MethodsThe decision-tree model assumed two settings for SRL administration, ie, by either hospital-based or community-based nurses. In the case of clogging, the first dose was assumed to be lost and a second injection performed. Successful injection depended on the probability of clogging. Direct medical costs were included. A set of scenarios were run, varying the cost drivers, such as the baseline risk of clogging, SRL administration time, and percentage of patients injected during a hospital stay.ResultsCosts per successful injection were less for Somatuline Autogel®/Depot, ranging from Euros (EUR) 13-45, EUR 52-108, and EUR 127-151, respectively, for France, Germany, and the UK. The prices for both long-acting SRL were the same in France, and cost savings came to 100% from differences other than drug prices. For Germany and the UK, the proportion of savings due to less clogging and shorter administration time was estimated to be around 32% and 20%, respectively. Based on low and high country-specific patient cohort size estimations of individuals eligible for SRL treatment among the patient population with acromegaly and neuroendocrine tumors, annual savings were estimated to be up to EUR 2,000,000 for France, EUR 6,000,000 for Germany, and EUR 7,000,000 for the UK.ConclusionThis model suggests that increasing usage of the Somatuline device for injection of SRL might lead to substantial savings for health care providers across Europe.

Pregnancy-associated breast cancer: Review of the literature.

245 Background: Overall, 0.2%-3.8% of all breast cancer cases are diagnosed during the pregnancy. It is to be expected that the incidences of pregnancy-associated breast cancer (PABCS) will likely increase. Therapy of PABCS is the challenge and requests team play of different experts in this area. The aim of this study was to review the actual therapy of PABCS. Methods: Publications relevant to PABCS and their therapy were identified by searching Pubmed database for the period between 1960 and 2010. We used the keywords “cancer”, “pregnancy”, “chemotherapy”, and “systemic treatment”. Search results were adjusted by references from relevant articles. 221 relevant articles and abstracts were found. Articles describing the same patient cohort and articles without data of the kind of drug, trimester of application and without size of patient cohort were excluded from analyses. 79 articles matched the search criteria and were included in analyses. Results: The use of anthracycline-based chemotherapy has been documented in 320 cases, congenital malformation (CM) occurred in 3.75% of the reported cases (similar to the standard population). 14 publications described a methotrexate-containing therapy during pregnancy, CM occurred in 6.67%. Use of taxanes has been documented in 29 cases, CMs were observed in 3.45%. 9 articles (20 cases) published the effects of vinca alkaloids-containing treatment, in 1 cases occur missed abortion. Tamoxifen use during pregnancy is described in 9 publications, 30% of the exposed newborns showed CM. The application of target-agent-trastuzumab during pregnancy is described in 16 case reports with developing of oligo- or anhydramnion, IUGR, pulmonal hypoplasia. Conclusions: Anthracyclines are regarded the safest chemotherapeutic agents during pregnancy and can be given with minimal fetal risk after the first trimester. The routine use of newer agents like taxanes or vinca alkaloids are with high possibility safe in 2. And 3. Trimenom, but because of limited data are not recommended so far. Methotrexate should be avoided during pregnancy. Tamoxifen, aromatase inhibitor and target agents are contraindicated during the pregnancy. Target agents can not be recommended for the use in the pregnancy.

Influenza-Associated Cystic Fibrosis Pulmonary Exacerbations

Although cystic fibrosis (CF) is the most common inherited respiratory disease, the burden of influenza among individuals with CF is not well characterized. We used the CF Foundation Patient Registry to determine the relationship between pulmonary exacerbation incidence rate and influenza virus season from July 2003 through June 2007. The outcome of interest, pulmonary exacerbation, was defined as treatment of a respiratory illness with IV antibiotics. Each influenza season was defined as all months during which >/= 15% of laboratory tests for influenza virus were positive in the US influenza virologic surveillance system. We calculated incidence rates of pulmonary exacerbation during the influenza and summertime seasons as well as relative rates with 95% CIs. A multivariate regression model adjusted for demographic and clinical predictors. In 2003, the patient cohort size was 21,506 patients, and 7,727 patients experienced at least one pulmonary exacerbation. The overall pulmonary exacerbation incidence rate in the influenza season was 595.0 per 10,000 person-months compared with a summertime baseline of 549.6 per 10,000 person-months. The incidence rate ratio was 1.08 (95% CI: 1.06, 1.10). Multivariate analysis did not change our estimate of risk (adjusted odds ratio: 1.07; 95% CI: 1.05, 1.10). An estimated annual excess of 147.6 per 10,000 person-months or an excess 2.1% of total exacerbations occur during the influenza season. Our data demonstrate a substantial contribution of the influenza season to CF morbidity. Further studies to determine any causal link between influenza infection and CF pulmonary exacerbations are necessary.

Oesophageal achalasia: An argument for primary surgical management

Achalasia is a primary oesophageal motility disorder resulting from damage to the ganglion cells of the myenteric plexus. Impaired relaxation of the lower oesophageal sphincter and aperistalsis causes its cardinal symptoms of dysphagia, chest pain and reflux-type symptoms. Management is somewhat controversial, with options including systemic and local pharmacotherapy, dilatation and oesophagomyotomy. We review the presentation, investigation and management of oesophageal achalasia and make an argument for primary surgical management. We performed a Medline search of the term 'achalasia', limiting the search to clinical trials and meta-analyses. We then selected articles based on their abstracts using four main criteria: previously unreported findings, previously unreported techniques, size of patient cohort and journal impact factor. References in selected articles were manually searched for other relevant articles. Achalasia has been managed using a variety of techniques including systemic and local pharmacotherapy, forced dilatation and oesophagomyotomy. Success rates vary widely between techniques. Mechanical disruption ofthe lower oesophageal sphincter is most successful. In achalasia, mechanical disruption of the lower oesophageal sphincter using forced dilatation or surgical myotomy offers the only realistic prospect of long-term symptom relief. Recent evidence suggests that previous medical treatment or dilatation makes oesophagomyotomy more difficult and increases the risk of complications. As the morbidity associated with surgery continues to decrease with improvements in minimal access techniques, the argument for primary management of achalasia with oesophagomyotomy becomes more compelling.