Stage IIB-IV Research Articles

Invasive thymoma - Which patients benefit from post-operative radiotherapy?

The aim of this study is to identify patients with thymoma who should receive post-operative radiotherapy. The Surveillance, Epidemiology, and End Results database was queried for stage IIB-IV thymoma patients diagnosed during 1988-2015. We analyzed the prognostic implications of various clinical-pathological factors by comparing the outcomes of those who received surgery with and without post-operative radiotherapy. A total of 1120 patients were identified; 62% received post-operative radiotherapy and 38% underwent surgery alone. In a propensity-matched cohort of 812 patients, no survival difference was seen in World Health Organization A, AB, B1, B2, or B3 tumors with the addition of post-operative radiotherapy to surgery (p>0.05). Post-operative radiotherapy also did not improve survival over surgery alone for tumors ≥ or < less than the 4 cm, 7 cm, 10 cm, and 13 cm cutoffs, all p>0.05. Post-operative radiotherapy was an independent, positive prognostic indicator only in the subgroup with stage III disease and in those receiving chemotherapy in addition to post-operative radiotherapy, both p<0.05. Patients with stage III thymoma are most likely to benefit from the addition of post-operative radiotherapy to surgical treatments. Tumor size or World Health Organization histology alone should not be criteria for determining the need for post-operative radiotherapy in locally advanced thymoma. Masaoka-Koga stage, which has traditionally been used to help make such decisions, appears to be the most reliable determinant of the use of post-operative radiotherapy.

Neoadjuvant Chemoradiation Combined with Regional Hyperthermia in Locally Advanced or Recurrent Rectal Cancer.

Simple SummaryThe HyRec trial was initially designed to optimize and standardize the treatment of locally recurrent rectal cancer (LRRC). An escalated neoadjuvant treatment schedule, consisting of curative radiotherapy, concurrent chemotherapy with 5-Fluorouracil and Oxaliplatin, and additional regional hyperthermia, was evaluated with the intention to increase the rate of curative resections. Primary endpoints were the feasibility rate defined by the number of therapy-limiting toxicity or treatment withdrawal, and the pathologically confirmed complete remission (pCR) rate. Between 2012 and 2018, 111 patients with Union for International Cancer Control (UICC) stage IIB-IV or any locally recurrent rectal cancer were included. The intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports. Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0–26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12). Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.

Terapijski pristup seroznom karcinomu jajnika niskog gradusa

Low-grade serous ovarian cancer (LGSOC) has less aggressive behavior and a better clinical outcome than high-grade serous ovarian cancer (HGSOC). Considering that this malignancy is relatively chemoresistant, surgery is the keystone of treatment, with a strong recommendation for maximal cytoreduction. Women with stage IA-IB disease should undergo observation alone after primary cytoreductive surgery. In contrast, observation, chemotherapy, or endocrine therapy are possible options for those with stage IC-IIA disease. Patients with stage IIB-IV disease receive either chemotherapy with carboplatin and paclitaxel for six cycles followed by endocrine therapy, most commonly with aromatase inhibitors, or endocrine therapy alone until disease progression or unacceptable toxicity. Surgery, chemotherapy, and endocrine therapy are also used in patients with recurrent disease. Targeted agents, especially mitogen-activated protein kinase (MEK) inhibitors and cyclin-dependent kinase (CDK) inhibitors, are currently under evaluation in this clinical setting. Additional research on the genomics of LGSOC to better define the activating gene mutations involved in the carcinogenesis is strongly warranted to improve the prognosis with this malignancy.

PRO140 Health-Related Quality of Life Associated with Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma Patients: Determination of Utility Values from a UK-Based Clinician Questionnaire

Utility studies quantify the impact of disease on patients’ health-related quality of life (HRQoL). In rare diseases particularly, utility data are often limited. Where direct elicitation of data from patients is unfeasible, indirect methods are required to determine health state utility values (HSUVs). Here, we present indirect elicitation of HSUVs for patients with mycosis fungoides (MF), a rare skin lymphoma characterised by painful, itchy skin patches and plaques, which can progress into tumours and may involve blood, lymph nodes and viscera. Twelve distinct vignettes were prepared, based on published literature and expert opinion. The vignettes were validated by a MF patient expert and described typical MF patients with varying disease stage (IA-IVB) and skin burden, as assessed by the modified Severity Weighted Assessment Tool (mSWAT). Other included patient characteristics (age, Eastern Cooperative Oncology Group [ECOG] score) were informed by a patient registry. UK clinicians, working at key NHS lymphoma treatment centres (N=7), acted as respondents and completed the EQ-5D-5L questionnaire (proxy version 2) electronically for each vignette, responding as they believed MF patients would. Responses were converted into HSUVs using the UK value set. In every disease stage, HSUVs decreased with increasing mSWAT score. Similarly, for each mSWAT range HSUVs decreased as disease stage advanced. This demonstrates the effect of increasing skin burden and disease progression on HRQoL. Despite this, HSUVs associated with mSWAT score=0 were similar, regardless of disease stage (0.945 in Stage IA, 0.924 in Stage IB-IIA and 0.917 in Stage IIB-IV). The results of this investigation suggest that proxy-reporting via EQ-5D represents a potential option for generating HRQoL data, if published estimates are not available. Despite the small sample size and indirect elicitation of data, the finding that HRQoL decreases with increased mSWAT score is aligned with published literature.

The role of postoperative radiotherapy for thymomas: a multicentric retrospective evaluation from three Italian centers and review of the literature.

BackgroundThymoma is a rare mediastinal neoplasia. Surgery is the backbone of the treatment, but the role of postoperative radiotherapy (PORT) remains controversial. We aimed to obtain data on survival and safety in patients treated with PORT in three different Italian institutions.MethodsWe retrospectively analyzed 183 consecutive patients who underwent surgery from 1981 to 2015. According to the Masaoka-Koga staging system, 39.3%, 32.7%, 18.6% and 9.8% patients were in stage I, II, III and IV of disease, respectively. PORT was indicated in 114 patients (62.3%), while 69 subjects underwent surgery alone. Complete resection was obtained in 68 patients who underwent PORT. Adverse events (AEs) were graded according to CTCAE v4.0. We analyzed the recent literature to describe the current reports on PORT for resected thymoma.ResultsMean follow-up was 130 months (range, 3–417 months). Overall survival (OS) at 1-, 5- and 10-year from surgery was 98.3%, 90.2% and 69.7% respectively. One-, 5- and 10-year disease specific survival (DSS) was 98.9%, 92.3% and 89.8% respectively. Disease free survival (DFS) at 1, 5 and 10 years from surgery was 96.7%, 88.3% and 82.8% respectively. Univariate analysis showed that complete resection, cell histology A-AB-B1 and stages I–II were significant predictors of better DSS and DFS. Multivariate analysis showed that sex, R0 margins and WHO histology was independent prognostic factors. Among patients treated with PORT, a trend towards better OS was evident with Masaoka stage I–II (P=0.09). Patients with R0 margins treated with PORT showed better OS and DSS (P=0.05). No differences in DSS for performance status (P=0.70), WHO histology (P=0.19), paraneoplastic syndrome (P=0.23) and surgical procedure (P=0.53) were evident. Patients treated with PORT had a higher level of acute AEs compared to surgery alone, but none of these was graded ≥3.ConclusionsOur results confirmed that patients with incompletely resected thymoma had the worst OS and DSS. High grade acute toxicity was not different between PORT and surgery alone. Other trials reported a significant benefit in OS, DSS and DFS in stage IIb–IV thymoma treated with PORT.

Adolescent and Young Adult Hodgkin Lymphoma: Is More Better?

Background: There is a lack of a uniform approach in the treatment of Classical Hodgkin lymphoma (CHL) in adolescents and young adults (AYA). Age cutoffs are arbitrary and based on institutional experience. Chemotherapy using ABVD (Adriamycin Bleomycin Vinblastine Dacarbazine) is the standard of care in most centers for the management of adult CHL. Children and adolescents have been managed with more chemo intense approaches like the EURONET protocol, with better Event-free survival (EFS) outcomes while reducing the need for radiation therapy (RT). There is a knowledge gap regarding the optimum treatment in the AYA group and this pertains to strategies to improve EFS while addressing increasing concerns of acute toxicities and long-term complications of therapy, RT especially. We share the retrospective experience of our center where young adults and adolescents received two different strategies based on an age cutoff alone, resulting in different outcomes. Methodology: A retrospective chart review of patients aged 10-30 years with newly diagnosed CHL between January 2014 to Dec, 2019 was undertaken. The demographic and clinical profile, treatment details, treatment related complications, RT requirement, and follow-up status for the entire cohort and for each of ABVD and EURONET treatment subsets were analysed. EURONET treatment strategy used 2 cycles of OEPA (Vincristine + Etoposide + Prednisone + Adriamycin) followed by 1-4 cycles of COPDAC (Cyclophosphamide + Vincristine + Dacarbazine + Prednisone), based on the risk level. ABVD protocol used 2 cycles of ABVD followed by 2 - 4 cycles of AVD/ABVD, or intensified chemotherapy based on the interim PET-CT scan response. RT was reserved for inadequate responders during interim assessment in both protocols. Events calculated were death, progression, refractory disease and relapse. Results: 470 patients with CHL were registered at our centre in the study period. 156 patients were in the 10-30yrs age group. 30 adolescents between ≥10 and &amp;lt;18 years of age (with median age 15.9 years) received the EURONET treatment strategy and 126 patients between ≥18 and ≤30 years (median age 22.7 years) received ABVD protocol. Median follow-up for the entire cohort was 28 months. The patient characteristics are shown in the Table 1. Advanced disease (Stage IIB-IV, and Bulky disease) was seen in 67.4% and 63.3% of patients treated with ABVD and EURONET treatment protocols, respectively. RT was administered in 37.7% of the patients on ABVD and 3.3 % patients on EURONET treatment protocol (Figure 1). 23% of the patients receiving the ABVD therapy had an event compared to 3.3% of the patients in the EURONET treatment group. The EURONET treatment group experienced more grade 3 or 4 acute toxicities (46.6%) when compared to ABVD (8%), the majority being neutropenic fever episodes. There was no treatment related mortality. The 3 year estimated EFS was 93.1% (Std.error=0.04) for the EURONET treated group whereas it was 71.9% (Std.error=0.044) for the ABVD group (Figure 2). Conclusions: This large single centre retrospective study of CHL in AYA patients shows better EFS and lesser requirement of RT in the EURONET treated group, at the cost of increased acute hematological toxicity. Though an age-matched direct comparison between the treatment groups was not feasible, this study suggests that chemotherapy intensification in the AYA group is possible and may potentially improve EFS while reducing the need for Radiotherapy. Disclosures Radhakrishnan: Pfizer, India: Honoraria, Speakers Bureau; Roche, India: Research Funding; Bristol Myers Squibb, India: Research Funding; Astra Zeneca, India: Honoraria, Speakers Bureau; Novartis, India: Honoraria, Speakers Bureau; NATCO pharmaceuticals: Research Funding; Emcure pharmaceuticals: Research Funding, Speakers Bureau; Dr. Reddys Laboratories: Speakers Bureau; Aurigene: Honoraria; Cipla: Honoraria, Research Funding, Speakers Bureau; Intas: Research Funding, Speakers Bureau. Chandy:NATCO Pharmaceuticals: Research Funding; Intas Pharmaceuticals: Research Funding. Nair:Intas Pharmaceuticals: Research Funding, Speakers Bureau; Cipla: Speakers Bureau; Dr Reddys Laboratories: Honoraria, Research Funding, Speakers Bureau.

Results from the International, Multi-Center, Retrospective B-Holistic Study: Describing Treatment Pathways and Outcomes for Classical Hodgkin Lymphoma

Results from the International, Multi-Center, Retrospective B-Holistic Study: Describing Treatment Pathways and Outcomes for Classical Hodgkin Lymphoma

Integrating the Melanoma 31-Gene Expression Profile Test with Surgical Oncology Practice Within National Guideline and Staging Recommendations

Aim: Define changes in clinical management resulting from theuse of the prognostic 31-gene expression profile (31-GEP) test for cutaneous melanoma in a surgical oncology practice. Patients & methods: Management plans for 112 consecutively tested patients with stage I-III melanoma were evaluated for duration and number of clinical visits, blood work and imaging. Results: 31-GEP high-risk (class 2; n=46) patients received increased management compared with low-risk (class 1; n=66) patients. Test results were most closely associated with follow-up and imaging. Of class 1 patients, 65% received surveillance intensity within guidelines for stage I-IIA patients; 98% of class 2 patients received surveillance intensity equal to stage IIB-IV patients. Conclusion: We suggest clinical follow-up and metastatic screening be adjusted according to 31-GEP test results.

1150P Long-term outcomes of stage IIB-IV melanoma patients: Nationwide data from Norway

1150P Long-term outcomes of stage IIB-IV melanoma patients: Nationwide data from Norway

Abstract 220: Disease monitoring of mycosis fungoides via high throughput sequencing of CDR3

Abstract Background High-throughput T-cell receptor sequencing (HTS) has been shown to be both sensitive and specific at diagnosing Mycosis Fungoides (MF); a sensitivity of 85% was achieved with superiority to TCRγ; PCR in detecting monoclonality and a specificity of 99.89% was achieved in detecting minimal residual disease, specifically Sezary Syndrome cells with superiority to flow cytometry. In this study, we look at the potential application of HTS as a method for monitoring treatment response in patients with MF. Methods We sequenced the CDR3 region of the T-cell receptor (TCR) subunit of T cells in the skin lesional tissue, as well as in pre- and post-treatment blood samples of 7 patients with late stage Mycosis Fungoides (stage IIB-IV). DNA and RNA were extracted from peripheral blood and skin samples. Library preparation followed the manufacturer's instructions (Illumina). The template DNA fragments of the constructed libraries were hybridized to the surface of Nimblegen sequence Capture chip and detected with Hiseq2000 platform. Raw data was analyzed and verified to obtain aberrantly expressed genes. A multiplex PCR system was used to amplify the specific CDR3 region. Distinct TCR CDR3 sequences were plotted on the basis of their frequency of appearance to generate the TCR “repertoire”. The malignant clonal TCR signature was determined by the highest frequency CDR3 sequence of the tumor cells from skin biopsy specimens and confirmed by pathological diagnosis. This malignant sequence was identified in pre-treatment blood and monitored in post-treatment blood. Further analysis of each patient's TCR repertoire allowed us to calculate a diversity index (Simpson's diversity index) for each patient's skin sample. Results of diversity index calculation was analyzed with unpaired T-test using GraphPad Prism version 7 (GraphPad Software, La Jolla, CA). All p-values were two-tailed, with a p&amp;lt;0.05 considered statistically significant. Results Frequency of the identified malignant TCR clone remained high in the post-treatment blood samples of the patients with poor treatment response, while the number of TCR signature clones diminished in the post-treatment blood samples of the patients with good treatment response. Higher levels of diversity of TCR was also seen in the skin pre-treatment for good responders to treatment. Conclusion This study used HTS to identify malignant TCR signatures from skin biopsy specimens and to monitor the changes in blood samples in MF patients. The findings suggest that HTS is a potential ancillary blood test to monitor treatment response in MF patients by comparing the levels of the TCR signature before and after therapy. A greater diversity of T-cells in the skin may also predict a better treatment response in MF, as the presence of tumor infiltrating lymphocytes has been correlated with better outcomes in many different cancers. Citation Format: Kevin Y. Wang, Tao Wang, Yuehua Liu, Christine Lian. Disease monitoring of mycosis fungoides via high throughput sequencing of CDR3 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 220.

Prognostic Factors and Local Treatment Modalities of Small-Cell Carcinoma of the Cervix: An Analysis According to the International Federation of Gynecology and Obstetrics Stage.

PurposeSmall-cell carcinoma of the cervix (SCCC) is a rare type of cervical cancer. This study aimed to investigate the clinicopathological characteristics and survival as well as the optimal local treatment modalities for SCCC.Patients and MethodsWe retrospectively evaluated the data of patients diagnosed with SCCC between 1988 and 2015 in our institution – those included in the Surveillance, Epidemiology, and End Results (SEER) database and those in the Periodical Database. Kaplan–Meier method and Cox regression proportional hazard methods were used to evaluate overall survival (OS). A nomogram that could predict OS was constructed based on the Cox proportional hazard model.ResultsIn total, 695 patients were included in this study. The 5-year overall survival in FIGO stage I-IIA and IIB-IV patients was 45.7% and 14.4%, respectively (P <0.01). Univariate and multivariate analyses showed that lymph node status (P <0.01) and cancer-directed surgery (P <0.01) were independent prognostic factors for FIGO I-IIA stage patients, and age (P <0.05), tumor size (P <0.01), chemotherapy (P <0.01) and radiation (P <0.01) were independent prognostic factors for FIGO stage IIB-IV patients.ConclusionBetter prognosis was associated with negative lymph node status, no lymphatic vasculature, surgery, and early-stage patients. Furthermore, our data showed that the prognosis and treatment pattern varied depending on the FIGO stage, and that optimal treatment modalities included radical surgery for early-stage SCCC and chemoradiotherapy for advanced-stage SCCC. It is helpful to assess the individual prognosis of SCCC patients and choose personalized treatment modalities.

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma.

ObjectiveThe impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked.MethodsBetween 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB–IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors.ResultsThe median follow-up duration of all surviving women was 52.8 (1.6–184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633–2.187; p=0.615).ConclusionsThis study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

Tailoring early-phase clinical trial design to address multiple research objectives.

In contemporary oncology drug development, implementation of novel early-phase designs with the ability to address multiple research objectives is needed to better refine regimens. This paper describes an adaptive design strategy for identifying a range of optimal regimens based on two endpoints within multiple cohorts. The proposed design was developed to address objectives in an early-phase trial of cancer vaccines in combination with agonistic antibodies to CD40 and CD27. We describe a model-based design strategy that was developed for a trial evaluating the safety and immunogenicity of vaccination with (1) peptides plus CD40 antibody and TLR3 ligand, (2) systemic administration of an agonistic CD27 antibody, and (3) to assess immune response from (1) and (2) compared to optimal controls in participants with stage IIB-IV melanoma. The proposed design is a practical adaptive method for use with combined immunotherapy regimens with multiple objectives within multiple cohorts of interest. Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining optimal strategies to take multiple regimens forward into later phases, incorporating additional endpoints in the dose selection process and testing drug combination therapies to improve efficacy and reduce toxicity. Our goal is to facilitate the acceptance and application of more novel designs in contemporary early development trials.

Upregulated OCT3 has the potential to improve the survival of colorectal cancer patients treated with (m)FOLFOX6 adjuvant chemotherapy.

To investigate the influence of organic cation transporter 3 (OCT3) expression on the effect of the combination regimen of 5-fluorouracil, folinic acid and oxaliplatin ((m)FOLFOX6) in colorectal cancer (CRC) patients. This is a retrospective study conducted at a single centre (Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, China). Patients with stage IIb-IV resectable CRC who were being postoperatively treated with (m)FOLFOX6 as a first-line adjuvant chemotherapy regimen for at least 5cycles and had resected primary tumour samples available were eligible for the study. Patients who preoperatively received chemotherapy and/or radiotherapy or were treated with targeted drugs or other anticancer drugs were excluded from the study. Immunohistochemical staining and digital image analysis were used to assess OCT3 expression in tumour samples. According to OCT3 expression level, the receiver operating characteristic curve (ROC curve) was used to divide the patients into two groups. Cox proportional risk regression was performed with the forward LR (forward stepwise regression based on maximum likelihood estimation) method using SPSS17.0 software. The primary endpoint was the 2-year progression-free survival. In total, 57 patients were included between 2014 and 2016 according to the inclusion and exclusion criteria (22 had low OCT3 expression, and 35 had high OCT3 expression). The mean age was 55.7 (30-74) years, and 37 of the total patients were male. According to TNM stage, 5 patients had stage IV disease, 44 patients had stage III disease, and 8 patients had stage II disease. Through Cox regression analysis, we found that among patients receiving the (m)FOLFOX6 regimen, those with higher OCT3 expression had a higher two-year progression-free survival rate than those with lower OCT3 expression (P = 0.038). The hazard ratio of patients with high OCT3 expression compared with patients with low OCT3 expression was 0.247. Besides, it was found that the age of patients was negatively correlated with expression level of OCT3, which can explain why patients over 70years do not benefit from oxaliplatin-containing chemotherapy. High OCT3 expression in CRC tissues may be a protective factor for CRC patients treated with (m)FOLFOX6.

3D Telomeric Fingerprint of Advanced Cutaneous T-Cell Lymphoma

Introduction Cutaneous T-cell lymphomas (CTCLs) are characterized by dermal and epidermal infiltration of skin homing clonal CD4+ memory T-cells. Little is known about the oncogenic events driving either the progression of skin-limited disease such as Mycosis Fungoides (MF) to a leukemic form or Sézary Syndrome (SS), and there are no histologic means to predict evolution. Genetic instability is a hallmark of malignancy progression and telomere remodeling has been shown to play a role in the progression of hematological malignancies. Thus, the aim of this study is to characterize the three-dimensional (3D) telomeric organization in early and advanced CTCLs. Methods We performed 3D telomeric quantitative fluorescent in situ hybridization (3D Telo-Q-FISH) of 5mm skin tissue slides of 10 patients with MF and SS and of CD4+ lymphocytes of 3 healthy controls (Figure 1). Using the program TeloView (Vermolen et al., 2005), the proportion of telomeres of low intensity (TLI) (&amp;lt;5000 u), the nuclear volume and the total number of telomeric signals per cell were calculated. Patients were stratified based on CD30 expression (CD30 high, n=3 versus CD30 low, n=7) and clinical stage (early stages I-IIA, n=6 versus advanced stages IIB-IV, n=4). Results TLI represented 27% of telomeres in CTCL cells compared to 16% in control lymphocytes (p&amp;lt;0.0001). The highest proportion of TLIs was found in tumors CD30 high (34%), compared to 22% in tumors CD30 low (p&amp;lt;0.0001). Similar findings were observed when stratifying for advanced and early clinical stages (30% vs 24%, p&amp;lt;0.0001). Nuclear volume and total number of telomeric signals increased in CTCL cells expressing CD30 (both p&amp;lt;0.0001), and in CTCL cells associated with advanced clinical stages (p=0.0021 and p=0.001, respectively). However, as expected, nuclear volume and total number of telomeric signals were higher in control cells compared to CTCL cells (both p&amp;lt;0.0001). Conclusion We report clear evidence that CTCLs with either CD30 expression or advanced clinical stage are associated with loss of telomeres and telomeric signal intensity. These very small telomeres, termed 't-stumps', are a hallmark feature in many tumor cells. Analysis of the nuclear volume and total number of telomeric signals suggest that CTCL cells undergo in a first step telomere shortening and loss compared to healthy controls. In a second step further telomeric shortening associated with chromosomal rearrangements and bridge-breakage-fusion cycles may be involved in the progression of CTCL. Disclosures Pehr: Merck: Consultancy, Other: Clinical research on Alzheimers Drug; Eli Lilly: Consultancy, Other: Clinical research on Alzheimers Drug; galderma: Consultancy, Other: tactupump Forte; Actelion: Consultancy; valeant: Consultancy; CeraVe: Consultancy; Janssen-Cilag: Other: Train the trainer.

Standard primary cytoreduction surgery (CRS) procedure for ovarian cancer (FIGO Stage IIB-IV)

In gynecologic oncology the ovarian cancer has become one of the leading cause of death in women. Overall prognosis for ovarian cancer patients is poor, therefore the management of this condition is restricted to expert multi-disciplinary teams (MDT) in gynecological oncology. Ovarian cancer requires accurate and complete staging so that the metastatic sites are not missed, omitting adequate staging can have significant consequences including a negative impact on survival rates. Thus the goal for survival benefit of ovarian cancer is to surgically remove all visible macroscopic tumor, because the complete cytoreductive surgery (CRS) has been shown to be associated with prolonged survival. In a remarkable number of women, complete CRS is very challenging. Especially in those with many small metastases on the peritoneal and intestinal surfaces. Primary CRS has been in practice for long time as an effective method of treating peritoneal metastases (PM) from ovarian cancer, it comprises extensive peritonectomy procedures and en bloc visceral resection. CRS is a technically challenging surgery that requires a considerable amount of skill and appropriate patient selection. Even though there are several conflicts on primary CRS but due to lack of strong evidence against comparable efficacy of primary CRS with adjuvant chemotherapy and neoadjuvant chemotherapy with interval debulking surgery, the former stays the priority, remaining the preferred method of management and which is practiced in western countries routinely. This article is a review of the CRS techniques we are currently performing for primary CRS, hereby we have described the operative details for removal of cancer in advanced epithelial ovarian cancer patients with widespread pelvic and abdominal involvement.

A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund\u2019s adjuvant in melanoma patients

BackgroundCancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8+ T cell responses, whereas addition of an incomplete Freund’s adjuvant (IFA) would reduce magnitude and persistence of immune responses.Patients and methodsParticipants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).ResultsFifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.ConclusionsLPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.Trial registrationThe clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.

Cervical cancer harboring a Rb1 mutation may sensitize to cisplatin via PI3K/AKT pathway by regulating apoptosis.

5531 Background: Cervical cancer is one of the most common malignant tumors in women and major causes of cancer death in women. Although concurrent chemoradiotherapy has improved the treatment of cervical cancer, due to the heterogeneity of the tumor to chemotherapy or radiation therapy, especially the varied response to chemotherapy, the patients respond differently to the same therapeutic regimen, furthermore some patients get rapid progression. Therefore, we attempted to analyze the potential relationship between genomic mutation and chemotherapy response and survival in cervical cancer patients. Methods: Clinical information and sequencing data of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) in Genomic Data Commons (GDC) data portal were obtained through TCGAbiolinks. Only patients with stage IIB-IV CESC who received cisplatin only and were included. Cisplatin sensitivity data and sequencing data of CESC cell lines were obtained from the Genomics of Drug Sensitivity in Cancer (GDSC). Cox regression analysis, Kaplan-Meier survival analysis, differential analysis of gene expression and functional enrichment were used to explore the role of different mutations in survival and cisplatin sensitivity. Results: A total of 48 patients with stage IIB-IV CESC were enrolled. 77 genes with mutation frequency &gt; 10% were included in final analysis . Multivariate analysis showed that the mutation of Rb1 was an independent predictor of overall survival (OS) (HR = 0.07, 95%CI 0.01-0.73, P = 0.026). Patients with mutant Rb1 had better overall survival (134.2 versus 86.8 months) compared with patients with wild-type Rb1. The half maximal inhibitory concentration (IC50) of the mutant Rb1 cell line to cisplatin was significantly lower than that of the wild-type cell line (3.49 versus 10.15μM, P = 0.038). A total of 332 differently expressed genes (DEGs) were identified and the KEGG pathway enrichment analysis showed that most DEGs were enriched in the PI3K/AKT pathway (P = 0.015). Conclusions: We found that Rb1 mutation was an independent survival predictor in stage IIB-IV CESC, and CESC patients with Rb1 mutation may be more sensitive to cisplatin.

Clinical efficacy and safety of paclitaxel liposomes as first-line chemotherapy in advanced gastric cancer.

Aim: To compare the performance of first-line paclitaxel liposome + oxaliplatin and SOX (tegafur/gimeracil/oteracil + oxaliplatin) in advanced gastric cancer patients.Materials& methods:Stage IIb-IV gastric cancer patients underwent either first-line paclitaxel liposome + oxaliplatin (n = 52) or SOX (n = 69) between 2010-2013, and followed up until 2015 or death. Results: Both groups had similar objective response rate (p = 0.48) and disease control rate (p = 0.992) after two chemotherapy cycles, median progression-free survival (p = 0.495) and median overall survival (p = 0.208). Liposome group had significantly lower rate of grade I-II platelet decline and liver function damage (p = 0.04 and 0.019). Multivariate COX regression identified pre-treatment neutrophil-to-lymphocyte ratio as an independent prognostic factor.Conclusion:First-line paclitaxel liposome + oxaliplatin has comparable efficacy, but causes reduced adverse reactions in advanced gastric cancer as compared with SOX.

Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician's Choice Irrespective of CD30 Level or Large Cell Transformation Status in the Phase 3 ALCANZA Study

Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician's Choice Irrespective of CD30 Level or Large Cell Transformation Status in the Phase 3 ALCANZA Study