Prior Chemoradiation Research Articles

Antibiotic Prophylaxis and Postoperative Wound Infection Rates in Salvage Surgery for Head and Neck Cancer

Wound infections are the most common complication after free flap reconstruction of head and neck defects. Patients who have undergone prior chemoradiation have higher infection rates following surgery. We hypothesized that patients who undergo salvage surgery for recurrent or persistent head and neck cancer may benefit from prolonged antibiotic prophylaxis. The objectives are to determine the rate of infection in salvage surgery following chemoradiation and to determine type and duration of antibiotic prophylaxis. Retrospective review of patients with recurrent or persistent head and neck cancer who underwent clean-contaminated procedures with violation of the aerodigestive tract mucosa following radiation therapy or chemoradiation between 2010 to 2015 at Loyola University Medical Center. All patients underwent immediate reconstruction using a free flap or regional flap. Univariate analysis was performed. Outcomes measured included duration and type of antibiotic prophylaxis, development of postoperative surgical site infections, and common cultured pathogens. Sixty-six patients underwent salvage surgery with free flap reconstruction of which, 59 patients received antibiotic prophylaxis for more than 24 hours, 6 patients received it for less than 24 hours or less, and 1 patient received no antibiotic prophylaxis. The most common prophylactic antibiotics choices were clindamycin (38%) and ampicillinsulbactam (26%). Surgical site infections occurred in 56% (N=36) of patients, with mucocutaneous fistula as the most common (47.5%). Staphylococcus aureus and Pseudomonas aeruginosa were the most commonly cultured organisms. Eightysix percent of patients receiving perioperative antibiotics for less than 24 hours developed a wound infection compared to 51% of patients receiving antibiotics for greater than 24 hours (p=0.08). There is no benefit to extending antibiotic prophylaxis in patients undergoing salvage surgery beyond 24

Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

Oncological Outcome and Toxicity With Upfront Neck Dissection Prior Chemoradiation Therapy for Clinically Node Positive Head and Neck Squamous Cell Carcinoma

Oncological Outcome and Toxicity With Upfront Neck Dissection Prior Chemoradiation Therapy for Clinically Node Positive Head and Neck Squamous Cell Carcinoma

Development of a prediction model of adverse events after stent placement for esophageal cancer

Self-expandable metal stent (SEMS) positioning is the recommended method for palliation of dysphagia from esophageal cancer, although it is not adverse event-free. The present study was aimed at identifying predictors for adverse events and at proposing a statistical model to predict them. We performed a retrospective analysis of a prospectively collected database. All patients who underwent SEMS placement for stricture due to esophageal cancer between 2002 and 2011 in a tertiary-care center were identified. Multivariable regression analysis in the presence of competing risk events was used to identify factors associated with SEMS-related adverse events and to build a prediction model. A total of 267 patients were included. According to the competing risk regression analysis, only 2 variables were significantly associated with the risk of SEMS-related adverse events: prior chemoradiotherapy (CRT), yielding a hazard ratio (HR) of 1.687 (95% confidence interval [CI], 1.076-2.644), and the SEMS length (HR 0.884; 95% CI, 0.798-0.980) for every 10-mm length increase. Based on the estimated probability curves, after 4 months from SEMS placement, the probability of an adverse event in patients who did receive prior CRT was 50.9% compared with 34.4% in those who did not receive prior therapy, which was reduced to 9.2% and 15.1%, respectively, if a 180 mm-length stent was used. The ability of the predictive model to differentiate between patients who did and did not experience the adverse event was moderate (c-index: 0.617). The rate of SEMS-related adverse events was higher in patients with previous CRT and lower in patients receiving longer stents. Both factors were used to build an accurate predictive model.

Novel Clonal t(2;4) (q23;p14) Secondary Cytogenetic Abnormality in a Primary Myxoid Liposarcoma

Myxoid liposarcomas are malignant lipomatous tumors with a predilection for young adults. They are characterized by the presence of reciprocal translocation between the CHOP (DDIT3) gene on chromosome 12 and the FUS gene on chromosome 16, t(12;16)(q13;p11.2) in >95% of cases, or less commonly, a translocation between the DDIT3 and EWSR1 genes, t(12;22)(q13;q12). Secondary aberrations involving trisomy 8 and chromosomes 1 and 16 have been reported. Herein, we report for the first time a novel secondary clonal translocation, t(2;4) (q23;p14) in addition to t(12;16)(q13; p11.2) in a 30-year-old woman with myxoid liposarcoma on the left posterior thigh region without any prior chemoradiation therapy. The significance of this translocation remains to be established.

Response to crizotinib in a squamous cell lung carcinoma patient harbouring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma translocation: A case report.

Squamous cell lung cancer (SCC) presenting with anaplastic lymphoma kinase (ALK) translocation is rare. We present a case of ALK gene translocation‐SCC in which a remarkable tumor response to crizotinib was achieved after the failure of prior chemoradiotherapy. Considering this remarkable response, we conclude that ALK testing in female non‐smokers or in any patient unresponsive to the initial regimen of chemotherapy, is recommended for SCC patients.

Little things make big things happen: angiolymphatic invasion and tumor necrosis prognosticate the outcome of locally advanced non-small cell lung cancer treated with a prior induction therapy.

Size, invasion of thoracic structures, and ipsilateral mediastinal lymph node involvement (pN2) are well-known prognostic factors that configure the staging of resectable, locally advanced non-small cell lung cancer (LA-NSCLC). The prognostic impact of angiolymphatic invasion (ALI) and tumor necrosis (TN) has been barely explored in LA-NSCLC treated with prior induction therapies. We retrospectively reviewed 47 resected LA-NSCLCs treated with a prior platin-based chemotherapy or chemoradiation. The impact of ALI, TN, and other pathologic features on survival was analyzed. ALI was presented in 23.4% of cases and TN in 29.8%. Disease-free and overall survival decreased when ALI, TN, or pN2 was present. The incidence of ALI was lower in LA-NSCLC with a good response to induction. Our series is the first to report the prognostic impact of ALI and TN in induction-treated LA-NSCLC. The presence of ALI and TN should be included in the pathologic reports.

PTH-264 Preoperative chemoradiotherapy does not appear to have short-term effects on human rectal neuromuscular functions: Abstract PTH-264 Table 1

Introduction Preoperative chemoradiotherapy may impair anorectal functions. Its effect on neuromuscular functions was investigated in human rectum ex-vivo . Method Following informed consent, 3 groups of patients undergoing surgery for anorectal cancer were studied: 13 patients treated by surgery alone (Group I); 13 with long course neoadjuvant chemoradiotherapy (capecitabine) (Group II); and 4 with prior platinum-based chemoradiotherapy (oxaliplatin/capecitabine n = 2, FOLFOX/capecitabine n = 1, carboplatin/paclitaxel n = 1) (Group III). Age and gender were similar between Group I and II. Group III [55 (range=51–60)] were younger than Group I [72 (range=50–87)]. Postoperatively, macroscopically-normal rectum (without taenia) was obtained 5–10cm away from tumour. Mucosa-free circular muscle strips were suspended in tissue baths for isometric recording and electrical field stimulation (EFS, 1–20Hz, 50V, 0.5ms, for 10s) applied. 1 Data are expressed as median (inter-quartile range) and analysed using ANOVA with multiple comparison post-tests. Results EFS usually caused contraction (or relaxation at low frequencies), often followed by an ‘after-contraction’ on termination. Amplitudes of contractions during and after EFS, and area under curve (AUC) of the full muscle movement increased with frequency (see table). Contractions were abolished by atropine 1 µM and tachykinin (NK 1–3 ) receptor antagonists (n = 4) and greatly reduced by the neurotoxin tetrodotoxin 1 µM (n = 2). All parameters of the movements evoked by EFS at all frequencies [AUC, amplitude of responses during EFS and after EFS] were similar amongst the 3 groups. There were no significant differences in tension generated by carbachol 10 µM (maximally-effective concentration) between groups (see Table 1, P > 0 .05 for all measurements). Conclusion In this pilot study, preoperative chemoradiotherapy with capecitabine or platinum-based agents does not appear to have short-term effects on human rectal neuromuscular function. Reported impairment of anorectal function may be due to its long term effects or via other mechanisms. Disclosure of interest V. Kung Grant/ Research Support from: AgeUK PhD studentship, Barts and the London Charity, J. Broad: None Declared, M. Machesney: None Declared, M. Thaha: None Declared, C. Knowles: None Declared, G. Sanger Grant/ Research Support from: Takeda. Reference Broad et al . Br J Pharmacol. 2013;179:1253–61

How unique is pure erythroid leukaemia? A retrospective analysis of seven cases and review of the literature

AimsPure erythroid leukaemia (PEL) is a rare subtype of acute myeloid leukaemia (AML) and its clinicopathological features are not well-defined. The aim of this study was to describe the immunophenotypic,...

Identifying factors impacting subsequent gemcitabine dose intensity in patients undergoing chemoradiation for locally advanced pancreatic cancer.

455 Background: Systemic therapy is a critical part of the management of locally advanced pancreatic cancer (LAPC) due to the risk of distant failure. In the clinic, anecdotal evidence suggests that maintaining dose intensity of chemotherapy is more challenging after prior chemoradiotherapy (CRT). We thus evaluated whether treatment or patient factors limit the amount of systemic therapy received in LAPC patients receiving CRT. Methods: Following IRB approval, we retrospectively reviewed all patients diagnosed with LAPC undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine chemotherapy or chemotherapy prior to CRT. Patient and treatment factors were evaluated for their relationship to total gemcitabine dose received during CRT and within the first three months post-CRT. Statistical analysis was performed using regression models. Results: A total of 76 patients met the inclusion criteria with a median age of 69 (range 44-89) and a median follow-up of 13.2 months (range 3-68). The median gemcitabine dose received during CRT was 3,000 mg/m2 of a planned 3,600 mg/m2 and post-CRT was 5000 mg/m2 of a planned 9,000 mg/m2. Patients receiving a higher percentage of the desired chemotherapy dose during CRT received a lower percentage of desired chemotherapy dose post-CRT (p<0.01). Patients who underwent subsequent surgical resection (p<0.01) or received a higher radiation dose (p=0.03) were more likely to have received a higher total post-CRT chemotherapy dose. There were no variables correlated to chemotherapy dose received during CRT. Conclusions: Our analysis suggests that chemotherapy dosing during CRT rather than radiation dose impacts subsequent gemcitabine dose intensity. As a number of different CRT regimens are utilized in practice, this finding warrants further confirmation in a larger database.

Identifying Novel Genes and Signaling Pathways That Predispose to Therapy Related MDS (t-MDS)

Background: Melodysplastic syndrome (MDS) constitutes a complex set of hematopoietic stem cell diseases that is characterized by defective differentiation into one, some or all of the hematopoietic lineages. MDS is caused due to the accumulation of mutations in hematopoietic stem/progenitor cells (HSPCs) that result in accumulation of defective HSPCs in the bone marrow. Therapy related MDS (t-MDS) is a secondary complication associated with prior chemo-radiation therapy for either cancer or non-cancer related diseases and accounts for about 20% of total MDS cases. Gene products and pathways predisposing to t-MDS are not yet identified. In an attempt to identify t-MDS predisposing genes and signaling pathways, we established a retroviral insertional mutagenesis approach in combination with a clinical radiation therapy regimen in a mouse model.Methods: Random mutations in the C57BL/6 HSCs were generated via a retroviral mediated random insertional mutagenesis approach with a replication deficient virus, and transduced cells were transplanted into BoyJ recipients. After confirming successful reconstitution of recipient mice 3-4 weeks post transplantation, we treated mice with either 0, 0.5 or 2Gy radiation once a day for 3 days. Mice were monitored for aberrations in any of the hematopoietic lineages in both peripheral blood (PB) and bone marrow (BM) at frequent intervals thereafter. Mice developing t-MDS/AML like disease were sacrificed and the bone marrow cells were collected for further analysis. We performed ligation-mediated PCR (LM-PCR) using retroviral long terminal repeats (LTR) sequence based primers and amplifying into the mouse genomic region to identify the unique insertion sites. Expression of genes located around integration site was determined by quantitative PCR.Results: Ranging from 23-59 weeks post radiation, 70% of the animals treated with 0.5Gy developed a tMDS/AML-like disease while interestingly only 17% of the 2Gy treated mice developed tMDS/AML like disease. None of the control animals developed tMDS/AML-like disease, confirming specificity for t-MDS of our experimental setup. BM of mice with tMDS/AML-like disease showed a high level of donor chimerism (measured by GFPpos cells, ranging from 82-97%) and these mice exhibited anemia, thrombocytopenia, splenomegaly and myeloid blasts in BM and/or PB at different time points.LM-PCR was performed to determine viral integration sites in affected animals. We observed unique band patterns for each of the t-MDS/AML mice, indicating that the clones driving the disease were probably unique. We sequenced the LM-PCR products to identify the genome integration sites for all of the mice. Further gene expression analysis was performed on the genes located around the integration site to identify individual genes and/or signaling pathways that are altered in these mice. Among others, C1q and tumor necrosis factor related protein 6 (c1qtnf6/CTRP6), a fatty acid oxidation regulatory gene involved in AMPK activation in muscle, Neuroblastoma ras oncogene (N-ras), a known oncogene in various cancers and miR10a, a microRNA regulating cell survival through Twist1 gene expression in myeloid cells, are the genes with altered expression in these mice compared to control mice. Summarizing all verified integration sites we have generated a presumptive t-MDS predisposing gene list that further needs to be validated in vivo.Conclusions/Future directions: We anticipate a detailed validation of these genes in mice will facilitate the identification of genes and gene products that predispose to t-MDS/AML. We believe this is a unique mouse model mimicking a radiation mediated tMDS clinical scenario. DisclosuresNo relevant conflicts of interest to declare.

Total glossectomy without laryngectomy - a review of functional outcomes and reconstructive principles.

To provide an overview of functional outcomes and reconstructive principles of total glossectomy without laryngectomy reported in recent series, and the evidence regarding which patients are at risk for poor functional outcomes. After total glossectomy with laryngeal preservation gastric tube dependency ranges from 30 to 44% for primary treatment. Between 85 and 95% of patients are able to have their tracheostomy tube removed. Many patients can also regain meaningfully intelligible speech. In the setting of prior radiation or chemoradiation therapy, achieving oral diet and tracheostomy decannulation is less likely.Reconstructions must have sufficient bulk to allow for contact with the palate, and achievement of this vertical height has been shown to be associated with improved speech and swallowing outcomes. Laryngeal suspension is an important adjunct to prevent both laryngeal prolapse and minimize aspiration risk. The role of either sensory or motor reinnervation is unclear, although there is currently more evidence for the benefit of sensory reinnervation. With meticulous reconstructive technique and appropriate patient selection, total glossectomy with laryngeal preservation can be performed as a primary or salvage procedure with acceptable functional outcomes.

Final Overall Survival Analysis of the Phase III Randomized Trial of Chemotherapy with and Without Bevacizumab for Advanced Cervical Cancer: a Nrg Oncology - Gynecologic Oncology Group Study

ABSTRACT Aim: On August 14, 2014, the United States Food and Drug Administration approved bevacizumab for women with advanced cervical cancer. This regulatory milestone was due to GOG protocol 240 having met its primary endpoint with the arms administering chemotherapy plus bevacizumab resulting in significantly improved overall survival (OS) compared to chemotherapy alone. These results were publically announced following a data freeze on Dec 12, 2012 when 271 deaths had occurred. We now report the planned final analysis of OS. Methods: Phase III randomized clinical trial using a 2x2 factorial design to determine whether chemotherapy plus bevacizumab and/or the non-platinum chemotherapy doublet (topotecan plus paclitaxel) improves OS in women with recurrent/persistent and metastatic cervical cancer. The primary endpoints were OS and toxicity with secondary endpoints being PFS and response. We calculated that we would need to enroll approximately 450 patients with approximately 346 deaths expected to provide the study with 90% power to detect a reduction in the risk of death of at least 30% with either experimental treatment, with the one-sided type I error rate limited to 2.5% for each regimen. Results: The median age was 49 yrs and groups were well-balanced for disease status (70-73% recurrent), prior chemoradiation (74-75%), and in-field pelvic recurrence (53-54%). Gastrointestinal (GI) perforations were reported in 3.2% of patients receiving bevacizumab, all of whom had prior radiotherapy. GI-vaginal fistula occurred in 8.2% of patients treated with bevacizumab vs. 0.9% of those treated with chemotherapy alone. Grade 3+ venous thromboembolic events were reported in 10.6% (chemotherapy plus bevacizumab) vs 5.4% (chemotherapy alone). On March 7, 2014, 348 deaths had occurred and the regimens administering bevacizumab continued to demonstrate a significant improvement in OS over chemotherapy alone: 16.8 mos vs 13.3 mos; HR 0.765 (95% CI: 0.62, 0.95; p = 0.0068). Conclusions: The benefit conferred by the incorporation of bevacizumab is sustained beyond 50 months as evidenced by the survival curves remaining separated. Bevacizumab is the first targeted agent to be granted regulatory approval in the U.S. for treatment of a gynecologic cancer. Disclosure: K.S. Tewari: Contracted research: Endocyte, Amgen, Genentech Speaker's Bureau: Vermillion Advisory Board: Genentech, Caris Extramural funding: National Cancer Institute, Intuitive Surgical Inc.; R.T. Penson: Advisory Board: Genentech; A. Oaknin: Advisory Board: Roche; B.J. Monk: Advisory Board: Genentech/Roche. All other authors have declared no conflicts of interest.

Primary Tracheoesophageal Puncture with Supraclavicular Artery Island Flap after Total Laryngectomy or Laryngopharyngectomy

Objectives: (1) Describe our perioperative experience of primary tracheoesophageal puncture (TEP) with intraoperative placement of voice prosthesis for patients undergoing total laryngectomy (TL) or laryngectomy with partial pharyngectomy requiring supraclavicular artery island flap (SCAIF) reconstruction. (2) Assess TEP voice outcomes in this patient group. Methods: Retrospective chart review of all patients undergoing SCAIF reconstruction following TL or laryngectomy with partial pharyngectomy at a single institution between 2011 and 2013 (N = 14). There were no exclusion criteria. Results: We identified 7 patients who underwent primary TEP with intraoperative placement of voice prosthesis (mean age = 64.1, 5M:2F). Six patients had prior chemoradiation for laryngeal squamous cell carcinoma. One patient had a dysfunctional larynx from radiation treatment for tonsillar squamous cell carcinoma. Five patients underwent TL and 2 patients underwent TL with partial pharyngectomy. Indwelling 16 French Blom-Singer prosthesis was placed intraoperatively prior to SCAIF reconstruction. There were no TEP-related complications, such as prosthesis displacement or leakage, intraoperatively or in the perioperative period. One patient developed a peristomal pharyngocutaneous fistula. In terms of voice outcomes, 6 patients achieved tracheoesophageal voice production within 10 months after TEP placement, and most occurred earlier (mean time = 2.9 months, SD= 3.1). One patient remained aphonic. Of the 6 patients who achieved successful voice acquisition, 2 required cricopharyngeal segment Botox injections with good response. Conclusions: Similar to free tissue transfer reconstruction, primary TEP with intraoperative placement of the voice prosthesis at the time of SCAIF reconstruction is safe and effective. Six of 7 patients had successful voice acquisition within 10 months.

Long-term survival for advanced esophageal cancer patients with an esophago-bronchial fistula can be achieved by timely multimodality therapy

We reported four consecutive advanced esophageal cancer patients with esophago-bronchial fistula (EBF) who were managed well and achieved long-term survival with timely multimodality therapy including bypass operation. Eighty-four patients with esophageal cancer located in the upper or middle esophagus who were treated in our institute from 2005 to 2013 were diagnosed with cT4 at the time of admission. Eight (9.5 %) of those 84 cT4 patients developed the esophago-bronchial/tracheal fistula. Out of eight patients, four (50 %) who responded to prior chemotherapy or chemoradiotherapy received esophageal bypass operations to manage their QOL and continue the following therapy. Not only nutrition and quality of life but also fighting spirit were maintained by allowing oral intake and resulted in completion of postoperative chemoradiotherapy in all 4 patients. Multimodality treatment including a bypass operation provided high QOL and long-term survival even in advanced esophageal cancer patients with EBFs.

Fistula rates after salvage laryngectomy: Comparing pectoralis myofascial and myocutaneous flaps

Salvage laryngectomy after failed organ preservation often has a high complication rate, pharyngocutaneous fistulas being the most common. These fistulas increase morbidity, prolong hospitalization, and potentially delay adjuvant treatment. Fistula rates in the literature range from 3% to 65%. Use of the pectoralis flap to prevent fistula formation has been adopted as a common practice at our institution. A review of our experience using the overlay myofascial showed a higher than desired complication rate. The aim of this study is to assess whether the use of integrated myocutaneous flap results in a lower fistula rate. A retrospective review of 30 patients followed by a pilot study of 10 patients. All underwent salvage laryngectomy after failed organ preservation. The operation notes of 40 laryngectomy patients were analyzed. The patient/tumor characteristics, pretreatment, neck dissection, flap type, and fistula rate were documented. The patient sample was 25% female. All patients received prior radiotherapy, but only 37.5% received prior chemoradiation. Neck dissections were performed in 80% of these patients, 76% of the myocutaneous group, and 84% of the myofascial group. Advanced tumor stage was found in 42% of the myofascial group and 52% of the myocutaneous group. Five of the 19 myofascial patients developed a fistula, whereas seven of the 21 myocutaneous patients developed a fistula. The use of the pectoralis myocutaneous flap (PMCF) in this pilot series did not show a lower rate of fistula; other alternatives should be pursued to decrease this complication. 4.

Readmission after lung cancer resection is associated with a 6-fold increase in 90-day postoperative mortality

Postoperative readmission affects patient care and healthcare costs. There is a paucity of nationwide data describing the clinical significance of readmission after thoracic operations. The purpose of this study was to evaluate the relationship between postoperative readmission and mortality after lung cancer resection. Data were extracted for patients undergoing lung cancer resection from the linked Surveillance Epidemiology and End Results-Medicare registry (2006-2011), including demographics, comorbidities, socioeconomic factors, readmission within 30 days from discharge, and 90-day mortality. Readmitting facility and diagnoses were identified. A hierarchical regression model clustered at the hospital level identified predictors of readmission. We identified 11,432 patients undergoing lung cancer resection discharged alive from 677 hospitals. The median age was 74.5 years, and 52% of patients received an open lobectomy. Thirty-day readmission rate was 12.8%, and 28.3% of readmissions were to facilities that did not perform the original operation. Readmission was associated with a 6-fold increase in 90-day mortality (14.4% vs 2.5%, P<.001). The most common readmitting diagnoses were respiratory insufficiency, pneumonia, pneumothorax, and cardiac complications. Patient factors associated with readmission included resection type; age; prior induction chemoradiation; preoperative comorbidities, including congestive heart failure and chronic obstructive pulmonary disease; and low regional population density. Factors associated with early readmission after lung cancer resection include patient comorbidities, type of operation, and socioeconomic factors. Metrics that only report readmissions to the operative provider miss one-fourth of all cases. Readmitted patients have an increased risk of death and demand maximum attention and optimal care.

Endoscopic CO2 Laser Management of Chemoradiation-related Cricopharyngeal Stenosis

Treatment of head and neck cancer with chemoradiation (CRT) can result in strictures of the cervical esophagus, often at the level of the cricopharyngeus. The objective of this study is to assess the feasibility of endoscopic CO2 laser cricopharyngeal myotomy for stricture ablation in the setting of prior CRT. A retrospective review of patients who underwent endoscopic CO2 laser cricopharyngeal myotomy for dysphagia after radiation for squamous cell carcinoma of the head and neck (SCCHN). Pre- and postoperative barium swallow and swallowing assessment were performed before and after surgery. Outcomes and complication rates were examined. Endoscopic CO2 laser cricopharyngeal myotomy was performed in 10 patients with dysphagia secondary to cricopharyngeal stenosis/stricture, which developed following treatment for SCCHN with chemoradiation. All patients demonstrated radiographic improvement in stricture, with complete resolution of stricture in 9 of 10 patients. All patients noted improvement in dysphagia with 9 of 10 patients demonstrating significant advancement of diet by modified barium swallow. No complications were observed. Endoscopic CO2 cricopharyngeal myotomy can be performed safely in the setting of prior CRT, with significant improvement in swallowing in select patients. Indications and technical considerations will be discussed.

Identification Of Genes/Signaling Pathways That Predispose To Therapy Related MDS (t-MDS)

Myelodysplastic syndrome (MDS) constitutes a complex set of hematopoietic stem cell diseases that involves defective differentiation into either one, some or all of the hematopoietic lineages. MDS is caused due to the accumulation of mutations in hematopoietic stem/progenitor cells (HSPCs). Therapy related MDS (t-MDS) is a secondary complication associated with prior chemo-radiation therapy for either cancer or non-cancer related diseases and accounts about 20% of the total MDS cases. Genes predisposing t-MDS in response to chemo-radiation therapy remain enigmatic. We combined a retroviral insertional mutagenesis approach with a radiation treatment regimen in the mouse in an attempt to identify novel t-MDS predisposing genes and signaling pathways. To this end, C57BL/6 low-density bone marrow (LDBM) cells were transduced with the SFβ91 EGFP+ retrovirus, which results in a very high level of insertional mutagenesis (dysregulation of genes in the vicinity of the integration site). Transduced LDBM cells were transplanted into BoyJ recipient mice. After confirming successful transplantation of donor cells into recipients, animals were treated 3-4 weeks post transplant with either 0, 0.5 or 2Gy radiation once a day for 3 days. Mice were monitored for aberrations in any of the hematopoietic lineages in both peripheral blood (PB) and bone marrow (BM, intra-femural aspirates) at frequent intervals thereafter. Mice irradiated with 2 Gy exhibited cytotoxic effects on different hematopoietic lineages 1-week post radiation. Currently at 35 weeks post-radiation, 4 mice treated with 0.5 Gy and 1 mouse treated with 2 Gy developed a tMDS/AML-like disease. In these animals, BM was saturated with transduced donor cells (measured by GFPpos cells, ranging from 82-97% in BM of different mice) and mice exhibited anemia, thrombocytopenia, splenomegaly and myeloid blasts in BM at different time points. Additionally, 1 mouse treated with 2 Gy developed T-cell leukemia with 95.5% GFPpos T cells in PB and lymphoid blasts in BM and 1 mouse with 98.7% GFPneg cells in BM, with 75% of contribution from Mac1/Gr1. Mice developing t-MDS/AML like disease were sacrificed and bone marrow (BM) cells were collected for analysis of retroviral integration sites. We performed ligation-mediated PCR (LM-PCR) using retroviral long terminal repeats (LTR) sequence based primers and amplifying into the mouse genomic region to identify the unique insertion sites. We observed unique band patterns for each of the four t-MDS/AML mice indicating that the clones driving the disease are probably unique, which were confirmed by sequencing of LM-PCR products to identify the genome integration sites. Further gene expression analysis will be performed on the genes located around the integration site to identify individual genes and/or signaling pathways that are altered in these mice. Validation of such genes or pathways in mice might facilitate the identification of novel genes that predispose to t-MDS/AML. Disclosures:No relevant conflicts of interest to declare.

External Beam Radiation Therapy Is Associated With Increased Variability in Retinal Venous Oxygenation

Purpose/Objective(s): The prognosis for squamous cell head and neck cancer after surgical treatment and adjuvant chemo radiation is unsatisfactory in cases of close resection margins <5 mm (CM) or extracapsular extent at the lymph nodes (ECE). Therefore, we conducted a multicenter Phase II study to investigate the toxicity and efficacy of adjuvant radiation therapy in combination with concurrent cisplatin, 5-fluorouracil (5-FU), and cetuximab followed by maintenance therapy with cetuximab for 6 months. Here, we present the preliminary results on feasibility and toxicity. Materials/Methods: Patients with squamous cell cancer of the head and neck after primary surgery were eligible for the study, if a CM or ECE was detected. Cisplatin (20 mg/m d1-5 and d29-33) and 5-FU as continuous infusion (600 mg/m d1-d5 + d29-33) were given concurrently to postoperative radiation therapy using an integrated boost IMRT-technique (1.8/ 2.0/2.2 Gy QD) to a total dose of 61.6 Gy. Cetuximab started 7 days prior chemoradiation therapy with a loading dose of 400 mg/m followed by weekly cetuximab (250 mg/m) during chemoradiation therapy. Maintenance cetuximab started after completion of chemoradiation therapy plus cetuximab with 500 mg/m every 2 weeks over a 6-month period. Results: Fifty-five of 80 planned pts (46 male, 9 female, mean age 55.6, range, 29-70 years) have finished chemoradiation therapy, 50 are evaluable for toxicity. Concurrent Chemoradiation therapy plus Cetuximab was associated with grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals in 46%, 28%, and 14% of pts, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 10% of all pts (allergic reactions) after the first application. In 22% of all pts Cetuximab was discontinued during the last 2 weeks or at the end of chemo radiation therapy. Of those pts embarking on maintenance therapy, 80% were still on Cetuximab after 3 and 63% after 5 months. 48% completed 6 months maintenance therapy. Conclusions: Adjuvant radio chemotherapy in combination with cetuximab followed by maintenance cetuximab is feasible with toxicity in the expected range. Compliance to maintenance cetuximab was satisfactory during the first 3-5 months. Author Disclosure: C. Matuschek: None. E. Boelke: None. C. Belka: None. U. Ganswindt: None. M. Henke: None. P. Stegmaier: None. M. Bamberg: None. S. Welz: None. J. Debus: None. W. Budach: None.