Metabolic Rate Responses Research Articles

Evaluation of postpartum metabolic and health response in dairy cows with different body condition score during the dry period

This study aimed to evaluate the effects of different pre-calving body conditions on some metabolic indices, health status and reproductive disorders in dairy cows. The study was conducted on a dairy farm in Eastern Slovakia during the pre-partum period (–1 to –10 DIM) and post-partum period (1 to 14 DIM). Total of 84 cows allotted in 3 groups were submitted to clinical examination and body condition score (BCS) evaluation. At the same intervals blood samples were collected for determination of beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), and calcium levels. During the postpartum period the incidence of reproductive diseases, such as metritis, retained placenta, metabolic disorders, such as milk fever, left displacement of abomasum and orthopaedic disorders were recorded. The strongest lipid mobilisation (NEFA elevation), ketone body production, and blood calcium drop were determined in postpartum dairy cows with the highest prepartum body condition score. In conclusion, the dairy cows with different BCS hade a different metabolic response during the postpartum period. The overcondition was connected with stronger lipid mobilisation and calcium drop after calving. Moreover, the higher BCS could contribute to higher incidence of production diseases.

First salvage treatment with bendamustine and brentuximab vedotin in Hodgkin lymphoma: a phase 2 study of the Fondazione Italiana Linfomi

Effective salvage options inducing high complete metabolic response (CMR) rates without significant toxicity are needed for Hodgkin lymphoma (HL) patients failing induction treatment and who are candidate to autologous stem cell transplantation (ASCT). Brentuximab vedotin (BV) and bendamustine are active monotherapies in the relapsed/refractory setting and their combination (the BBV regimen) possibly enhances their activity. This single-arm multicenter phase 2 study investigated the efficacy and safety of BBV as first salvage therapy in 40 patients with relapsed/refractory HL. Thirty-eight patients were evaluable for efficacy: 30 (78.9%) had a CMR and 2 (5.3%) a partial response, leading to an overall response rate (ORR) of 84.2%. The ORR in the primary refractory subset was 75.0%, among relapsed patients it was 94.4%. Thirty-five patients could mobilize peripheral blood stem cells and 33 underwent ASCT. At a median follow-up of 23 months, the estimated 3-year overall survival and progression-free survival are 88.1% and 67.3%. During therapy, only 3 grade IV cases of neutropenia occurred and resolved within a week. No grade 4 extrahematologic toxicities were reported; skin reactions were however rather frequent (65%). These results suggest that the BBV regimen exhibits promising efficacy and a manageable toxicity in a challenging subpopulation of HL patients.

The effect of androgen deprivation therapy on 68Ga-PSMA tracer uptake in non-metastatic prostate cancer patients.

To evaluate the effect of neoadjuvant androgen deprivation treatment (ADT) on prostate-specific membrane antigen (PSMA) tracer uptake demonstrated in 68Ga-PSMA-positron emission tomography (PET/CT) in non-metastatic hormone-naïve prostate cancer (PC) patients. The clinical data of 108 PC patients who received neoadjuvant ADT were retrospectively analyzed. All patients had a baseline 68Ga-PSMA-PET/CT scan, and a second scan was delivered median of 2.9 months after the initiation of ADT. The maximum standardized uptake value (SUVmax) of primary tumor (SUVp) and metastatic lymph nodes (SUVln) as well as PSA response were assessed between pre- and post-ADT 68Ga-PSMA-PET/CT scans. There were significant decreases in posttreatment serum PSA, SUVp, and SUVln. A decrease in SUVp was seen in 91 patients (84%) with a median value of 66% (range, 5-100%), while 17 patients (16%) had no change in or an increase in PSMA tracer uptake with a median value of 24% (range, 0-198%). Patients with Gleason score (GS) of 7 had significantly higher metabolic response rates compared to other patients. The disease progression was significantly higher only in patients with GS > 7 disease compared to GS 7 disease. The PSA response to ADT was the lowest in patients with ISUP high-grade tumors. A total of 16 patients (15%) had progressive disease, and in 9 patients (8%), radiotherapy decisions were modified according to posttreatment 68Ga-PSMA-PET/CT scans. The current study includes the largest number of patients analyzed to date and demonstrates that ADT causes a significant decrease in serum PSA values and SUVp and SUVln. The authors demonstrate that 68Ga-PSMA-PET/CT may be used as a quantitative imaging modality after neoadjuvant ADT in hormone-naïve non-metastatic PC patients.

Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)

Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)

Brentuximab Vedotin in First Refractory/Relapsed Classical Hodgkin Lymphoma Patients Treated By Chemotherapy (ICE) before Autologous Transplantation. Final Analysis of Phase II Study

Introduction: About 10-15% of patients with localized and 25-30% with disseminated classical HL failed to respond or relapse after primary conventional treatment. For the youngest, autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy leading to an increased disease free survival (DFS). With this strategy 50 to 70% of patients with chemo sensitive disease become eligible for ASCT. As the disease status before ASCT appears to be the most important factor predicting outcome, second line chemotherapy has to be more efficient. Brentuximab-Vedotin (BV) has shown significant activity (SG035-0003) in patients with relapsed or refractory HL. Therefore, it seems logical to use BV in patients treated with ICE before ASCT in order to induce a better Complete Metabolic Response (CMR) rate evaluated by FDG-PET (Deauville score 1-3). Methods: BV was added to ICE in a phase I/II trial chemotherapy trial sponsored by LYSARC with a financial support by Millenium. The optimal dose of BV (1.8 mg/kg) with ICE (3 cycles) was established in the phase I of the study (10 patients). In the second part of the study (phase II), efficacy and toxicity of the Recommended Phase II Dose (RP2D) was assessed. Patients received 2 cycles of BV ICE before evaluation and only CMR received the third course, than an injection of brentuximab alone before ASCT. Primary endpoint was CMR after 2 cycles of treatment. Results: Final analysis was performed in 42 patients for toxicity and 39 patients for the efficacy set. Baseline characteristics were median age: 30 years (range: 18-65), Sex ratio (M/F): 27/15, nodular sclerosis histology in 83%, stage III/IV in 67 % and status of the disease: 12 refractory patients and 30 relapsed patients with a median time to first relapse of 19 months (9-159). First-line treatment was escBEACOPP (n =21) ABVD (n= 17) OEPA/copdac (n= 2) PVAB (n=1) CHOP (n =1). All patients received the two first cycles, 78.6 % the third cycle and 71 % the brentuximab alone without modification of doses but with delay of at least one cycle in 45 %. Grade 3-4 adverse events were encountered in 35 patients (83%) mainly due to hematologic toxicity (71%) followed by infection (21%) and gastro-intestinal disorders (10%). No neuropathy and no toxic death were observed. Most patients (69.2%, n=27) had CMR, followed by PMR (25.6%, n=10). Among the 39 patients, three patients (7.7%) had progressive disease during treatment phase. Leukaphereses were performed in 31 patients (79%) median collected D34+ cells was 7.2 (106/kg) and 20 patients out of the 25 with CMR underwent ASCT. Thirteen patients relapsed mainly during follow-up (10) and no death was observed without progression. The median PFS was not reach and the one-year-PFS was 69% [95% CI: 53%-81%]. Conclusion: Two cycles of BV in R/R HL patients who are treated by ICE chemotherapy allows a CMR in 69.2 % of evaluable patients with sufficient harvest for an ASCT. These results are comparable to other salvage chemotherapies only after two cycles with acceptable toxicities. Disclosures Stamatoullas: Takeda: Consultancy; Celgene: Honoraria. Quittet:Novartis: Honoraria, Speakers Bureau. Morschhauser:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Ribrag:Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses . Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria.

Prednisone, Vinblastine, Doxorubicin and Bendamustine (PVAB) Regimen in First Line Therapy for Older Patients with Advanced-Stage Classical Hodgkin Lymphoma: Results of a Prospective Multicenter Phase II Trial of the Lymphoma Study Association (LYSA)

Prednisone, Vinblastine, Doxorubicin and Bendamustine (PVAB) Regimen in First Line Therapy for Older Patients with Advanced-Stage Classical Hodgkin Lymphoma: Results of a Prospective Multicenter Phase II Trial of the Lymphoma Study Association (LYSA)

AvR-CHOP: Feasibility Study of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Whilst up to 60% of DLBCL patients (pts) are cured with frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), outcomes remain poor for those with relapsed or refractory disease. 1 New strategies to improve frontline cure rates are needed. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade the host immune system. PD1/PDL1 over-expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for immune checkpoint inhibition (ICI) in this disease. Although single agent PD1 inhibition yields an overall response rate (ORR) of only 10%-30% in heavily pre-treated unselected DLBCL, many responses are durable.2 Immunosuppressive effects of prior therapy may contribute to the modest response to ICI in relapsed disease. A number of considerations influence the incorporation of ICI into upfront DLBCL treatment. Although concurrent PD1/PDL1 inhibition and R-CHOP is safe,3 corticosteroid-related immunosuppression may negate PDL1-inhibitor efficacy. Evidence supporting host immune priming with ICI prior to chemotherapy is promising,4 and maintenance ICI post chemotherapy may assist with immune reconstitution and enhance the anti-tumour immune response. Additionally, avelumab (Av, an anti-PDL1 monoclonal antibody with antibody dependent cellular cytotoxicity activity) acts synergistically with rituximab (R) in vitro (unpublished data, Pfizer 2016). Thus, we present our phase II study assessing the safety of sequential Av+R induction, R-CHOP and Av maintenance as upfront therapy for DLBCL. Methods: AvR-CHOP (NCT03244176) is a phase II multicentre single-arm trial of Av induction + maintenance with R-CHOP in newly-diagnosed adult pts with DLBCL. Pts aged >18 years, ECOG 0-2, stage II-IV and with no active autoimmune disease are eligible. Exclusion criteria include the necessity for urgent cytoreduction, grade 3B or transformed follicular lymphoma, CNS involvement, chronic steroid use, prior transplantation or pneumonitis. Treatment (Fig 1) comprises R (375mg/m2 IV) + Av (10mg/kg IV) x 2 cycles q2-weekly, followed by R-CHOP21 x 6 cycles. Maintenance Av x 6 cycles q2-weekly is given to patients achieving a complete metabolic response by PET/CT at the end of R-CHOP. PET/CT is performed after R+Av 2 cycles, cycle 2 R-CHOP, end of R-CHOP and end of Av maintenance. The primary endpoint is immune-related toxicity within 30 days post-treatment. Secondary endpoints include ORR, failure free survival (FFS), overall survival (OS) and toxicity of treatment. Complete metabolic response rates by PET-CT after R-Av induction and after C2 R-CHOP are exploratory endpoints. Biomarker sample collection is synchronised with PET response assessment. A comprehensive translational substudy will apply high throughput technologies to tissue and sequential blood samples to characterise the tumour-immune system interaction and correlate novel host, tumour and tumour microenvironment factors with treatment responses and toxicity. Planned enrolment is 28 pts across 3 sites in Australia. The study follows a Simon 1 stage design, with an 80% power and a 1-sided alpha of 0.05 to rule out an Av-related toxicity rate of 30% (p0=70%), assuming an expected immune related toxicity rate of 10% [p1=90%]. 23 pts are enrolled to date. Acknowledgements: Merck KgA (avelumab and funding)

Obinutuzumab Plus Gemcitabine, Dexamethasone and Cisplatin (O-GDP) As Salvage Chemotherapy Prior to Autologous Stem Cell Transplant in Aggressive B Cell Lymphoma

Background: CCTG LY.12 defined GDP (gemcitabine, dexamethasone and cisplatin) (GDP) as an effective outpatient salvage chemotherapy regimen in relapsed/refractory (R/R) patients with aggressive lymphomas who are candidates for autologous stem cell transplant (ASCT) (Crump et al. JCO 2014). Obinutuzumab (O) is an alternative anti-CD20 that may produce responses in rituximab-refractory lymphomas. Head-to-head, O did not improve efficacy compared to R when combined with CHOP as initial therapy (Vitolo JCO 2017). However, salvage therapy differs from initial therapy in that patients have been previously exposed to, and have relapsed after, prior R. We therefore performed a single centre, single arm clinical trial of O-GDP to assess safety and efficacy in R/R aggressive B cell lymphoma as a salvage regimen prior to consolidation with ASCT. Methods: Transplant eligible patients with DLBCL and transformed indolent lymphoma were treated with O-GDP for two cycles, followed by response assessment by CT. Non-progressers received a third cycle of O-GDP for stem cell mobilization and final response assessed by CT-PET prior to ASCT. O was given at 1000 mg weekly during the first cycle of GDP and then on day 1 of cycles 2 and 3. Responses were determined by Lugano criteria using investigator assessment. The primary outcome is ORR by CT imaging after 2 cycles. The pre-specified statistical analysis stated that the trial will be declared positive if the ORR is >60%, negative if the ORR is <40% and indeterminate if in-between. Secondary outcomes included complete metabolic response rate after 3 cycles of O-GDP and the rate of proceeding to ASCT. Exploratory outcomes included measurements of circulating tumor (ct) DNA during protocol therapy, and analysis of individual mutations. Double-hit score and cell of origin assessments were as previously described (Ennishi et al. JCO 2019). Outcomes: 30 patients were enrolled with a median age of 59.5 years (range 30 - 70). 20 patients had DLBCL, 9 had transformed indolent lymphoma (TRIL; all but one patient having transformed follicular lymphoma) and 1 patient had follicular lymphoma grade 3B. IPI at diagnosis was 0-1 (20% of patients), 2 (30%) or 3+ (50%). Dose delays of O during cycle 1 occurred in 10% of patients due to toxicity with delays in cycle 2 or 3 of O-GDP in 30% of patients. 87% of patients had a dose reduction of chemotherapy with 46% of day 8 gemcitabine doses being held or reduced. Grade 3-4 AEs were seen in 87% of patients (grade 3-4 neutropenia: 77% [febrile neutropenia: 13%]; grade 3 anemia: 13%; grade 3-4 thrombocytopenia: 43%). The ORR (CR + PR) by CT imaging after 2 cycles of study therapy was 60% (95% CI 41-77%). The best ORR (by Lugano criteria including PET/CT) after 3 cycles of study therapy was 70% (51-85%; CMR in 33%) of patients. Of all enrolled patients, 67% (47-83%) proceeded to ASCT. With a median follow up 1.3 years for all enrolled patients, the estimated 1 year OS was 76% (62-93%) and PFS was 59% (44-80%). The OS and PFS in transplanted patients at 1 year was 90% (77-100) and 70% (53-93%) respectively with a median follow-up of 1 year. In post hoc subset analysis, de novo DLBCL had a best ORR of 55% while TRIL/FL3B had an ORR of 100%. The presence of the double hit (DHIT) signature and cell of origin (COO) by gene expression was analyzed in 26/30 patients. Best ORR for DHIT positive was 3/4 patients (75%), DHIT negative was 11/16 (69%) and DHIT indeterminate was 5/6 (83%). Best ORR for ABC-type was 7/10 (70%), GCB-type was 9/13 (69%), unclassified was 1/1 (100%) and PMBL was 1/2 (50%). Conclusions: O-GDP is a feasible outpatient salvage regimen that enables ASCT in patients with R/R aggressive B cell lymphoma across histological and molecular subtypes. Higher rates of cytopenias with O-GDP contributed to treatment delays and dose reductions or holds. Further mutational analysis will be presented. The ORR of 60% met the study primary endpoint and the 1 year OS and PFS are encouraging. Disclosures Jain: Kite/Gilead: Consultancy. Prica:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Kridel:Gilead Sciences: Research Funding. Crump:Servier: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Kite/Gilead: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Kuruvilla:Abbvie: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Janssen: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Roche: Consultancy; Karyopharm: Consultancy; Novartis: Honoraria; Gilead: Consultancy; Janssen: Research Funding; Roche: Research Funding; BMS: Consultancy; Merck: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Obinutuzumab is an anti-CD20 antibody being tested here in a prospective clinical trial for relapsed/refractory aggressive B cell lymphomas

The effect of normoxia exposure on hypoxia tolerance and sensory sampling in a swamp-dwelling mormyrid fish

Effects of energetic limitations on the performance of sensory systems are generally difficult to quantify. Weakly electric fishes provide an ideal model system to quantify the effects of metabolic stressors on sensory information acquisition, because they use an active-sensing strategy that permits easy measurement of the sensing effort. These fishes discharge an electric signal and sense perturbations of the resulting electric field. We used the mormyrid Petrocephalus degeni to quantify the relationship between routine metabolic rate and the rate of sensory sampling (rate of electric organ discharge, EOD) while under progressive hypoxia by quantifying the critical oxygen tension (PC-MR) and the critical electric organ discharge threshold (PC-EOD). PC-MR was significantly higher in fish acclimated to normoxia for over 40 days compared to animals tested within 1–5 days of capture from a hypoxic swamp, which suggests high costs of maintaining hypoxia tolerance; however, there was no acclimation effect on PC-EOD. All P. degeni reached their PC-EOD prior to their PC-MR. However, below the respective critical tension value, EOD rate decreased more gradually than the metabolic rate suggesting that the fish were increasing the proportion of their energy budget allocated to acquiring sensory information as dissolved-oxygen levels dropped. Trade-offs between sensory sampling and other physiological functions are also suggested by the increase in routine EOD rate with long-term normoxia acclimation, in contrast to metabolic rate, which showed no significant changes. These results highlight the relationship between sensory sampling and metabolic rate in response to progressive hypoxia and the plasticity of hypoxia tolerance.

Randomized Phase II Trial of Triapine-Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers.

Uterine cervix or vaginal cancers have inherent overactivity of ribonucleotide reductase (RNR), making these cancers rational targets for therapy based on interruption of cisplatin-radiotherapy-induced DNA damage repair. We conducted a pilot, open-label randomized phase II trial to evaluate the efficacy and safety of cisplatin-radiotherapy with or without triapine, a small molecule with RNR-inhibitory activity, in patients with advanced-stage uterine cervix or vaginal cancers (NCT01835171), as a lead in to a randomized phase III study (NCT02466971). A total of 26 women were randomly assigned to receive 6 weeks of daily radiotherapy followed by brachytherapy (80 Gy) and once-weekly cisplatin (40 mg m−2)—with or without three-times weekly intravenous triapine (25 mg m−2)—in one 56-days cycle. Primary end points were metabolic complete response by positron emission tomography and safety. Additional end points included the rate of clinical response, rate of methemoglobinemia, and progression-free survival. The addition of triapine to cisplatin-radiotherapy improved the rate of metabolic complete response from 69 to 92% (P = 0.32) and raised the 3-year progression-free survival estimate from 77 to 92% (hazard ratio for progression, 0.30; P = 0.27). The most frequent grade 3 or 4 adverse events in either treatment group included reversible leukopenia, neutropenia, fatigue, or electrolyte abnormalities. No significant differences were seen between the two groups in the rate of adverse events. Symptomatic methemoglobinemia was not encountered after triapine infusion. In conclusion, the addition of triapine to cisplatin-radiotherapy improved the rate of metabolic complete response in patients with advanced-stage uterine cervix or vaginal cancers without significant toxicity. A phase III trial adequately powered to evaluate progression-free and overall survival is underway (NCT02466971).

771P - PALAESTRA: A phase II trial with short-course radiotherapy followed by chemotherapy as palliative treatment in esophageal adenocarcinoma

BackgroundPatients with esophageal cancer commonly suffer from dysphagia, leading to nutritional problems and impaired quality of life. Self-expanding metallic stents (SEMS) is frequently used in the palliative setting providing a rapid but short-term relief. In this phase II study we assessed a novel first-line treatment schedule with short-course radiotherapy followed by chemotherapy with the primary aim to achieve a long-term improvement of dysphagia. MethodsPatients with dysphagia due to adenocarcinoma of the esophagus or esophagogastric junction, not eligible for curative treatment, were recruited. Treatment consisted of radiotherapy (5 x 4Gy) followed by 4 cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a 5-grade scale and a response was defined as an improvement from baseline with at least one step in dysphagia score during the study treatment period or within 4 weeks after end of study treatment. Response of the primary tumour was assessed using endoscopy and PET imaging. ResultsFrom October 2014 to May 2018 a total of 29 patients were enrolled. Median age was 68 years. WHO PS (0/1/2); 10/12/7, female/male; 6/23, stage III/IV; 3/26, dysphagia score (0/1/2/3/4); 0/15/6/7/1. In the per-protocol (PP) population of 23 patients (treated with at least 4 fractions of radiotherapy and 2 cycles of chemotherapy) the rate of dysphagia improvement was 91%, the median time to improvement was 2.0 months (95% CI: 1.5, 2.5) and the median duration of improvement was 12.2 months (95% CI: 6.2, 18.2). 5 patients received SEMS during follow-up. In the PP population the endoscopic response rate was 78% with 22% complete responders, the metabolic response rate of the primary tumor was 61% with 30% complete responders. Median overall survival was 16.0 months (95% CI: 9.6, 22.5). In the safety population (28 patients who started treatment) the most frequent grade 3-4 adverse events were neutropenia (32%), infection (25%), pain (14%), esophagitis (11%) and anorexia (11%). ConclusionsPalliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma. Clinical trial identification2014-002362-74. Legal entity responsible for the studySkåne University Hospital, Department of Oncology. FundingLund University Faculty of Medicine and Skåne University Hospital Funds and Donations. DisclosureAll authors have declared no conflicts of interest.

Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial

AimWe evaluated the efficacy and safety of TAS-116, a novel class of an orally active selective inhibitor of heat shock protein 90, in patients with advanced gastrointestinal stromal tumour (GIST) after failure of three or more lines of standard treatment with imatinib, sunitinib and regorafenib. MethodsIn this single-arm phase II study, patients received 160 mg/day oral TAS-116 for five consecutive days, followed by a 2-day rest. The primary end-point was centrally assessed progression-free survival (PFS). The secondary end-points were objective response rate, disease control rate, overall survival (OS), metabolic response rate, safety, pharmacokinetics and pharmacogenomics. ResultsForty-one patients were enrolled in Japan, and 40 patients underwent efficacy and safety evaluation. At the cut-off date, the median PFS was 4.4 months (95% confidence interval [CI], 2.8–6.0) and 12-week progression-free rate was 73.4% (95% CI, 58.1–88.7). Thirty-four patients (85.0%) had stable disease for ≥ 6 weeks. The median OS was 11.5 months (95% CI, 7.0–not reached). All patients experienced at least one treatment-related adverse event (AE), including diarrhoea (80.0%), decreased appetite (45.0%) and increase in blood creatinine level (42.5%). Grade ≥3 AEs and treatment-related grade ≥3 AEs occurred in 23 (57.5%) and 21 (52.5%) patients, respectively. All AEs resolved after dose modification, and no TAS-116–related AEs led to treatment discontinuation. ConclusionTAS-116 showed significant activity in advanced GIST refractory to standard treatment. Further development of TAS-116 is warranted. Trial registrationJapicCTI-163182.

Metastatic or locally advanced mediastinal neuroendocrine tumours

Primary neuroendocrine tumours (NETs) of mediastinum are unusual tumours with aggressive biological behaviour with limited treatment options and guarded prognosis. Twenty-seven patients with histopathologically and radiologically proven metastatic or advanced mediastinal NET, who had undergone 177Lu-DOTATATE PRRT, were included in this retrospective analysis. Descriptive statistics was employed to calculate the cumulative overall survival (OS) and progression-free survival (PFS), determining correlation and strength of correlation between different variables with OS and PFS and finally, predictors of outcome (OS and PFS). In all 27 patients enrolled and analyzed, complete symptomatic response was observed in 10 patients (37%), partial response in seven patients (25.9%), symptomatically stable disease in four patients (14.8%), and symptoms progressed or worsened in six patients (22.2%). Metabolic response evaluation demonstrated complete metabolic response in one patient (3.7%), partial metabolic response was seen in nine patients (33.3%), metabolically stable disease was seen in five patients (18.5%), and 12 patients (44.4%) showed metabolic disease progression. None of the patients achieved complete anatomical/morphological response, six (22.2%) showed partial response, seven (25.9%) showed stable disease, and in 14 patients (51.9%), there was morphological disease progression. At the time of analysis, 10 patients (37%) succumbed to the disease. The median PFS was 36 months and the median OS was 66 months. Bivariate analysis showed significant level of association of PFS with surgical intervention, higher cumulative PRRT dose, metabolic response, smaller sized primary lesion, and low lesional FDG uptake. With regard to OS, higher cumulative PRRT dose, low FDG uptake and longer PFS showed significant association. Previous surgical intervention (including debulking surgery with R1 resection), higher cumulative dose of PRRT, and low FDG uptake of the tumour are associated with prolonged OS and PFS in patients with metastatic or advanced mediastinal NETs and were independent favourable prognostic markers.

Therapy of nodal Follicular Lymphoma (WHO grade 1/2) in clinical stage I/II using response adapted Involved Site Radiotherapy in combination with Obinutuzumab (Gazyvaro) - GAZAI Trial (GAZyvaro and response adapted Involved-site Radiotherapy): a study protocol for a single-arm, non-randomized, open, national, multi-center phase II trial

BackgroundLarge field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera® and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30–40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy.Methods/designThe GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro®) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the “full dose” of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach.DiscussionThe goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial.Trial registrationEudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520.

Impact of Hepatic Steatosis on Resting Metabolic Rate and Metabolic Adaptation in Response to Intentional Weight Loss.

Weight loss is the primary intervention for nonalcoholic fatty liver disease (NAFLD). A decrease in resting metabolic rate (RMR) out of proportion to the degree of weight loss may promote weight regain. We aimed to determine the impact of hepatic steatosis on weight loss‐associated changes in RMR and metabolic adaptation, defined as the difference between predicted and measured RMR after weight loss. We retrospectively analyzed prospectively collected data from 114 subjects without diabetes (52 with NAFLD), with body mass index (BMI) >35, and who enrolled in a 6‐month weight loss intervention. Hepatic steatosis was determined by unenhanced computed tomography scans by liver:spleen attenuation ratio <1.1. RMR was measured by indirect calorimetry. At baseline, patients with hepatic steatosis had higher BMI, fat mass (FM), fat‐free mass (FFM), and RMR (RMR, 1,933 kcal/day; 95% confidence interval [CI], 841‐2,025 kcal/day; versus 1,696; 95% CI, 1,641‐1,751; P < 0.0001). After 6 months, the NAFLD group experienced larger absolute declines in weight, FM, and FFM, but percentage changes in weight, FFM, and FM were similar between groups. A greater decline in RMR was observed in patients with NAFLD (−179 kcal/day; 95% CI, −233 to −126 kcal/day; versus −100; 95% CI, −51 to −150; P = 0.0154) for the time × group interaction, and patients with NAFLD experienced greater metabolic adaptation to weight loss (−97 kcal/day; 95% CI, −143 to −50 kcal/day; versus −31.7; 95% CI, −74 to 11; P = 0.0218) for the prediction × group interaction. The change (Δ) in RMR was significantly associated with ΔFM, ΔFFM, and baseline RMR, while metabolic adaptation was significantly associated with female sex and ΔFM only. Conclusion: Hepatic steatosis is associated with a greater reduction in FM, which predicts RMR decline and a higher metabolic adaptation after weight loss, potentially increasing the risk of long‐term weight regain.

Monitoring of individual bacteria using electro-photonic traps.

Antimicrobial resistance (AMR) describes the ability of bacteria to become immune to antimicrobial treatments. Current testing for AMR is based on culturing methods that are very slow because they assess the average response of billions of bacteria. In principle, if tests were available that could assess the response of individual bacteria, they could be much faster. Here, we propose an electro-photonic approach for the analysis and the monitoring of susceptibility at the single-bacterium level. Our method employs optical tweezers based on photonic crystal cavities for the trapping of individual bacteria. While the bacteria are trapped, antibiotics can be added to the medium and the corresponding changes in the optical properties and motility of the bacteria be monitored via changes of the resonance wavelength and transmission. Furthermore, the proposed assay is able to monitor the impedance of the medium surrounding the bacterium, which allows us to record changes in metabolic rate in response to the antibiotic challenge. For example, our simulations predict a variation in measurable electrical current of up to 40% between dead and live bacteria. The proposed platform is the first, to our knowledge, that allows the parallel study of both the optical and the electrical response of individual bacteria to antibiotic challenge. Our platform opens up new lines of enquiry for monitoring the response of bacteria and it could lead the way towards the dissemination of a new generation of antibiogram study, which is relevant for the development of a point-of-care AMR diagnostics.

BRENTUXIMAB VEDOTIN SALVAGE FOLLOWED BY CONSOLIDATION POST AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN HIGH RISK RELAPSED REFRACTORY HODGKIN LYMPHOMA

Introduction: Brentuximab vedotin (Bv) improves PFS post autologous HCT in high risk relapsed/refractory classical Hodgkin Lymphoma (r/r cHL). Furthermore, chemoimmunotherapy salvage with Bv results in a higher rate of complete metabolic response (CMR) compared with chemotherapy alone as shown by multiple groups. Attainment of such CMR status prior to HCT is highly predictive of prolonged remissions. Aim: To examine the outcome of Bv containing salvage followed by consolidation in high risk r/r cHL. Primary endpoint was overall response rate (ORR) including rate of CMR. Secondary endpoint was 2-year PFS and overall survival (OS). Methods: Pts with high risk r/r cHL whom were candidates for curative HCT were identified and all records were retrieved retrospectively after IRB approval. High risk r/r cHL was defined as patients with primary refractory disease, relapse within 12 months of front line therapy or relapse with extranodal disease. Patients received Bv with salvage at 1.8 mg/kg on day 1 of each cycle. Post-HCT Bv consolidation was given starting day 30-45 at 1.8 mg/kg every 3 weeks for up to 16 cycles. Response assessment was done in accordance with the Lugano criteria including the definition of CMR as deauville score ≤ 3. OS and PFS were computed using Kaplan-Meir method with log ranks test. Results: A total of 20 patients were identified and all records retrospectively collected. Baseline characteristics were as follows; 11 (55%) male with median age at HCT of 22 years. 12 (60%) had refractory disease with median time to relapse following front line therapy of 3.7 months. Bv was given with IGEV in 14 (70%), ESHAP in 4 (20%) and Bendamustine in 2 (10%). The ORR was 100% and all patients had evidence of partial response or better. Furthermore,14 (70%) of patients achieved CMR status pre-HCT. A total of 19 patients were collected during salvage with GCSF while the remaining patient was mobilized with GCSF alone. Median CD34 x106/kg collected was 12.75 (2.51-42.5) and the median time to ANC and platelet engraftment was 12 (9-15) and 16 (11-20) days, respectively. Post HCT, all patients received Bv consolidation with a median number of doses of 12 (3-16). Observed adverse events on Bv consolidation were; grade 3 neutropenia in 9 (45%) requiring GCSF support in all and dose reduction in 6 (30%), neuropathy grades 1-3 in 2 patients (15%), 3 (15%) and 1 (5%) leading to early discontinuation of planned consolidation in 4 (20%). Neuropathy resolved or improved in all cases. A total of 2 patients relapsed, both while on Bv consolidation. Median follow up was 15.4 months (3.8-56) with estimated 2-year PFS and OS of 83% and 95%, respectively as shown in table 2 and figure 1 A-B. Keywords: brentuximab vedotin; classical Hodgkin lymphoma (cHL); Deauville's criteria.

PS1090 OBINUTUZUMAB DOES NOT COMPROMISE MOBILIZATION AND ENGRAFTMENT OF AUTOLOGOUS PERIPHERAL BLOOD STEM CELLS IN LYMPHOMA PATIENTS: RESULTS FROM A FIL PROSPECTIVE PHASE II STUDY (THE GIOTTO STUDY)

Background:Salvage immunochemotherapy and transplant consolidation is the standard treatment for young relapsed refractory (R/R) DLBCL. Many studies have demonstrated that Rituximab combined with second line chemotherapy do not permit to obtain satisfactory results particularly in patients previously treated with Rituximab (see Coral and Scholar study). Moreover these regimens do not affect negatively the stem cell mobilization.Aims:Patients with first R/R DLBCL were prospectively treated with a combination of Obinutuzumab‐DHAP (G‐DHAP). The primary end point study was to demonstrate an increase in the metabolic complete response (CMR) rate with this regimen. Secondary end points were stem cell mobilization, stem cell engraftment, overall survival and feasibility.Methods:In thisprospective, phase‐2, single‐arm trial (EudraCT2014–004014–17), R/R DLBCL patients received Obinutuzumab‐DHAP with the standard three doses (1000 mg) of Obinutuzumab in the first cycle ad then one dose for the remaining three cycles. The stem cells apheresis was programmed after the third or the fourth cycle. At the end of therapy a restaging was performed and patients with CMR were consolidated with BEAM/FEAM condictioning regimen and autologous stem cell transplantation (ASCT). The protocol provided an interim analysis after the first 29 patients enrolled to confirm the initial null hypothesis of obtaining at leasr 10/29 CMR.Results:At first interim analysis 29 patients were evaluated. The median age was 56 years, 17 patients had a primary refractory lymphoma and 12 were relapsed. Fifteen patients completed the four programmed cycles and were evaluated for CMR. Six patients obtained a CMR (6/29 patients: 21%), the number of CMR pre‐ASCT was lower than the level set for continuing the study. According to the results of the interim analysis study enrolment was stopped. The haematological toxicity was that expected with DHAP, obinutuzumab has not added toxicity. Extrahematologic toxicity &gt; = 3 was reported in 9 patients.We have evaluated the peripheral blood progenitors harvest. Nineteen patients started stem cell mobilization, one failed mobilization (5%) and 18 patients mobilized (95%). Nine out 18 patients did not reinfuse and 9 reinfused: 7 (24%), after a median follow up of 24 months, are alive and without evidence of disease, 1 was in partial remission and 1 progressed immediately after transplant. The overall survival and progression free survival are reported in Figures 1 and 2.Sixteen patients (89%) mobilized after 1 or 2 apheresis and the other two patients after three or four. The mean number of CD34+ cells mobilized was 5.8, the median number was 5.5 (IQR: 5 – 6.75). The mean number of reinfused CD34+ cells in the 9 patients was 4.1, the median number was 4.1 (IQR: 3.5 – 5).Summary/Conclusion:The association of Obinutuzumab and DHAP did not pass the interim analysis because a lower rate of CMR reported in comparison with the hypothesis. To note that seven patients (4 refractory and 3 relapsed) among the nine transplanted are alive and free from disease after a median follow‐up of 24 months.imageObinutuzuamb associated with a standard mobilizing chemotherapy (DHAP) did not compromise stem cell mobilization and engraftment after ASCT in this group of DLBCL patients.

S821 NIVOLUMAB PLUS DOXORUBICIN, VINBLASTINE AND DACARBAZINE FOR NEWLY DIAGNOSED ADVANCED‐STAGE CLASSICAL HODGKIN LYMPHOMA: 2‐YEAR EXTENDED FOLLOW‐UP FROM COHORT D OF THE PHASE 2 CHECKMATE 205 STUDY

Background:Up to 30% of newly diagnosed patients (pts) with advanced‐stage classical Hodgkin lymphoma (cHL) are not cured by multi‐agent chemotherapy. High expression of the programmed death‐1 (PD‐1) ligands in these pts, associated with frequent genetic alterations at chromosome 9p24.1 in Hodgkin Reed‐Sternberg cells, supports the investigation of front‐line PD‐1 blockade in cHL (Roemer MG et al. J Clin Oncol 2016). Promising activity and acceptable safety was previously reported in newly diagnosed pts with advanced‐stage cHL treated with nivolumab, an anti–PD‐1 immune checkpoint inhibitor monoclonal antibody, followed by nivolumab plus doxorubicin, vinblastine and dacarbazine (N‐AVD) at a 9‐month follow‐up of Cohort D of the CheckMate 205 study (NCT02181738; Ramchandren R et al. EHA 2018).Aims:To further characterize the efficacy, including post hoc Deauville assessment, and safety of nivolumab followed by N‐AVD in pts with newly diagnosed advanced‐stage cHL with 2‐year extended follow‐up of CheckMate 205 Cohort D.Methods:Pts ≥ 18 years of age with newly diagnosed advanced‐stage cHL (stage IIB with unfavorable risk factors, III, or IV) received 4 doses of nivolumab monotherapy (240 mg IV every 2 weeks) followed by N‐AVD combination therapy for 6 cycles (12 doses). Primary endpoint was safety; secondary endpoints included complete remission (CR) rate per independent review committee (IRC) at end of study therapy (EOT) using 2007 International Working Group criteria. Complete metabolic response (CMR) was defined as a Deauville score of ≤ 3 (PET negative). Overall survival (OS) and modified progression‐free survival (PFS) were exploratory endpoints; PFS was assessed in a post hoc analysis.Results:Fifty‐one pts were treated (median age 37 years); minimum follow‐up was 24.4 months at data cutoff. Other baseline characteristics have been previously described (Ramchandren R et al. EHA 2018). Monotherapy was completed by 49/51 (96%) pts, combination therapy by 45/50 (90%); 48 pts entered follow‐up. After 2 combination cycles, CR rate was 51% per IRC (71% CMR) and 71% per investigator; at EOT, CR rate was 69% (75% CMR) per IRC and 80% per investigator. At 21 months, modified PFS rate per investigator was 80% (95% CI, 66–89) and PFS rate per investigator was 83% (95% CI, 69–91; Figure). Overall, 30 (59%) pts experienced grade 3–4 TRAEs, most commonly neutropenia in 21 (41%). The most common grade 3–4 immune‐mediated AE was hepatitis (2 pts, 4%). No grade 5 TRAEs occurred ≤ 30 days from last dose; 2 deaths were reported during the extended follow‐up: 1 pt (age 68 years) died 38 days after last dose due to study drug toxicity; another (age 85 years) died 451 days after last dose due to disease progression.Summary/Conclusion:With extended follow‐up, nivolumab followed by N‐AVD demonstrated a 21‐month PFS rate of 83% per investigator, a high metabolic response rate with 75% CMR at EOT per IRC, with no new safety signals. Incorporation of Deauville assessment improved the concordance of CR between IRC‐ and investigator‐assessed responses. Nivolumab followed by N‐AVD provides a promising alternative treatment option in newly diagnosed advanced‐stage cHL.image

Hormonal and metabolic substrate status in response to exercise in men of different phenotype.

ObjectivesThe present study verified the effect of moderate-to-high-intensity aerobic exercise on the endocrine response profile and adipose tissue in young healthy men with different phenotype characteristics.DesignEighteen men were divided into three experimental groups with defined body components and specific physical fitness: Endurance phenotype – EP (n = 6; low body mass; low fat content; aerobic endurance trained), Athletic phenotype – AP (n = 6; high body mass; low fat content, resistance trained), Obesity phenotype – OP (n = 6; high body mass; high fat content, untrained).MethodsThe participants performed an progressive exercise protocol on a treadmill (30% VO2max, 50% VO2max, 70% VO2max), separated by 45 s of passive rest for blood collection.ResultsPlasma glucose oxidation increased in relation to exercise intensity, but to a greater extent in the AP group. The free fatty acids’ plasma level decreased with a rise in exercise intensity, but with different kinetics in particular phenotypes. Plasma growth hormone increased after the cessation of exercise and was significantly higher in all groups 45 min into recovery compared to resting values. Plasma insulin decreased during exercise in all groups, but in the OP, the decrease was blunted.ConclusionsThe results indicate that the rate of lipolysis, hormonal and metabolic response to aerobic exercise depends on the individuals’ phenotype. Thus, exercise type, duration and intensity have to be strictly individualized in relation to phenotype in order to reach optimal metabolic benefits.