Lawrence E. Feldman

Defective expression of the SHP-1 phosphatase in polycythemia vera

The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid progenitors of patients with polycythemia vera are hypersensitive to the mitogenic effects of these growth factors despite the fact that the numbers and binding affinities for their receptors are not increased. To determine whether post-receptor signaling defects may account for growth factor-hypersensitivity in polycythemia vera, we determined the expression of SHP-1 in highly purified erythroid progenitors from polycythemia vera patients. Our data demonstrate that in approximately 60% of the patients, expression of SHP-1 in the colony forming unit-erythroid population is diminished. The decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit-erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, SHP-1 expression in normal colony forming unit-erythroid demonstrated downregulation of mRNA and protein levels during terminal differentiation, suggesting that its function is required for growth control during the early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.

Improved Survival Associated with Neoadjuvant Chemoradiation in Patients with Clinical Stage IIIA(N2) Non–Small-Cell Lung Cancer

Introduction: Optimal management of clinical stage IIIA-N2 non–small-cell lung cancer (NSCLC) is controversial. This study examines whether neoadjuvant chemoradiation plus surgery improves survival rates when compared with other recommended treatment strategies. Methods: Adult patients from the National Cancer Database, with clinical stage IIIA-N2 disease definitively treated between 1998 and 2004 at American College of Surgeons Commission on Cancer accredited facilities, were included in the study. Treatment was defined as neoadjuvant chemoradiation plus either lobectomy (NeoCRT+L) or pneumonectomy (NeoCRT+P), lobectomy plus adjuvant therapy (L+AT), pneumonectomy plus adjuvant therapy (P+AT), and concurrent chemoradiation (CRT). Median follow-up and overall survival (OS) were defined from date of diagnosis to last contact. Five-year OS was estimated using Kaplan–Meier methods. Cox proportional hazard regression was used to estimate hazard ratios and 95% confidence intervals (CIs), adjusting for sociodemographic, clinical, and facility characteristics. Results: Median follow-up was 11.8 months for 11,242 eligible patients. Five-year OS was 33.5%, 20.7%, 20.3%, 13.35%, and 10.9% for NeoCRT+L, NeoCRT+P, L+AT, P+AT, and CRT, respectively (p < 0.0001). On multivariable analysis, the estimated hazard ratio was 0.51 (CI: 0.45–0.58) for NeoCRT+L; 0.77 (0.63–0.95) for NeoCRT+P; 0.66 (0.59–0.75) for L+AT; 0.69 (0.54–0.88) for P+AT; and 1.0 (reference) for the CRT group. Comorbidity did not attenuate the relationship between treatment and survival. Conclusion: This large study demonstrates that patients with clinical stage IIIA-N2 NSCLC, who underwent neoadjuvant chemoradiation followed by lobectomy, were associated with an improved survival.

Review of current treatment practices for carcinoma of the head and neck

The past two decades have witnessed a paradigm shift in the treatment of squamous cell carcinoma of the head and neck. Innovation in chemotherapy, radiotherapy and surgery has led to the assimilation of these modalities into our treatment algorithms. This modern multipart treatment plan has led to improved survival; however, this has come at the cost of increased toxicity. New and future therapies will be more tumour specific and, ideally, less toxic. Current research centres on these tumour-specific therapies with the anticipation of improved survival with decreased toxicity. This article will review the standard of care, recent advances and unfulfilled needs in the treatment of squamous cell carcinoma of the head and neck.

Cold Agglutinin Disease in a Patient with Uterine Sarcoma

Cold agglutinin disease is a rare clinical scenario. It is usually associated with infection, drug reaction, and hematologic malignancy, such as non-Hodgkin lymphoma or lymphocytic leukemia. We report a case of cold agglutinin disease in a patient with solid-tumor uterine sarcoma. Immunological dysregulation has been proposed as the pathogenesis for this disease. We also summarize recently reported cases of cold agglutinin disease, the underlying conditions, and advances in the management of cold agglutinin disease.

Comparison of carboplatin–paclitaxel to docetaxel–cisplatin-5–flurouracil induction chemotherapy followed by concurrent chemoradiation for locally advanced head and neck cancer

OBJECTIVES In head and neck squamous cell carcinoma (HNSCC), docetaxel, cisplatin and 5-fluorouracil (TPF) has become an accepted induction chemotherapy regimen. However, carboplatin-paclitaxel (CT) regimens have shown comparable outcomes. Here, we compared the outcomes of patients treated with either TPF or CT as induction chemotherapy followed by definitive chemoradiation. PATIENTS AND METHODS We performed a single-institution retrospective analysis of patients with Stage III-IV HNSCC. From a database of 803 patients, we identified 143 patients treated with TPF or CT induction chemotherapy between 1999 and 2012. RESULTS 53 patients and 90 patients received TPF or CT induction chemotherapy, respectively. The median follow-up was 18.9 months. The 1 year locoregional control was 80.5% for CT compared to 55.5% for TPF (HR 0.32, P=.0002). The 1 year progression free survival was 73.2% for CT compared to 60.7% for TPF (HR 0.57; P=.02). On multivariable analysis, CT remained significant for LRC (HR 0.28; P=0.04). TPF induction chemotherapy was associated with worse renal toxicity as measured by peak creatinine increases during induction chemotherapy (P=0.001). TPF was also associated with a trend toward more chemotherapy dose reductions or changes in systemic agents during concurrent chemoradiation (43.4% for TPF vs. 27.8% for CT; P=0.06). CONCLUSIONS Compared to TPF induction chemotherapy, CT induction chemotherapy had at least similar if not better LRC and PFS in patients while having less renal toxicity. Thus, CT induction chemotherapy may benefit patients with locally advanced HNSCC by facilitating adequate chemoradiation regimens that enhanced disease control.

Cetuximab activity in dysplastic lesions of the upper aerodigestive tract

BACKGROUND High risk head and neck mucosal premalignancy has a malignant conversion rate of up to 40%, despite adequate surgical therapy. Epidermal Growth Factor Receptor (EGFR) blocking agents, including cetuximab, have shown activity in head and neck squamous cell carcinoma (HNSCC) and have potential for therapy in high risk premalignancy. METHODS We conducted a randomized, prospective, phase II clinical trial to determine the effects of cetuximab on patients with high risk premalignancy. Patients were randomized to treatment with cetuximab 400mg/m(2) on week one followed by 250mg/m(2) on week 2-8 or observation, with the option for crossover to cetuximab therapy for patients originally randomized to the observation arm. RESULTS Two of 19 enrolled patients did not complete therapy due to treatment toxicity. Analysis of 17 patients who completed the trial regimen show a trend toward a larger mean decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2) (P=0.082, one-sided exact Wilcoxon rank sum test). However, in the observation group, none of the 5 patients (0%) achieved complete resolution of dysplasia; while 4 of 12 (33.3%) cetuximab treated patients had no remaining dysplasia after therapy. CONCLUSIONS Treatment of high risk premalignancy of the upper aerodigestive tract with cetuximab alone may result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients. These results warrant further investigation in larger studies with increased statistical power.

Early identification of high-risk neutropenia in the ambulatory setting.

87 Background: The University of Illinois Cancer Center (UICC) utilizes nurse (RN) visits for laboratory review and toxicity evaluations for patients (pts) receiving chemotherapy. Upon review of nursing visits, we observed that RN visit documentation for neutropenia was variable without standard language, communication with physicians (MD), or requirement for MD evaluation. We sought to implement an early intervention strategy to prevent morbidity and mortality from high risk neutropenia (HRN). METHODS A multidisciplinary task force of oncology RNs and MDs created actual and ideal process maps, from identification of neutropenia to patient disposition. We developed a Standard Operating Protocol (SOP) involving a HRN checklist (created based on NCCN and ISDA guidelines) and new process for triage of HRN pts. RNs were required to complete the HRN checklist within the electronic health record for all pts with ANC < 1,000. If high risk features were identified, MD evaluation was required within 1 hour of RN call, with SOAP note and attending notification. RESULTS Over an 8 week period, 17 HRN templates were generated. The process and checklist were adjusted after the first 4 weeks with clinic wide feedback. Within the first 4 weeks, 8 templates were generated (5 MD, 3 RN); no patients met high risk neutropenia criteria and all were discharged home. Within the second 4 weeks, 9 templates were generated (3 MD, 6 RN); 3 HRN pts were identified with two direct admissions and one home discharge with favorable outcomes. Clinic staff reported greater understanding of HRN, increased satisfaction with multidisciplinary interactions, and more comfort with calling MDs for prompt patient evaluation. CONCLUSIONS UICC successfully piloted the creation and implementation of an early identification and intervention strategy for HRN with strong multidisciplinary support. Compared to the prior 6 month period, we found that use of the SOP and checklist resulted in improvement in evaluation of quality and timeliness of HRN pts and prevented morbidity and mortality. Additionally, the checklist provoked critical thinking from end users with more thorough patient evaluations and improved documentation, resulting in aggressive intervention and better outcomes.

A Myeloproliferative Disorder Associated with Isochromosome 14q

&NA; We present a case of isochromosome 14q‐related myeloid cell disorder. To our knowledge, this report describes the first case of an unclassifiable chronic myeloproliferative disorder associated with this karyotypic abnormality.

Outcomes From a Minority-Based Lung Cancer Screening Program vs the National Lung Screening Trial

This population-based study assesses demographic characteristics, CT scan findings, and lung cancer detection in minority populations compared with outcomes from the National Lung Screening Trial.

Abstract C89: Lung cancer screening in high risk populations: Developing community based screening and navigation program

Purpose: The National Lung Cancer Screening Trial (NLST) resulted in a 20% reduction in lung cancer (LC) deaths and 6.7% reduction in all-cause mortality. The NLST also resulted in lung cancer screening guidelines from the USPSTF. The population of the NLST was 91% white with less than 5% African Americans (AA) in the trial. AA are known to carry greatest burden of incidence/mortality due to LC. There is little data on populations such as the UI Health population who are predominantly AA with varied smoking behaviors. Objective: We examined lung cancer screening trends and demographics in AA populations to describe screening outcomes in diverse population compared to the population in the NLST Methods: The community based LC screening and navigation program of the UI Cancer Center and UI Health navigates patients from a FQHC in Chicago and patients from UI Health to tobacco cessation and LC screening. The screening program navigates high risk patient to screening and examines structural and social barriers that impact screening uptake and examines outcomes in high risk minority population compared to NLST cohort. Eligible screening populations from the FQHC affiliated with UI Health and the outpatient care population were screening and structural and social determinants such as a) age, b) race, c) insurance status, d) educational level, e) smoking status and f) gender were compared to that of the NLST population. The prevalence of LC and abnormal findings were compared in our diverse cohort compared to the NLST population along with an examination of impact of social determinants on LC screening outcomes. Results: Results from the UI Health Community Based Lung Cancer Screening program demonstrated that the UI Health population which includes patients from the FQHC (Mile Square Health Center) affiliated with UI Health have higher rates of positive screens with 4 of the first 125 patients diagnosed with lung cancer. The comparison of UI Health LC screening population demonstrated the UI Health population has three times higher rate of LC screening finding at baseline screens compared to NLST population. The findings also demonstrate that UI Health population carried larger burden of current smokers and had increased determinants of health associated with poor health outcomes. The results further demonstrated that a community based lung cancer screening program built with a tobacco cessation program can increase LC screening compliance in a high risk population. Discussion: The outcomes from our research demonstrate that a community based lung cancer screening and navigation program within an FQHC setting can increase lung cancer screening within a high risk population. The findings also suggest that the results from the NLST trial may not be generalizable to high risk racially and ethnically diverse populations. Community based screening and navigation programs may benefit from addressing social determinants such as SES, race and ethnicity, smoking status and insurance status that may impact cancer screening outcomes. The findings also suggest that additional data needs to be collected on lung cancer outcomes in racially and ethnically diverse populations to ensure current screening guidelines are able to ensure early detection and improved survival in racially and ethnically diverse populations not previously included in the pivotal screening trial. Citation Format: Mary Pasquinelli, Karriem Watson, Scott Grumeretz, Lawrence E. Feldman, Kevin Kovitz, Arkadiusz Z. Dudek, Martha Menchaca, Matthew Koshy, Robert Winn. Lung cancer screening in high risk populations: Developing community based screening and navigation program. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C89.