Partial Tumor Response Research Articles

P2-071 - Hyperthermic Isolated Pelvic Perfusion to Treat Pelvic Malignancies: First Russian Experience

Isolated pelvic perfusion (IPP) is a locoregional treatment of pelvic malignancies allowing delivery of high doses of chemotherapeutic agents directly to the arteries supplying the tumor. 9 patients underwent IPP in I.I. Dzhanelidze Research Institute of Emergency Medicine. 5 patients had locoregional recurrence of colorectal cancer cT4N+M0, 4 patients – lower vaginal tumors cT4N+M0. All patients had unfavorable premorbid background and local spread of the tumor. IPP was performed in endovascular manner with two balloon catheters occluding aorta and inferior vena cava. For the IPP minimal extracorporeal perfusion circuit with centrifugal pump (Research Institute of Robotics and Technical Cybernetics) but without oxygenator (hypoxic perfusion) was used. IPP was performed with mitomycin C 30 mg/m2 + cisplatin 100 mg/m2 in saline (1.3 L). IPP was performed for 30 minutes with flow speed of 250 ml/min, perfusate temperature of 42.0–42.5°C, pressure in the arterial line (pre-cannula) of 200 mm Hg. After 30 minutes drugs from the circuit were washed out with 3.5 L of saline using plasma filter during 20 minutes. Systemic leakage of the drugs was evaluated retrospectively by means of mass-spectrometry of the blood samples. There were no intra- or early postoperative complications associated with IPP, all patients were discharged on the third or fourth days after the procedure. Systemic leakage of cisplatin during IPP was 4.4–9.1% resulting in no significant hematological toxicity. On the fourth postoperative day pain relief was achieved in all 9 patients. Complete and partial tumor responses were achieved in 2 and 6 patients respectively. Three patients underwent surgical resection of the tumor in 1.5–2.5 months after IPP. IPP is a feasible, reasonably safe and effective procedure in patients with locally advanced pelvic malignancies allowing to improve patients outcomes.

Operating Procedures of the Electrochemotherapy for Treatment of Tumor in Dogs and Cats.

Electrochemotherapy (ECT) is a local approach which is used for treating solid tumors of different histologies. Its mechanism is based on cell membrane permeabilization by means of "electroporation". To achieve the "electroporation" of the cells, electric pulses are generated by a generator and delivered to the target tissue by the use of electrodes. Electroporation is a physical method which is used to introduce molecules, like cytostatic drugs, into the cells that could not pass the cell membrane on their own. In electrochemotherapy, currently, cisplatin and bleomycin are clinically used. Electrochemotherapy antitumor effectiveness is high, for example up to 100% complete response of canine mast cell tumors smaller than 2 cm3 was achieved. Additionally, electrochemotherapy can be used for the treatment of inoperable tumors. One of the important characteristics of electrochemotherapy is that it can be effective as a one-time treatment only. However, in the case of failure or partial tumor response it can be repeated several times with equal or improved effectiveness. Electrochemotherapy is already a standard treatment for cutaneous and subcutaneous tumors of various histologies in human and veterinary oncology. Furthermore, several clinical studies exploiting electrochemotherapy for deep-seated tumors are on-going.

Operating Procedures of the Electrochemotherapy for Treatment of Tumor in Dogs and Cats

Electrochemotherapy (ECT) is a local approach which is used for treating solid tumors of different histologies. Its mechanism is based on cell membrane permeabilization by means of "electroporation". To achieve the "electroporation" of the cells, electric pulses are generated by a generator and delivered to the target tissue by the use of electrodes. Electroporation is a physical method which is used to introduce molecules, like cytostatic drugs, into the cells that could not pass the cell membrane on their own. In electrochemotherapy, currently, cisplatin and bleomycin are clinically used. Electrochemotherapy antitumor effectiveness is high, for example up to 100% complete response of canine mast cell tumors smaller than 2 cm3 was achieved. Additionally, electrochemotherapy can be used for the treatment of inoperable tumors. One of the important characteristics of electrochemotherapy is that it can be effective as a one-time treatment only. However, in the case of failure or partial tumor response it can be repeated several times with equal or improved effectiveness. Electrochemotherapy is already a standard treatment for cutaneous and subcutaneous tumors of various histologies in human and veterinary oncology. Furthermore, several clinical studies exploiting electrochemotherapy for deep-seated tumors are on-going.

A Pilot Study: Predictive Value of Early Responses With 18F-Alfatide RGD PET/CT in Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation Therapy

Integrin αvβ3 has been shown to play an important role in angiogenesis, tumor growth and progression, and it is significantly up-regulated in various types of tumor cells and the activated endothelial cells of tumor angiogenesis. Because the tripeptide sequence of Arginine-Glycine-Aspartic (RGD) can specifically bind to integrin αvβ3, RGD PET/CT can be used for imaging of integrin αvβ3 and it can help evaluate tumor neovascularization and be used for the diagnosis and treatment of malignant tumors. In this clinical study, we use a new tracer, 18F-alfatide to evaluate the predictive value of the early response by 18F-Alfatide RGD PET/CT for patients with advanced NSCLC during CCRT. This study is supported by NSFC 81172133 and NSFC 81372413. 12 patients with NSCLC have undergone 18F-Alfatide RGD PET/CT examination before and during CCRT. The PET-CT parameters of maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and metabolic tumor volume (MTV) before treatment and those during treatment were obtained and the changes were calculated. These changes of PET-CT parameters were compared with the standard tumor response according to the revised response evaluation criteria in solid tumors (RECIST) criteria (v.1.1) using the chest CT one month after CCRT. 18F-Alafatide RGD PET/CT was performed successfully in all patients and no clinically significant adverse events were observed. One month after the completion of CCRT, 9 patients with a partial response of tumor (responder group) and 3 patients achieved stable disease (non-responder group). The percent changes of MTV (%ΔMTV) were significantly more pronounced in responder group than in non-responder group (47.50±5.89 vs 18.29±12.53, P < 0.001). If the %ΔMTV were decreased 30% or more during CCRT, the tumors were more likely to achieve partial response after treatment than those with less than 30% of decrease. The percent changes of SUVmax (%ΔSUVmax) or SUVmean (%ΔSUVmean) had no correlation with the tumor response after treatment. %ΔMTV from two serial 18F-18F-Alfatide RGD PET/CT scans, before and during CCRT, allow prediction of the treatment response in advanced NSCLC.

Killer immunoglobulin-like receptor (KIR) and KIR–ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2

NK cells play a role in many cancer immunotherapies. NK cell activity is tightly regulated by killer immunoglobulin-like receptor (KIR) and KIR-ligand interactions. Inhibitory KIR-ligands have been identified as HLA molecules, while activating KIR-ligands are largely unknown. Individuals that have not inherited the corresponding KIR-ligand for at least one inhibitory KIR gene are termed the "KIR-ligand missing" genotype, and they are thought to have a subset of NK cells that express inhibitory KIRs for which the corresponding KIR-ligand is missing on autologous tissue, and thus will not be inhibited through KIR-ligand recognition. In some settings where an anticancer immunotherapeutic effect is likely mediated by NK cells, individuals with a KIR-ligand missing genotype have shown improved clinical outcome compared to individuals with an "all KIR-ligands present" genotype. In addition, patients receiving hematopoietic stem cell transplants for leukemia may do better if their donor has more activating KIR genes (i.e., KIR haplotype-B). In a recent multi-institution clinical trial of patients with metastatic renal cell carcinoma receiving high-dose IL2 (HD-IL2), 25% of patients showed a complete or partial tumor response to this therapy. We genotyped KIR and KIR-ligand genes for these patients (n=107) and tested whether KIR/KIR-ligand genotypes correlated with patient clinical outcomes. In these analyses, we did not find any significant association of KIR/KIR-ligand genotype (either KIR-ligand missing or the presence of KIR haplotype-B) with patient outcome in response to the HD-IL2 therapy.

The safety and efficacy of nivolumab in advanced (metastatic) non-small cell lung cancer

ABSTRACTIntroduction: Advanced non-small cell lung cancer (NSCLC) is a challenging oncological problem. Following standard initial therapy, disease progression will typically develop. Patients with relapsed or refractory disease are left with limited treatment options. The advent of nivolumab, a monoclonal antibody against Program Death-1 (PD-1), has substantially changed the outlook for such patients.Area covered: Nivolumab is the first checkpoint immunotherapeutic agent to gain regulatory approval for NSCLC. By enabling host immune-mediated cytotoxic activity against tumor cells, nivolumab induces a partial or complete tumor response in 15–20% of patients, regardless of number of previous lines of anti-cancer therapy. Nivolumab-related adverse effects are generally milder and less frequent than those observed with conventional cytotoxic chemotherapy. Although immune-related adverse events such as fatal pneumonitis have been reported with nivolumab therapy, most adverse events are reversible with a prompt immunosuppression. Studies investigating nivolumab in combination with other agents are ongoing.Expert commentary: Nivolumab represents a significant breakthrough in the treatment of advanced NSCLC. Its therapeutic role for NSCLC may soon expand to include consolidation or maintenance setting. Furthermore, several clinical trials investigating the combination of nivolumab with other immunologic or non-immunologic treatments are ongoing and these will likely result in additional roles of nivolumab in NSCLC.

Abstract CT016: Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies

Abstract Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and c-KIT approved for use in renal cell carcinoma (RCC). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models suggest that HDACi-mediated epigenetic modulation of VEGF expression prevents PAZ resistance and potentiates efficacy. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors with an expansion cohort in RCC. Methods: The primary endpoint was the maximal tolerated dose (MTD) of PAZ plus ABX. Secondary endpoints included pharmacokinetics (PK) and efficacy. PAZ was dosed days 1-28 and ABX days 1-5, 8-12, and 15-19 of 28-day cycle (schedule A) with at a starting dose of 400 mg/day and 45 mg/m2 orally twice daily respectively. An alternate ABX dosing schedule days 1-4, 8-11, and 15-18 was investigated (schedule B) due to toxicity of Schedule A. Results: 52 patients (pts) (RCC; N = 23) with advanced solid tumors were enrolled (N = 22 schedule A; N = 30 schedule B). There were six dose-limiting toxicities including fatigue (N = 2), thrombocytopenia (N = 2), and elevated AST/ALT (N = 2). The most common grade ? 3 related adverse events observed were fatigue (13%), thrombocytopenia (12%), and diarrhea (10%). The MTD was PAZ 800 mg/day + ABX 45 mg/m2 BID on schedule B. 8 evaluable pts (19%) (N = 6 RCC; 2 thyroid; median number of prior lines of therapy = 3) achieved partial tumor response (PR), with median duration of response of 9.2 months (1-33.2+). 7/9 (78%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. 15 out of 48 evaluable pts (31%) experienced stable disease or better for ? 6 months, and two previously PAZ-refractory pts with PRs remain on study for &amp;gt; 20 and 37 mos respectively. PK analyses did not reveal drug-drug interaction. Degree of histone acetylation and metabolomic profile are being evaluated. Conclusion: The combination of PAZ + ABX was well tolerated and durable tumor control (&amp;gt; 3 yrs) was observed in RCC and thyroid cancer. Tumor regressions observed in majority of PAZ-refractory tumors preliminarily support the potential of ABX to reverse therapeutic resistance. A randomized phase 2 study with cross-over design is planned to further evaluate the combination of PAZ + HDACi. Citation Format: Rahul Aggarwal, Scott Thomas, Jennifer Grabowsky, Armand Harb, Jim Leng, Anne Reinert, Ilaria Mastroserio, Thach-Giao Truong, Pamela N. Munster. Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT016.

Abstract CT070: Biomarker and clinical response of oral cavity squamous cell carcinoma to the MEK 1/2 inhibitor trametinib: A phase II neoadjuvant window of opportunity clinical trial

Abstract Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). To determine biomarker and clinical tumor response of MEK inhibition in patients with OCSCC, we performed a neoadjuvant window of opportunity trial in which the MEK inhibitor trametinib was administered before surgery (NCT01553851). Patients and Methods: Patients with untreated Stage II-IV OCSCC were scheduled to receive trametinib 2 mg/day orally for 7-14 days prior to surgery (last dose 24 hours before surgery). Tumor specimens from the primary site obtained before and after trametinib underwent immunohistochemistry staining for p-ERK1/2 (a marker of Ras/MEK/ERK activation) and CD44 (a protein upregulated by ERK activation), which represented the primary endpoint. Secondary endpoints included comparison of changes in pre- and post-trametinib tumor measurement by clinical examination and in metabolic activity (SUVmax) by FDG-PET/CT (partial response: &amp;gt;25% reduction). Adverse events (AE) and surgical/wound complications were evaluated. Results: Of the 20 enrolled patients, 17 (85%) completed the study as planned. Three patients withdrew from the study due to AE, two (nausea; duodenal perforation) related to trametinib and one (constipation) related to narcotics. The most common drug-related AE was mild rash (9/20 patients, 45%). Nineteen patients (95%) underwent surgery and neck dissection with no unexpected surgical/wound complications. Fifteen patients (75%) were evaluable for the primary biomarker endpoint. 5 (25%) patients either had insufficient pre- or post-treatment biopsies or did not complete the trial. Reduction in p-ERK1/2 expression occurred in 7/15 evaluable patients (47%), whereas a reduction in CD44 occurred in 3/15 (20%). Reduction in tumor size (median 40%, range -74 to +17%) assessed by clinical examination was observed in 12/17 (71%) evaluable patients, and partial metabolic tumor response assessed by FDG-PET/CT was observed in 5/13 (38%) patients. Conclusions: Trametinib was safe to administer as a neoadjuvant treatment in patients with OCSCC and several patients displayed significant reduction in Ras/MEK/ERK pathway activation, and in clinical and metabolic tumor responses. Further exploration of trametinib response in OCSCC patients is warranted. Citation Format: Ravindra Uppaluri, Ashley Winkler, Tianxiang Lin, Jonathan Law, Bruce Haughey, Brian Nussenbaum, Randal Paniello, Jason Rich, Jason Diaz, Loren Michel, Tanya Wildes, Gavin Dunn, Dorina Kallogjeri, Paul Zolkind, Farrokh Dehdashti, Barry Siegel, Rebecca Chernock, James S. Lewis, Jay Piccirillo, Douglas Adkins. Biomarker and clinical response of oral cavity squamous cell carcinoma to the MEK 1/2 inhibitor trametinib: A phase II neoadjuvant window of opportunity clinical trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT070.

Drug-Eluting Bead Transarterial Chemoembolization as Bridge Therapy for Hepatocellular Carcinoma Before Living-Donor Liver Transplantation

BackgroundThe majority of hepatocellular carcinoma (HCC) patients is diagnosed in late stages and therefore becomes ineligible for potentially curative treatment such as resection or liver transplantation. Transarterial chemoembolization (TACE) with drug-eluting beads (DC beads, Biocompatibles, Farnham, United Kingdom) has been proven with less side effects and better efficacy than conventional TACE, especially among patients with poor liver function. PurposeThe aim of this study is to evaluate outcomes of HCC patients who received TACE with DC beads, which resulted to eligibility for liver transplantation. Methods and MaterialsFrom January 2012 to June 2015, 60 patients with HCC received pre–liver transplantation evaluation whose cases were managed with TACE using DC beads at Kaohsiung Chang Gung Memorial Hospital were included in the study. DC beads loaded with doxorubicin were used. ResultsForty percent of the patients had complete tumor response. Thirty-three percent of the patients had partial tumor response, of which 15% showed stable disease, 11.7% exhibited disease progression including 3 with portal vein thrombosis, 1 with both hepatic vein and portal vein thrombosis, and 3 with increase in tumor size. Twenty-three patients were beyond University of California, San Francisco (UCSF) criteria initially. The successful downstage rate was 73.9% (17 of 23). Thirty-seven patients fit the USCF criteria initially. The 3-, 6- and 12-month drop rates of these patients were 0%, 3.9%, and 16.8%, respectively. Twenty-four (40%) patients successfully underwent liver transplantation. Three patients (12.5%) demonstrated recurrent HCC after liver transplantation. ConclusionTACE with DC bead can effectively induce tumor necrosis and appears to be a successful approach as bridge therapy for patients with advanced HCC and poor liver function.

The effect of neoadjuvant chemotherapy on hormone receptor status, HER2/neu and prolactin in breast cancer.

Histological and immunohistochemical findings may vary in cases of breast cancer. Possible changes in tumor markers between biopsies performed before and after neoadjuvant chemotherapy are controversial and pose a challenge when a clinical decision is needed. The objectives of the present study were: (i) to compare the immunohistochemical expression of estrogen, progesterone and prolactin receptors and HER-2/neu in breast cancer before and after neoadjuvant chemotherapy; and (ii) to correlate the expression of these tumor markers with partial tumor response to neoadjuvant chemotherapy. Immunohistochemical staining for breast tumor markers was performed in 90 cases of breast cancer. Statistical analysis was carried out using Fisher's exact test, McNemar's test, Spearman's correlation and the Kappa index with linear weighting (k). Agreement between markers before and after neoadjuvant chemotherapy was fair to moderate (k = 0.37-0.51). The immunohistochemical expression of HER-2/neu and prolactin receptors showed a significant, albeit weak correlation before and after neoadjuvant chemotherapy (HER-2/neu, rho = 0.34; P = 0.0009; k = 0.35 [95% CI, 0.19-0.51]). Prolactin status changed in 28/90 cases (P = 0.001; McNemar's test), whereas no changes were found in estrogen or progesterone receptors. No association was found between tumor marker expression and tumor response. It seems prudent to reevaluate immunohistochemical markers such as HER-2/neu after neoadjuvant chemotherapy, since the findings will guide the strategy for implementation of adjuvant systemic treatment. No correlation was found between the tumor markers analyzed in the present study and partial tumor response to neoadjuvant chemotherapy.

Safety and Efficacy of Low-Dose Metronomic Capecitabine in the Treatment of Elderly Patients with Breast Cancer: Report of Two Cases and Literature Review

Summary Capecitabine, a 5-fluorouracil prodrug, is increasingly used in breast cancer due to its more convenient oral route of administration compared to 5-fluorouracil. Despite its widespread use, there are only a few reports on low-dose efficacy, while the clinical significance of such agents remains to be illustrated. Here, we report two cases of breast cancer in women older than 85 years. Both were treated with capecitabine 500 mg t.i.d. every day for 9 and 12 courses, respectively; each course was 21 days. After treatment with low-dose capecitabine, both patients achieved partial tumor response. The side-effects were analyzed during chemotherapy; the primary adverse effects included mild fatigue, loss of appetite, and diarrhea. In conclusion, we observed that the administration of low-dose metronomic capecitabine improved two elderly patients with advanced breast cancers. It might be a well-tolerated treatment option, but its clinical significance still remains to be explored in large scale cohorts.

Abstract P2-02-17: T-DM1 in HER2-negative metastatic breast cancer patients with HER2-amplified circulating tumor cells: Current status of the CirCe T-DM1 phase II trial

Abstract Background: Liquid biopsy can reassess key therapeutic targets in metastatic breast cancer. Several studies showed that a low albeit significant rate of metastatic breast cancer initially considered as HER2-negative can be reclassified as HER2-positive by systematic biopsy procedures. We report here the current status of the CirCe T-DM1 trial [NCT01975142] which aims to demonstrate the clinical utility of HER2 status reassessment on circulating tumor cells (CTCs). Methods: The first step of the trial consists in CTC count and HER2/CEP17 FISH on detected CTCs (CellSearch, Janssen Diagnostics) in patients (pts) with measurable disease progressing after the second line of chemotherapy. Pts with amplified CTCs (HER2/CEP17 ratio equal or higher than 2.2) are eligible to the treatment step of the study in two distinct cohorts: low CTC count (1 or 2 HER2-amplified CTCs) and high CTC count (3 and more HER2-amplified CTCs). In the treatment step has a Simon's two stage design, the anti-HER2 antibody-drug conjugate T-DM1 being administered until tumor progression. The primary objective of the trial is the confirmed response rate (RECIST). This trial is supported by Roche. Results: CirCe T-DM1 has been initiated in 10 centers in France. As of June 2015, 105 metastatic breast cancers pts considered as HER2-negative were screened. 29 pts (27%) had no CTC detected, 68 pts (65%) had at least 1 CTC detected with no HER2 amplification, and 8 pts (8%) exhibited HER2-amplified CTCs. Among the 8 pts, 1 pt had 5 HER2-amplified CTC, 2 pts had 2 HER2-amplified CTC and 5 pts had 1 HER2-amplified CTC. HER2/CEP17 ratios among HER2-amplified CTCs ranged from 2.5 to 7. Five of the 8 pts were treated by T-DM1. One objective confirmed partial tumor response has been observed (20%). Conclusion: The accrual is ongoing; the first efficacy assessment will occur after having treated 14 pts. This innovative trial highlights the promise and the complexity of liquid biopsy-based programs in the era of precision medicine: scarcity of the target, reliability and reproducibility of the target assessment, major efficacy when the target is matched to the appropriate drug. Citation Format: Bidard F-C, Romieu G, Jacot W, Cottu P, Dieras V, Lerebours F, Servent V, Luporsi E, Lortholary A, Tubiana-Mathieu N, Espie M, Bollet M, Bourgeois H, Renaud N, Pelissier S, Armanet S, Baeten K, Pierga J-Y. T-DM1 in HER2-negative metastatic breast cancer patients with HER2-amplified circulating tumor cells: Current status of the CirCe T-DM1 phase II trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-17.

COMPARATIVE CHARACTERISTICS OF THE METHODS OF CHEMODRUGS ADMINISTRATION IN THE TREATMENT OF PATIENTS WITH LOCALLY-ADVANCED BREAST CANCER

COMPARATIVE CHARACTERISTICS OF THE METHODS OF CHEMODRUGS ADMINISTRATION IN THE TREATMENT OF PATIENTS WITH LOCALLY-ADVANCED BREAST CANCER

Bevacizumab in neurofibromatosis type 2 (NF2) related vestibular schwannomas: a nationally coordinated approach to delivery and prospective evaluation.

NF2 patients develop multiple nervous system tumors including bilateral vestibular schwannomas (VS). The tumors and their surgical treatment are associated with deafness, neurological disability, and mortality.Medical treatment with bevacizumab has been reported to reduce VS growth and to improve hearing. In addition to evaluating these effects, this study also aimed to determine other important consequences of treatment including patient-reported quality of life and the impact of treatment on surgical VS rates. Patients treated with bevacizumab underwent serial prospective MRI, audiology, clinical, CTCAE-4.0 adverse events, and NFTI-QOL quality-of-life assessments. Tumor volumetrics were classified according to the REiNs criteria and annual VS surgical rates reviewed. Sixty-one patients (59% male), median age 25 years (range, 10-57), were reviewed. Median follow-up was 23 months (range, 3-53). Partial volumetric tumor response (all tumors) was seen in 39% and 51% had stabilization of previously growing tumors. Age and pretreatment growth rate were predictors of response. Hearing was maintained or improved in 86% of assessable patients. Mean NFTI-QOL scores improved from 12.0 to 10.7 (P < .05). Hypertension was observed in 30% and proteinuria in 16%. Twelve treatment breaks occurred due to adverse events. The rates of VS surgery decreased after the introduction of bevacizumab. Treatment with bevacizumab in this large, UK-wide cohort decreased VS growth rates and improved hearing and quality of life. The potential risk of surgical iatrogenic damage was also reduced due to an associated reduction in VS surgical rates. Ongoing follow-up of this cohort will determine the long-term benefits and risks of bevacizumab treatment.

Immune thrombocytopenia exacerbated by nivolumab in a patient with non-small-cell lung cancer

Abstract Introduction Nivolumab is a programmed death 1 (PD-1) immune-checkpoint inhibitor antibody currently approved for second-line therapy of metastatic non-small-cell lung cancer (NSCLC). PD-1 inhibitors including nivolumab are associated with a unique spectrum of immune-related adverse events (irAEs), though hematologic irAEs are rare and have not been previously reported in patients with NSCLC. Presentation of case Here we report a patient who experienced an exacerbation of underlying immune thrombocytopenia (ITP) while receiving nivolumab for NSCLC. The patient's ITP was successfully managed with romiplostim during nivolumab therapy, allowing for 7 months of clinical benefit and a partial tumor response. Discussion Using this case as an example, we provide a brief review of irAEs associated with PD-1 blockade, with particular attention to hematologic events. We also describe our approach to the use of nivolumab in this patient with underlying autoimmune disease. Conclusion Patients with NSCLC and underlying autoimmune disease may experience a flare of the autoimmune condition while receiving immune checkpoint inhibition. As illustrated by this case of ITP exacerbated by nivolumab, careful management of the autoimmune disease may allow for the safe administration of PD-1 directed agents in these patients.

Patients harboring EGFR mutation after primary resistance to crizotinib and response to EGFR-tyrosine kinase inhibitor

Anaplastic lymphoma kinase (ALK) rearrangement lung cancer responds to ALK tyrosine kinase inhibitors. It is known that many cases ultimately acquired resistance to crizotinib. However, a case of primary resistance is rare. We present a case of harboring exon 19 deletion in epidermal growth factor receptor in ALK rearranged lung adenocarcinoma, who experienced a partial tumor response to icotinib after failure with crizotinib therapy and chemotherapy. Considering the partial response, we conclude that it is important to find the cause of resistance to crizotinib. We detected gene mutations with plasma by the next-generation sequencing; the next-generation sequencing demonstrates an attractive system to identify mutations improving the outcome of patients with a deadly disease.

Brachytherapy of Uveal Melanomas with Ruthenium-106 Plaques

Background:Brachytherapy is the most commonly used conservative treatment for the uveal melanoma. The aim of this study was to evaluate therapeutic results of Ruthenium-106 plaque brachytherapy in the management of localized uveal melanoma cases.Methods:We reviewed retrospectively the clinical records of all patients treated in our department for an uveal melanoma, undergoing Ruthenium-106 plaque brachytherapy, from January 1996 to December 2015. We focused on clinical features, therapeutic characteristics, local and distant tumor control and side effects.Results:Nineteen patients were enrolled in our study. Mean age was 56.2 years (28-79) and the sex ratio was 1.37:1 males to females. Diagnosis was made on the basis of ophthalmological clinical examination, angiography, ultrasound and/or magnetic resonance. Median tumor diameter was 9.7 mm (6-13) and median thickness 4.4 mm (2.5-8). The dose of Ruthenium-106 plaque brachytherapy prescribed to the apex of each tumor was 70 Gy in all cases. The median radiation dose to the sclera surface was 226.4 Gy (range: 179.6–342.3) and the median total application time 115.2 hours (range: 27 to 237). After a median follow-up of 61.5 months, local control was achieved in 17 patients (89%): 16 demonstrated a partial tumor response and 1 tumor stabilization. Two patients suffered local progression leading to enucleation, one dying of hepatic metastasis. Radiation-induced complications were cataracts in 3 cases and vitreal hemorrhage in 2.Conclusion:Ruthenium-106 plaque brachytherapy is an efficient treatment for localized uveal melanoma, offering good local control with low toxicity.

Bilateral and synchronous testicular teratoma: a case report and literature review

Abstract Background Testicular germ-cell carcinoma is the most frequent neoplasm in males aged 15–35 years old. It is bilateral in 2–3%, and synchronous in 20–25% of the cases. Clinical case The case is presented of a 19 year-old male, with abdominal pain. Physical examination revealed abdominal mass in the umbilical region, and the computed tomography scan showed a retroperitoneal tumor, with α-fetoprotein, lactate dehydrogenase, and human chorionic gonadotropin above limits. Testicular ultrasound showed bilateral lesions. Exploratory laparotomy was performed, identifying an unresectable retroperitoneal tumor. Biopsies were taken, reporting mixed germ cell tumor composed of choriocarcinoma and embryonal carcinoma. Six cycles of chemotherapy were given, based on bleomycin, etoposide and cisplatin, with partial tumor response. Later on, the patient underwent bilateral radical orchiectomy, with pathology reporting a synchronous bilateral testicular teratoma. A second line of chemotherapy was given, based on vincristine, etoposide, ifosfamide and cisplatinum. Nevertheless, the disease progressed, with metastatic dissemination and the patient died. Discussion Germ cells tumors can be presented in primary extra-gonadal locations. It is difficult to distinguish a retroperitoneum primary germ cell tumor from metastatic disease of a clinically undetected gonadal tumor or one that has regressed, like the situation described in the case presented. Conclusions Ninety percent of patients diagnosed with germ cell tumors can be cured. However, delay in diagnosis correlates with an advanced clinical stage and poor prognosis.

Abstract 3159: In vitro characterization of third-generation chimeric antigen receptor T cells directed toward GD2-expressing and BRAF-inhibitor resistant melanoma target cells

Abstract Advances in the treatment of metastatic melanoma include the recent approval of the immunotherapy ipilimumab, an anti-CTLA-4 monoclonal antibody, and of the targeted therapies vemurafenib, dabrafenib and trametinib, which are mitogen-activated protein kinase (MAPK)-pathway inhibitors. Cancer immunotherapy also includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells are responsible for significant tumor responses in leukemia and neuroblastoma patients. We have manufactured third-generation GD2-specific CAR T cells to be used in our open CARPETS Phase I clinical trial of autologous GD2-CAR T cells in patients with advanced GD2-expressing melanoma (ACTRN12613000198729). However, although these promising new targeted- and immuno-therapies can produce complete or partial tumor responses, tumor resistance via alteration or bypass of the targeted molecules inevitably occurs.Combination therapies have been proposed as a way to exploit the high-level but short-term responses associated with kinase-inhibitor therapies and the low-level but longer-term responses associated with immunotherapy, and could potentially overcome tumor resistance by targeting multiple tumor-associated molecules. To this end, we have investigated the effects of vemurafenib, dabrafenib and trametinib on the function of our GD2-CAR T cells and found that dabrafenib does not inhibit effector functions at concentrations equivalent to reported plasma concentrations in treated patients. We have also observed that although GD2-CAR T cells have reduced killing of BRAF inhibitor -resistant melanoma cell lines, their function is not inhibited by PD1 blockade in vitro.These effects depend on whether GD2-CAR T-cell activation occurs via the native TCR or the CAR and upon the nature of apoptosis resistance in the GD2-expressing melanoma target cells. Citation Format: Tessa Gargett, Michael P. Brown. In vitro characterization of third-generation chimeric antigen receptor T cells directed toward GD2-expressing and BRAF-inhibitor resistant melanoma target cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3159. doi:10.1158/1538-7445.AM2015-3159

A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial

Background. A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.Material and methods. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.Results and Conclusion. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.