Therapy In Cancer Patients Research Articles

Dentist Role in Oral Treatment Before Head Neck Cancer Therapy

<p class="AbstractContent"><strong>Background:</strong> Various intra-oral conditions can be found in patient prior the cancer treatment that might include lesions associated with decreased immunity, such as viral infections and fungal infections. Dentist has a significant role to prepare the oral cavity to be in the best possible condition, in order to minimize oral disturbance and complaints of cancer patients.</p><p class="AbstractContent"><strong>Objective</strong>: The purpose of this article is to review the importance of intra-oral treatment prior cancer therapy in patients with head and neck cancer.</p><p class="AbstractContent"><strong>Case Report</strong>: A 35-years-old male patient was referred from the ENT Department, Cipto Mangunkusumo Hospital with suspected Nasopharyngeal Carcinoma for investigating the intra oral focal infection sources. Intra oral examination revealed various focal infection sources and pseudomembranous candidiasis. The candidiasis was completely healed after antifungal medication.</p><p class="AbstractContent"><strong>Conclusion:</strong> Dentists’ role in preparing the oral condition prior cancer treatment is very important to reduce further oral complication. All oral lesions including fungal infection should be treated before the commencement of cancer treatment.</p>

Computer aided prognosis for cell death categorization and prediction in vivo using quantitative ultrasound and machine learning techniques.

At present, a one-size-fits-all approach is typically used for cancer therapy in patients. This is mainly because there is no current imaging-based clinical standard for the early assessment and monitoring of cancer treatment response. Here, the authors have developed, for the first time, a complete computer-aided-prognosis (CAP) system based on multiparametric quantitative ultrasound (QUS) spectroscopy methods in association with texture descriptors and advanced machine learning techniques. This system was used to noninvasively categorize and predict cell death levels in fibrosarcoma mouse tumors treated using ultrasound-stimulated microbubbles as novel endothelial-cell radiosensitizers. Sarcoma xenograft tumor-bearing mice were treated using ultrasound-stimulated microbubbles, alone or in combination with x-ray radiation therapy, as a new antivascular treatment. Therapy effects were assessed at 2-3, 24, and 72 h after treatment using a high-frequency ultrasound. Two-dimensional spectral parametric maps were generated using the power spectra of the raw radiofrequency echo signal. Subsequently, the distances between "pretreatment" and "post-treatment" scans were computed as an indication of treatment efficacy, using a kernel-based metric on textural features extracted from 2D parametric maps. A supervised learning paradigm was used to either categorize cell death levels as low, medium, or high using a classifier, or to "continuously" predict the levels of cell death using a regressor. The developed CAP system performed at a high level for the classification of cell death levels. The area under curve of the receiver operating characteristic was 0.87 for the classification of cell death levels to both low/medium and medium/high levels. Moreover, the prediction of cell death levels using the proposed CAP system achieved a good correlation (r = 0.68, p < 0.001) with histological cell death levels as the ground truth. A statistical test of significance between individual treatment groups with the corresponding control group demonstrated that the predicted levels indicated the same significant changes in cell death as those indicated by the ground-truth levels. The technology developed in this study addresses a gap in the current standard of care by introducing a quality control step that generates potentially actionable metrics needed to enhance treatment decision-making. The study establishes a noninvasive framework for quantifying levels of cancer treatment response developed preclinically in tumors using QUS imaging in conjunction with machine learning techniques. The framework can potentially facilitate the detection of refractory responses in patients to a certain cancer treatment early on in the course of therapy to enable switching to more efficacious treatments.

Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function.

Dendritic cells (DCs) are a critical component of anti-tumor immunity due to their ability to induce a robust immune response to antigen (Ag). Alcohol was previously shown to reduce DC ability to present foreign Ag and promote pro-inflammatory responses in situations of infection and trauma. However the impact of alcohol exposure on generation of an anti-tumor response, especially in the context of generation of an immune vaccine has not been examined. In the clinic, DC vaccines are typically generated from autologous blood, therefore prior exposure to substances such as alcohol may be a critical factor to consider regarding the effectiveness in generating an immune response. In this study, we demonstrate for the first time that ethanol differentially affects DC and tumor Ag-specific T cell responses depending on sex. Signaling pathways were found to be differentially regulated in DC in females compared to males and these differences were exacerbated by ethanol treatment. DC from female mice treated with ethanol were unable to activate Ag-specific cytotoxic T cells (CTL) as shown by reduced expression of CD44, CD69, and decreased production of granzyme B and IFNγ. Furthermore, although FOXO3, an immune suppressive mediator of DC function, was found to be upregulated in DC from female mice, ethanol related suppression was independent of FOXO3. These findings demonstrate for the first time differential impacts of alcohol on the immune system of females compared to males and may be a critical consideration for determining the effectiveness of an immune based therapy for cancer in patients that consume alcohol.

A retrospective analysis of preoperative staging modalities for oral squamous cell carcinoma.

An accurate preoperative assessment of cervical lymph node status is a prerequisite for individually tailored cancer therapies in patients with oral squamous cell carcinoma. The detection of malignant spread and its treatment crucially influence the prognosis. The aim of the present study was to analyze the different staging modalities used among patients with a diagnosis of primary oral squamous cell carcinoma between 2008 and 2015. An analysis of preoperative staging findings, collected by clinical palpation, ultrasound, and computed tomography (CT), was performed. The results obtained were compared with the results of the final histopathological findings of the neck dissection specimens. A statistical analysis using McNemar's test was performed. The sensitivity of CT for the detection of malignant cervical tumor spread was 74.5%. The ultrasound obtained a sensitivity of 60.8%. Both CT and ultrasound demonstrated significantly enhanced sensitivity compared to the clinical palpation with a sensitivity of 37.1%. No significant difference was observed between CT and ultrasound. A combination of different staging modalities increased the sensitivity significantly compared with ultrasound staging alone. No significant difference in sensitivity was found between the combined use of different staging modalities and CT staging alone. The highest sensitivity, of 80.0%, was obtained by a combination of all three staging modalities: clinical palpation, ultrasound and CT. The present study indicates that CT has an essential role in the preoperative staging of patients with oral squamous cell carcinoma. Its use not only significantly increases the sensitivity of cervical lymph node metastasis detection but also offers a preoperative assessment of local tumor spread and resection borders. An additional non-invasive cervical lymph node examination increases the sensitivity of the tumor staging process and reduces the risk of occult metastasis.

Using natural products to promote caspase-8-dependent cancer cell death.

The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.

Mo1511 Predictors of Survival With “Destination” Loco Regional Therapy of Hepatocellular Cancer in Patients Either Ineligible or Unwilling for Liver Transplantation: Score Yet Another One for MELD

Mo1511 Predictors of Survival With “Destination” Loco Regional Therapy of Hepatocellular Cancer in Patients Either Ineligible or Unwilling for Liver Transplantation: Score Yet Another One for MELD

Abstract MP33: Heart Failure Following Cancer Therapy in Patients with Hematological Malignancies Aged 18 Years and Under: A Linked Health Data Analysis (1996-2009)

Introduction: The causal link between chemotherapy treatments and subsequent cardiotoxicity is well established, particularly for children with hematological malignancies. Little information exists on the characteristics and outcomes for patients with heart failure (HF) after chemotherapy. This study aimed to describe the characteristics, survival and mortality of patients who received chemotherapy for hematological cancer (leukemias, lymphomas and related disorders) before 18 years old and subsequently developed HF compared to those who did not. Methods: Linked health data (1996-2009) from the Queensland Cancer Registry, Death Registry and Hospital Administration records for HF and chemotherapy admissions were reviewed. From all breast and hematological cancers patients (n=73,158), 15,987 received chemotherapy, including 819 patients aged ≤18 years at time of cancer diagnosis. Patients were categorized as those with an index HF admission (occurred after cancer diagnosis) and those without an index HF admission (non HF). Results: Of the 819 patients, 3.7% (n=30) had an index HF admission. Median age of HF patients at time of cancer diagnosis was 5 years (IQR 3-12) compared to 7 years (IQR 3-14) in the non HF group (p=0.503). Median follow up from cancer diagnosis was 2.5 years in the HF group compared to 5.42 years in the non HF group (p&lt;0.01). Of those who developed HF, 70% (n=21) had the index admission within 12 months of their cancer diagnosis. Of those with HF, 53.3% (n=16) died (all cause) compared to 14.6% (n=115) with no HF. On adjustment for age, sex and chemotherapy admissions, HF patients had an almost 5 fold increased mortality risk compared to non HF patients (HR 4.91 [95% CI, 2.88-8.36]) (Figure 1). Conclusions: This study demonstrated that in children with hematological cancers the onset of HF occurred soon after chemotherapy and mortality risk is almost 5 times that of children who do not develop HF. Innovative strategies are still needed for the prevention and management of cardiotoxicity in this population.

SY17-3 - Oral supportive care in cancer therapy at Hokkaido University Hospital

Background: Oral supportive care is required as part of the cancer therapy pretreatment assessment to manage conditions that may impact the cancer therapy and affect the ability of the person to complete the planned therapy. Programs to prevent acute and chronic complications of the cancer treatment are initiated. Oral complications of cancer therapy can be the most distressing of side effects and affect quality of life. The complications include oral infection, oral mucositis, altered saliva, change in taste, and coincidental dental infection, all of which can result in pain, and affect all aspects of oral function.Methods & Results: We examined the effects of oral supportive care on the prevention of complications induced by cancer therapy in patients of Hokkaido University Hospital. In this symposium, I will show the data and evidence-based management strategies for oral complication from cancer treatment.Conclusions: Oral supportive care providers, acting as part of the medical team, can facilitate the delivery of cancer treatment, and affect the quality of life during and following cancer therapy. Background: Oral supportive care is required as part of the cancer therapy pretreatment assessment to manage conditions that may impact the cancer therapy and affect the ability of the person to complete the planned therapy. Programs to prevent acute and chronic complications of the cancer treatment are initiated. Oral complications of cancer therapy can be the most distressing of side effects and affect quality of life. The complications include oral infection, oral mucositis, altered saliva, change in taste, and coincidental dental infection, all of which can result in pain, and affect all aspects of oral function. Methods & Results: We examined the effects of oral supportive care on the prevention of complications induced by cancer therapy in patients of Hokkaido University Hospital. In this symposium, I will show the data and evidence-based management strategies for oral complication from cancer treatment. Conclusions: Oral supportive care providers, acting as part of the medical team, can facilitate the delivery of cancer treatment, and affect the quality of life during and following cancer therapy.

2765 Re-treating with carboplatin and paclitaxel as first line therapy for recurrent endometrial cancer in patients who have previously received this regimen in the adjuvant setting

2765 Re-treating with carboplatin and paclitaxel as first line therapy for recurrent endometrial cancer in patients who have previously received this regimen in the adjuvant setting

Effect of dendritic cell/cytokine-induced killer cell immunobiological cancer therapy combined with adjuvant chemotherapy in patients with triple-negative breast cancer ⁎

Abstract Objective The aim of the present study was to investigate the effect of dendritic cell (DC)/cytokine-induced killer cell (CIK) immunobiological cancer therapy in patients with triple-negative breast cancer (TNBC) who underwent adjuvant chemotherapy. Methods From January 2010 to October 2013, 120 patients with postoperative TNBC were recruited and included in the study. Patients were enrolled in one of two groups according to whether they accepted DC/CIK immunobiological cancer therapy during adjuvant chemotherapy; the patients in the DC/CIK group underwent adjuvant chemotherapy combined with DC/CIK immunobiological cancer therapy, and the control group underwent adjuvant chemotherapy alone. When six cycles of adjuvant chemotherapy and six cycles of DC/CIK immunobiological cancer therapy had been completed, differences between the two groups with regard to quality of life (QoL), immunological indicators (CD3, CD4, CD8, and NK cell levels), disease-free survival (DFS), and side effects of chemotherapy and DC/CIK treatment were evaluated. Results In the DC/CIK group, the proportion of NK cells and CD3+ and CD4+ T-cell subgroups significantly increased, and the proportion of CD8+ cells decreased when they were compared before and after DC/CIK therapy (P &lt; 0.05). However, there were no significant changes in the control group. By the final follow-up, DFS of the treatment group and the control group was 38.4 and 34.2 months, respectively. The QoL improved in the patients treated with chemotherapy plus DC/CIK therapy compared with the patients treated with chemotherapy alone, and the difference between groups was significant (P &lt; 0.05). The side effects of two groups were tolerable and not significantly different between the two groups. Conclusion The DC/CIK treatment had potential benefits for patients with TNBC compared with the control group, and was not associated with any obvious side effects. Therefore, DC/CIK therapy is a safe and effective method for the treatment of TNBC.

Hot flash management: update of the evidence for patients with cancer

Hot flashes are a distressing symptom frequently experienced by survivors of breast cancer or prostate cancer who are receiving estrogen or androgen-deprivation therapies. The frequency and intensity of hot flashes can lead to diminished quality of life and decreased adherence with prescribed antineoplastic therapies. This evidence-based review synthesizes and updates the findings of the highest quality evidence-based studies of interventions to manage hot flashes resulting from cancer therapies in patients with breast or prostate cancer since the initial Putting Evidence Into Practice review of hot flashes in 2011. Recent studies involving a variety of pharmacologic and nonpharmacologic interventions were evaluated and, as reported in 2011, the drugs gabapentin and venlafaxine were the only therapies rated as likely to be effective. In addition, a strong placebo effect was noted in several studies that included a placebo intervention and should be considered when reviewing interventions for hot flashes.

Abstract 2837: Hitting the target: Dynamic BH3 profiling, a novel functional assay to predict chemotherapy response

Abstract Background: Most chemotherapeutic agents kill via the mitochondrial pathway of apoptosis, but unfortunately there is a lack of effective predictive biomarkers to assess the optimal treatment for each patient. When effective death signaling is initiated by a targeted therapy, an increase in mitochondrial apoptotic sensitivity (or ‘priming for death’) can be observed within hours. We developed a new technique, Dynamic BH3 Profiling, that measures changes in priming induced by chemotherapy in cancer cells, without the requirement for prolonged ex vivo culture, and we assessed if it could be used as predictive assay to personalize cancer therapy in patients. Hypothesis : Early apoptotic signaling detected via Dynamic BH3 Profiling can predict later cytotoxic cellular response. Results: Our first test was whether dynamic BH3 profiling performed following only 16 hours of drug exposure could predict cytotoxicity at a much later (72-96 hours) time point. We initiated our studies on a diverse panel of human cancer cell lines treated with a wide range of kinase inhibitors. These cell lines included solid tumors: NSCLC, breast cancer, melanoma and colon carcinoma; and hematological malignancies: multiple myeloma, CML, diffuse large B cell lymphoma and AML. We used different treatments (primary targets): Gefitinib (EGFR inh), Imatinib (BCR-ABL inh), Lapatinib (HER2 inh), TAE-684 (ALK inh), MK-2206 (Akt inh), PLX-4032 (BRaf V600E inh), AZD6244 (MEK inh), BEZ235 (PI3K/mTOR inh) and others. We observed a significant correlation between the increase in priming following short-term exposure to the agents and cell death at 72-96 hours, demonstrating the predicting capacity of dynamic BH3 profiling in different cancer cells. We then tested if dynamic BH3 profiling can predict clinical response in cancer patients. For that purpose, we used samples from stable phase CML and ovarian adenocarcinoma patients of known clinical outcome to imatinib or carboplatin treatment respectively. In both cases we found that the induction of mitochondrial priming caused by short term (16 hr) ex vivo exposure to treatment predicted clinical response. Moreover, the ROC curve analysis demonstrated that Dynamic BH3 profiling is an excellent binary predictor of response in vitro and in the clinic. Conclusions: Our cell line and clinical experiments demonstrate the potential for Dynamic BH3 profiling to be used as a powerful real-time tool to predict chemotherapy response across many cancers and many agents, including combinations of agents. It is an excellent binary predictor in multiple cell lines and different types of primary samples. and could be used to recognize the best agent from a list of possible therapies for an individual tumor and improve cancer therapy. Citation Format: Joan Montero, Kris A. Sarosiek, Joe D. DeAngelo, Huiying Piao, Neil Horowitz, Ross Berkowitz, Ursula Matulonis, Ronny Drapkin, Anthony Letai. Hitting the target: Dynamic BH3 profiling, a novel functional assay to predict chemotherapy response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2837. doi:10.1158/1538-7445.AM2014-2837

Abstract 4752: Targeting senescence-induced pro-survival pathways in PR+ ovarian cancer cells

Abstract Despite major advances in surgical techniques and chemotherapeutics, over 90% of women with advanced ovarian cancer ultimately succumb to recurrent chemo-resistant disease. Accordingly, the discovery of molecular targets that appropriate multiple signaling pathways is desperately needed. In recent years, the progesterone receptor (PR) has become an attractive target in ovarian cancer. Like estrogen receptors (ER), expression of PR in ovarian tumors is associated with longer progression-free survival of ovarian cancer patients. Both steroid hormone receptors are typically expressed in normal ovarian surface epithelial (OSE) cells, but PR mRNA and protein levels decrease during the transformation to malignancy. However, up to 35% of ovarian cancers (primarily endometrioid and serous sub-types) express abundant PR. The detailed molecular mechanisms of loss of PR expression in OSE cells and its anti-tumorigenic effects remain poorly understood. Recently, we demonstrated that PR-B is an ovarian cancer tumor suppressor that exhibits anti-proliferative properties by inducing cellular senescence. Progesterone and progestins induce FOXO1-dependent p21 expression. We showed that PR-B and FOXO1 were co-recruited to the same PRE-containing region of the p21 upstream promoter upon progestin (R5020) treatment. Both proteins were required to cooperatively induce p21 mRNA and protein expression as determined using PR-null control cells and lentiviral-delivered shRNA FOXO1-knockdown studies. Stable knock-down of FOXO1 inhibited progestin-induced p21 expression in ES-2 cells stably expressing GPF-tagged PR-B and blocked progestin-induced cellular senescence. Senescent cells, although growth arrested, remain viable and metabolically active for an extended period of time. To sustain long-term viability, senescent cells are “oncogene addicted” to intrinsically activated pro-survival pathways. For example, the epidermal growth factor (EGF) and hepatocyte growth factor (MET) receptors are constitutively active in ovarian cancer cells. Interestingly, treatment of PR+ ovarian cancer cells with small molecule inhibitors to either receptor in combination with progestin caused a dramatic increase in cell death relative to either kinase inhibitor alone. These findings, although preliminary, suggest a means to dramatically improve the sensitivity of PR+ ovarian cancer cells to apoptosis-inducing chemotherapeutic agents. Future studies will validate the biological effects of combination treatments of progestin and receptor-specific inhibitors in novel ex vivo ex-plant models, wherein primary ovarian tumors are supported by hemostatic gelatin sponges. Combination therapies that exploit mechanisms of cellular senescence may provide a novel strategy to improve current cancer therapy for patients with PR+ ovarian cancer. (Studies supported by NIH R01 CA159712, T32 CA009138, CTSA 8UL1TR000114-03, and MN Ovarian Cancer Alliance.) Citation Format: Caroline H. Diep, Carol A. Lange. Targeting senescence-induced pro-survival pathways in PR+ ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4752. doi:10.1158/1538-7445.AM2014-4752

146IN - Overcoming Implementation Challenges of Personalized Cancer Therapy in Patients with Breast Cancer

ABSTRACT Breast cancer includes large number of genomic segments defined by genomic alteration on a putative oncogenic driver. Based on this background, it has been suggested to develop genomics-based trials where each patient receives a drug matched to the genomic alteration observed in the tumor. This approach has been evaluated in a molecular screening program called SAFIR01. This program has allowed defining limitation of the approach. First, the genomic test can not be provided in a significant proportion of patients for which % of cancer cells is low. This problem should be overcome by the development of in depth sequencing for clinical use. Second, the identification of oncogenic driver is challenging in breast cancer. Three solutions could be developed to overcome this issue. First, there is a need to develop catalogues of genes that are validated as cancer-related genes. Second, there is a need to better understand what are the rules that makes a genomic alteration a driver within a tumor. This includes clonal dominance, characteristics of the mutations, structure of amplicon etc etc… Third, there is a need to assess pathway activation. This could better understand the functional implication of the genomic alteration and could also allow identify drivers in patients without genomic alterations. Once the drivers have been identified, we then face the challenge of avoiding resistance to targeted therapies. There are currently three strategies to overcome this issue. First, there is a need to early identify subclones that mediate resistance to targeted therapies. Second, there is a need to combine targeted therapies with immunotherapeutics and DNA targeting agents. Finally, there is a need to better understand to what extent the level of intratumor heterogeneity (ITH) predicts resistance to targeted therapies, in order to exclude patients with high level of ITH from personalized medicine approaches. Disclosure: The author has declared no conflicts of interest.

Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.

Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function. Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer.

Risk of Pneumonitis After Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer in Patients With Prior Anatomic Resection

Purpose/Objective(s): Stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option for early stage, medically inoperable non-small cell lung cancer (NSCLC). Dosimetric factors including lung volume receiving 20 Gy (V20) >10%and mean lung dose (MLD) >4 Gy are established risk factors for radiation pneumonitis (RP) following SBRT, but limited data evaluate the relative risk of RP in patients undergoing SBRT following prior anatomic lung resection (ALR). This study assessed the incidence of RP and all grade 2+ pulmonary toxicity in patients treated with SBRT for NSCLC following ALR and compare toxicity rates to patients without prior ALR. Materials/Methods: The medical records of 83 consecutive patients with T1-T3 NSCLC treated with 87 courses of SBRT for 93 lung tumors (16 central, 77 peripheral) between January 2007 and September 2013 were reviewed. Sixteen patients with a history of prior ALR were identified, including lobectomy (n Z 12), bilobectomy (nZ 1), and pneumonectomy (n Z 3), with 67 patients without history of prior ALD. The most commonly used fractionation regimen was 50Gy in 5 fractions. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Rates of grade 2+ RP and any grade 2+ pulmonary toxicity were compared between patients with and without prior ALR. Crude rates of RP and all grade 2+ pulmonary toxicity were compared using Fisher’s exact test. Actuarial estimates of freedom from RP (FFRP), in-lobe control (ILC), and overall survival (OS) were calculated with the Kaplan-Meier method and compared between cohorts via the log rank method. Results: At a median follow up of 11.9 months (range 1.2 to 81 months), 3 patients developed grade 2+ RP at a median of 4.0 months (range: 1.0-14.8 months). The crude rates of RP were 6.3% and 2.9% for patients with and without prior ALD, respectively (p>0.05). The 2 year Kaplan-Meier estimates of freedom from RP were 86% and 97% (p>0.05). Crude rates of all grade 2+ pulmonary toxicity were 11.8% and 2.9%, respectively, with associated 2 year estimates of 97% and 81%, respectively (p>0.05). The 2 cohorts were well matched by mean lung dose (4.67 Gy vs 4.15 Gy), lung V20 (5.16% vs 4.35%), mean PTV (30.63 cc vs 36.16 cc), and median prescribed dose (50 Gy vs 54) (p>0.05 for all). Conclusions: Observed rates of pulmonary toxicity were low among patients treated by SBRT after ALR. These data provide reassurances that SBRT can be performed safely for patients with prior ALR when conventional lung DVH constraints are utilized. Author Disclosure: J.T. Hayes: None. A.M. Chen: None. M.E. Daly: None.

Predictive Performance of Microarray Gene Signatures: Impact of Tumor Heterogeneity and Multiple Mechanisms of Drug Resistance

Gene signatures have failed to predict responses to breast cancer therapy in patients to date. In this study, we used bioinformatic methods to explore the hypothesis that the existence of multiple drug resistance mechanisms in different patients may limit the power of gene signatures to predict responses to therapy. In addition, we explored whether substratification of resistant cases could improve performance. Gene expression profiles from 1,550 breast cancers analyzed with the same microarray platform were retrieved from publicly available sources. Gene expression changes were introduced in cases defined as sensitive or resistant to a hypothetical therapy. In the resistant group, up to five different mechanisms of drug resistance causing distinct or overlapping gene expression changes were generated bioinformatically, and their impact on sensitivity, specificity, and predictive values of the signatures was investigated. We found that increasing the number of resistance mechanisms corresponding to different gene expression changes weakened the performance of the predictive signatures generated, even if the resistance-induced changes in gene expression were sufficiently strong and informative. Performance was also affected by cohort composition and the proportion of sensitive versus resistant cases or resistant cases that were mechanistically distinct. It was possible to improve response prediction by substratifying chemotherapy-resistant cases from actual datasets (non-bioinformatically perturbed datasets) and by using outliers to model multiple resistance mechanisms. Our work supports the hypothesis that the presence of multiple resistance mechanisms in a given therapy in patients limits the ability of gene signatures to make clinically useful predictions.

Monitoring and optimising cognitive function in cancer patients: Present knowledge and future directions

The potentially detrimental effects of cancer and related treatments on cognitive functioning are emerging as a key focus of cancer survivorship research. Many patients with central nervous system (CNS) or non-CNS tumours develop cognitive problems during the course of their disease that can result in diminished functional independence. We review the state of knowledge on the cognitive functioning of patients with primary and secondary brain tumours at diagnosis, during and after therapy, and discuss current initiatives to diminish cognitive decline in these patients. Similarly, attention is paid to the cognitive sequelae of cancer and cancer therapies in patients without CNS disease. Disease and treatment effects on cognition are discussed, as well as current insights into the neural substrates and the mechanisms underlying cognitive dysfunction in these patients. In addition, rehabilitation strategies for patients with non-CNS disease confronted with cognitive dysfunction are described. Special attention is given to knowledge gaps in the area of cancer and cognition, in CNS and non-CNS diseases. Finally, we point to the important role for cooperative groups to include cognitive endpoints in clinical trials in order to accelerate our understanding and treatment of cognitive dysfunction related to cancer and cancer therapies.

Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising.

The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.

Definitive Concurrent Chemoradiation Therapy via Intensity Modulated Radiation Therapy for Synchronous Esophageal Cancer in Patients With Head-and-Neck Cancer

Definitive Concurrent Chemoradiation Therapy via Intensity Modulated Radiation Therapy for Synchronous Esophageal Cancer in Patients With Head-and-Neck Cancer