Entire Treatment Duration Research Articles

Enhanced pendulum appliance utilizing temporary anchorage device-based Nance arch and modified springs for optimized molar distalization control: a case report.

A 20-year-old female patient with severe maxillary crowding and skeletal Class III malocclusion was successfully treated using an enhanced pendulum appliance. Camouflage treatment was chosen because the patient refused surgical intervention. Detailed examination and analysis revealed that labial inclination of the maxillary anterior teeth could provide the alignment space necessary after tooth extraction in the maxillary arch but it would not be beneficial esthetically and would increase the moment perpendicular to the tooth long axis as well as increase the risk of bone dehiscence. Therefore, lingual inclination of the mandibular anterior teeth was performed. To create space for aligning the maxillary arch, an enhanced pendulum appliance was utilized, in addition to premolar extraction. The enhanced pendulum appliance had one mesial and one distal helix on each spring, exerting opposing forces in the buccolingual direction and reducing the buccolingual inclination of the molars. In addition, miniscrews were integrated into the Nance arch of the enhanced pendulum appliance to provide skeletal anchorage, minimizing the reciprocal movement of anchorage teeth. This modification not only enhanced control over tooth movement but also improved treatment efficiency. During the entire treatment duration of 17 months, substantial improvement in facial and occlusal aspects were noted. Additionally, the patient retained these positive changes until the subsequent 2-year follow-up period.

Abstract PO2-04-05: FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES

Abstract Background Brain metastases (BM) are a severe complication of HER2-positive metastatic breast cancer. In the absence of any immediate indication for local therapy, the tyrosine-kinase inhibitor tucatinib combined with trastuzumab and capecitabine (TTC) is regarded as the preferred systemic treatment option for active BM, while data on the activity of antibody-drug conjugates (ADC) is limited. In the primary outcome analysis of TUXEDO-1, an intracranial response rate (RR) of 73.3% was reported with the ADC trastuzumab-deruxtecan (T-DXd). Here, we report final progression-free survival (PFS) and overall survival (OS) results of this study. Patients and Methods: TUXEDO-1 is a prospective, single-centre, single-arm phase 2 trial. Adult patients with HER2-positive BC and active BM (newly diagnosed untreated or progressing after prior local therapy), prior treatment with trastuzumab and pertuzumab, ECOG performance status 0 or 1 without indication for immediate local therapy were accrued and received T-DXd until progression, inacceptable toxicity, or withdrawal for any other reason. The primary endpoint was intracranial RR centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria in the intention-to-treat population; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population (PPP). Results A total number of 15 patients were accrued; one patient was found to have dural metastases only upon restaging, resulting in a PPP of 14 patients. Patients had received a median number of two prior treatment lines (range, 1-5), 60% had progressive brain metastases and 60% had received prior T-DM1. At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). A total of 238 cycles of T-DXd were administered (median 11.5 cycles; range 4-42). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event (AE) was fatigue (n=3; 20%). A total of 8 serious AEs were reported in 8 patients. Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL and neurocognitive functioning were maintained over the entire treatment duration and a significant deterioration of global QoL was observed upon progression (p=0.036). Most patients received TTC (n=5) or local therapy (n=4) as next subsequent treatment line. Ancillary biomarker studies are ongoing, and results will be presented at the meeting. Discussion In TUXEDO-1, T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive breast cancer BM. The safety profile was consistent with previous reports. T-DXd did not impair QoL and neurocognitive functioning was maintained. Results therefore support the concept of ADCs as systemic therapy for active BM. Citation Format: Rupert Bartsch, Anna Sophie Berghoff, Julia Furtner, Maximilian Marhold, Elisabeth Sophie Bergen, Sophie Roider-Schur, Angelika Maria Starzer, Maximilian Mair, Heidrun Forstner, Beate Rottenmanner, Marie-Bernadette Aretin, Karin Dieckmann, Zsuzsanna Bago-Horvath, Helmuth Haslacher, Georg Widhalm, Aysegül Ilhan-Mutlu, Christoph Minichsdorfer, Thorsten Fuereder, Thomas Szekeres, Leopold Oehler, Birgit Gruenberger, Georg Pfeiler, Christian F. Singer, Ansgar Weltermann, Luzia Berchtold, Matthias Preusser. FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-05.

Agreement among Radiation Oncologists and Radiologist in Contouring GTV on Planning and Mid-Treatment MRI for Locally Advanced Oropharynx Cancer

Over the 7-week radiotherapy course, patients with head and neck cancers undergo significant anatomical changes, including weight loss and tumor shrinkage (with complete response at mid-treatment in as high as 50% of patients). The current standard of care is to maintain the same plan for the entire treatment duration, unless major dosimetric deviations are suspected. The use of MRI for treatment adaptation has the advantage of increased soft tissue contrast and is being integrated into several clinical practices with the recent implementation of the MR-Linac technology. In this interim secondary analysis of a phase 2, randomized trial, we assessed inter-observer variability (IOV) in the delineation of GTV at planning and mid-treatment in locally advanced oropharynx cancer (OPC). Three expert radiation oncologists (RO) and 1 expert radiologist, with a minimum of 5 years' experience in MRI contouring, blinded to each other's volumes, were provided with planning and mid-treatment MRI (T1 gadolinium, T2-weighted and DWI) of 9 patients with locally advanced OPC. Primary gross tumor volume (GTV) was independently contoured by all 3 ROs and the radiologist. Contouring agreement was analyzed using the dice similarity coefficient (DSC) index and the average Hausdorff distance. Nine cases of locally advanced OPC were included. Fifty percent of the patients were stage 3 (AJCC 8th edition) and all were p16+ OPC. There was moderate IOV in the delineation of GTV on planning MRI as evidenced by mean DSC index and Hausdorff distance of 0.75 (range 0.53 - 0.87) and 0.30 cm (max 2.14 cm). At mid-treatment, the GTV IOV had a mean DSC index and Hausdorff distance of 0.30 (range 0.19 - 0.76) and 0.55 cm (max 2.83), respectively. The contours of the radiologist compared to RO shown a mean DSC index and Hausdorff distance on planning MRI 0.63 (range 0.53 - 0.69) and 0.41 cm (max 2.14 cm), and on mid-treatment MRI of 0.36 (range 0.19 - 0.59) and 0.68 cm (max 1.08 cm). Although this study demonstrates the presence of moderate IOV between 3 experienced head and neck ROs and one radiologist in an academic institution for the delineation of GTV on planning MRI, we observed a higher IOV between the 4 experts on mid-treatment MRI. We also experienced a higher IOV between the radiologist and RO on planning and mid-treatment images. These results show high degree of GTV volume variability on mid-treatment MRI. Therefore, peer review of contours is important and guidelines for MR adaptive tumor delineation are needed.

Utility of Smartphone-Based Digital Phenotyping Biomarkers in Assessing Treatment Response to Transcranial Magnetic Stimulation in Depression: Proof-of-Concept Study.

Identifying biomarkers of response to transcranial magnetic stimulation (TMS) in treatment-resistant depression is a priority for personalizing care. Clinical and neurobiological determinants of treatment response to TMS, while promising, have limited scalability. Therefore, evaluating novel, technologically driven, and potentially scalable biomarkers, such as digital phenotyping, is necessary. This study aimed to examine the potential of smartphone-based digital phenotyping and its feasibility as a predictive biomarker of treatment response to TMS in depression. We assessed the feasibility of digital phenotyping by examining the adherence and retention rates. We used smartphone data from passive sensors as well as active symptom surveys to determine treatment response in a naturalistic course of TMS treatment for treatment-resistant depression. We applied a scikit-learn logistic regression model (l1 ratio=0.5; 2-fold cross-validation) using both active and passive data. We analyzed related variance metrics throughout the entire treatment duration and on a weekly basis to predict responders and nonresponders to TMS, defined as ≥50% reduction in clinician-rated symptom severity from baseline. The adherence rate was 89.47%, and the retention rate was 73%. The area under the curve for correct classification of TMS response ranged from 0.59 (passive data alone) to 0.911 (both passive and active data) for data collected throughout the treatment course. Importantly, a model using the average of all features (passive and active) for the first week had an area under the curve of 0.7375 in predicting responder status at the end of the treatment. The results of our study suggest that it is feasible to use digital phenotyping data to assess response to TMS in depression. Early changes in digital phenotyping biomarkers, such as predicting response from the first week of data, as shown in our results, may also help guide the treatment course.

The role of a combination of N-acetylcysteine and magnesium sulfate as adjuvants to standard therapy in acute organophosphate poisoning: A randomized controlled trial

BackgroundMortality in acute organophosphate (OP) poisoning remains high despite current standard therapy with atropine and oximes. Due to dose-limiting side effects of atropine, novel therapies are targeting other putative mechanisms of injury, including oxidative damage, to reduce atropine dosage. ObjectivesN-acetylcysteine (NAC) and magnesium sulfate (MgSO4) have different mechanisms of actions and should act synergistically in OP poisoning. In this study, we wanted to evaluate whether this novel combination, used as an adjuvant to standard care, could improve clinical outcomes. MethodsThe study was conducted in the Emergency Department and ICU of AIIMS Bhubaneswar (a tertiary care center and government teaching institute) between July 2019 and July 2021. Eighty-eight adult patients with history and clinical features of acute OP poisoning were randomly allocated (1:1) into two groups. The Study group received 600 mg NAC via nasogastric tube thrice daily for 3 days plus a single dose of 4 g Inj. MgSO4 IV on first day and the Control group received suitably matched placebo (double-blinding) – in addition to standard care in both the groups. The primary outcome measure was to compare the total dose of Inj. Atropine required (cumulative over the entire treatment duration) between the control group and the study group receiving NAC and MgSO4. The secondary outcome measures were lengths of ICU and hospital stays, need and duration of mechanical ventilation, the differences in BuChE activity, oxidative stress biomarkers – MDA and GSH levels, the incidences of adverse effects including delayed sequalae like intermediate syndrome and OPIDN, and comparison of mortality between the two groups. ResultsData from 43 patients in Control and 42 patients in Study group was finally analyzed. The baseline parameters were comparable. Total atropine requirements were lower in the Study group [175.33 ± 81.25 mg (150.01–200.65)] compared to the Control [210.63 ± 102.29 mg (179.15–242.11)] [Mean ± SD (95% CI)], but was not statistically significant. No significant differences in any of the other clinical or biochemical parameters were noted. ConclusionThe N-acetylcysteine and MgSO4 combination as adjuvants failed to significantly reduce atropine requirements, ICU/hospital stay, mechanical ventilatory requirements, mortality and did not offer protection against oxidative damage.

Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study.

ObjectiveTo report long‐term post hoc efficacy and safety data from 10 US study sites from an open‐label Phase 3 study of adjunctive cenobamate (NCT02535091).MethodsPatients with uncontrolled focal seizures taking stable doses of 1–3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2‐week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50‐mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019.ResultsOf 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic–clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1–4 (12.5–25 mg/day cenobamate) and 61.7% during Weeks 5–8 (50–100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12‐month duration of 100% seizure reduction. Common treatment‐emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).SignificanceThis post hoc analysis of a subset of patients from the long‐term open‐label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.

Activation, development, and attenuation of modeling- and remodeling-based bone formation in adult rats

Activation of modeling-based bone formation (MBF - bone formation without prior activation of bone resorption), has been identified as an important mechanism by which anabolic agents, such as intermittent parathyroid hormone (PTH), rapidly elicit new bone formation. Using a novel cryohistology imaging platform, coupled with sequential multicolor fluorochrome injections, we demonstrated that MBF and remodeling-based bone formation (RBF) in the adult rat tibia model have similar contributions to trabecular bone homeostasis. PTH treatment resulted in a 2.4–4.9 fold greater bone formation rate over bone surface (BFR/BS) by RBF and a 4.3–8.5 fold greater BFR/BS by MBF in male, intact female, and ovariectomized female rats. Moreover, regardless of bone formation type, once a formation site is activated by PTH, mineral deposition continues throughout the entire treatment duration. Furthermore, by tracking the sequence of multicolor fluorochrome labels, we discovered that MBF, a highly efficient but often overlooked regenerative mechanism, is activated more rapidly but attenuated faster than RBF in response to PTH. This suggests that MBF and RBF contribute differently to PTH's anabolic effect in rats: MBF has a greater contribution to the acute elevation in bone mass at the early stage of treatment while RBF contributes to the sustained treatment effect.

Impact of Ibrutinib Dose Intensity on Patient Outcomes in Previously Treated Waldenström Macroglobulinemia

Introduction: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib recently became the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Temporary interruption of therapy is recommended to manage treatment-related toxicities and when patients undergo invasive procedures. However, the impact of interrupted therapy with ibrutinib has not been evaluated in patients with WM. We therefore examined the clinical implications of dose intensity in previously treated WM patients treated with ibrutinib in the multicenter phase 2 trial supporting regulatory approval.Methods: Patient charts were retrospectively analyzed and pertinent clinical data were collected surrounding ibrutinib drug holds. Treatment adherence to ibrutinib was documented during the clinical trial, and was measured by overall dose intensity (DIoverall). DI was defined as the proportion of administered versus planned doses from initiation of therapy until last dose received. Response was assessed based on current criteria. Time to events was estimated using the Kaplan-Meier method and comparisons between groups were made using the log-rank test.Results: Sixty-three patients with WM were enrolled and began therapy with ibrutinib 420 mg once daily. Fifty patients (79%) held ibrutinib at least once, and there were 102 drug-hold events in total. The median drug hold length was 6 days (range, 2-50 days). An increase in serum IgM level was observed on 63 occasions at the next response assessment after a drug hold. The median increase in serum IgM level was 50% (range, 4-555%), and 37 increases (59%) met criteria for progressive disease (PD). Following the reinitiation of ibrutinib, the median time to a response of stable disease (SD) or better was 125 days (95% CI 109-186 days) for patients who met PD criteria, and was significantly longer for patients with the MYD88MUTCXCR4WHIM versus MYD88MUTCXCR4WT tumor genotype (207 vs. 101 days; p<0.0001). The mean DIoverall was 97% after a median 3.9 years of ibrutinib therapy. Eighteen patients (29%) had a DIoverall below the mean (low DI), and 45 patients (71%) had a DIoverall above the mean (high DI). Patients with low DIoverall versus high DIoverall had no difference in age at ibrutinib initiation, sex, number of prior therapies, beta-2-microglobulin, serum IgM, hemoglobin level, bone marrow involvement, adenopathy, splenomegaly, and MYD88 and CXCR4 mutational status (p>0.05 for all comparisons). Overall PFS was significantly shorter in patients with low DIoverall versus high DIoverall (median, 22 months vs. not reached [NR]; p=0.008). The mean DIoverall for patients with MYD88MUTCXCR4WT (n=37), MYD88MUTCXCR4WHIM (n=21), and MYD88WTCXCR4WT (n=5) tumor genotype was 99%, 95%, and 99%, respectively. A subgroup analysis demonstrated a significant difference in PFS for MYD88MUTCXCR4WHIM patients with low DIoverall versus high DIoverall (median, 9.4 months vs. NR; p=0.0003), whereas no difference was observed in MYD88MUTCXCR4WT and MYD88WTCXCR4WT patients (p>0.05 for both comparisons). Twenty-five patients missed ³8 consecutive days of ibrutinib therapy. Among patients who held ibrutinib, those who missed doses for ³8 consecutive days experienced a shorter PFS compared to patients who missed <8 consecutive days (median, 35 months vs. NR; p=0.005). This was observed for patients with both the MYD88MUTCXCR4WT (median, 48 months vs. NR; p=0.01) and MYD88MUTCXCR4WHIM (median, 22 months vs. NR; p=0.03) tumor genotype. No patients with MYD88WTCXCR4WT held ibrutinib for ³8 consecutive days.Conclusion: Temporary interruption of ibrutinib therapy is associated with transient increases in serum IgM level which appear to persist longer for patients with the MYD88MUTCXCR4WHIM tumor genotype. Patients with DI higher than 97% had longer PFS, and holding ibrutinib >1 week during the entire treatment duration was associated with increased PFS events. These findings suggest ibrutinib holds should be minimized and ibrutinib restarted as soon as clinically indicated to achieve optimal patient outcomes. DisclosuresTreon:Pharmacyclics: Consultancy, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding.

Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) - Updated Data from the Phase 2 ACE-536-MF-001 Study

Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) - Updated Data from the Phase 2 ACE-536-MF-001 Study

Evolution of Electrical and Optical Parameters of a Helium Plasma Jet in Interaction With Liquids

A helium-operated atmospheric pressure plasma jet was used to treat biologically relevant liquids, such as ultrapure water and phosphate-buffered saline. The present experiments are focused on the behavior and evolution of selected electrical and optical signals of the helium plasma jet, while in contact with the liquid targets. To that extent, this article presents multiple results extracted from the monitoring of the electrical current over the entire treatment duration, with emphasis on the identification of a minute order long plasma warm-up duration and the differences observed when using the two liquid targets. Moreover, spectral monitoring of the intensity of lines and bands corresponding to helium, oxygen, and nitrogen excited species in the gas phase also points to a similar evolution towards a steady state level. The existence of transient regimes should not be disregarded when plasma jets are used for industrial and life science applications, where the exposure duration of biological targets, liquids, and solid state materials is usually of the order of a few minutes.

Correction of motion-induced susceptibility artifacts and B0 drift during proton resonance frequency shift-based MR thermometry in the pelvis with background field removal methods.

PurposeThe linear change of the water proton resonance frequency shift (PRFS) with temperature is used to monitor temperature change based on the temporal difference of image phase. Here, the effect of motion‐induced susceptibility artifacts on the phase difference was studied in the context of mild radio frequency hyperthermia in the pelvis.MethodsFirst, the respiratory‐induced field variations were disentangled from digestive gas motion in the pelvis. The projection onto dipole fields (PDF) as well as the Laplacian boundary value (LBV) algorithm were applied on the phase difference data to eliminate motion‐induced susceptibility artifacts. Both background field removal (BFR) algorithms were studied using simulations of susceptibility artifacts, a phantom heating experiment, and volunteer and patient heating data.ResultsRespiratory‐induced field variations were negligible in the presence of the filled water bolus. Even though LBV and PDF showed comparable results for most data, LBV seemed more robust in our data sets. Some data sets suggested that PDF tends to overestimate the background field, thus removing phase attributed to temperature. The BFR methods even corrected for susceptibility variations induced by a subvoxel displacement of the phantom. The method yielded successful artifact correction in 2 out of 4 patient treatment data sets during the entire treatment duration of mild RF heating of cervical cancer. The heating pattern corresponded well with temperature probe data.ConclusionThe application of background field removal methods in PRFS‐based MR thermometry has great potential in various heating applications and body regions to reduce motion‐induced susceptibility artifacts that originate outside the region of interest, while conserving temperature‐induced PRFS. In addition, BFR automatically removes up to a first‐order spatial B0 drift.

High Rate of Complete Response (CR) with Undetectable Bone Marrow Minimal Residual Disease (MRD) after Chemo-Sparing and MRD-Driven Strategy for Untreated Fit CLL Patients: Final Results of the Icll 07 Filo Trial

Achievement of CR with undetectable minimal residual disease (uMRD) may be associated with a longer survival in CLL, but BCR signaling inhibitors alone seldom allow reaching uMRD. We conducted a multicenter phase II trial aiming at exploring the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy for patients who do not reach CR with uMRD. Previously untreated fit patients with active Binet stage A and B or stage C CLL, no TP53 mutation/deletion, CIRS score Between November 2015 and May 2017, 135 patients (89 males/46 females) were enrolled; 7% were Binet stage A, 67% stage B and 26% stage C. Median age was 62 years (range, 35-80). Genetic alterations included 26% del(11q), 19% trisomy 12 and 56% del(13q); 15% had a complex karyotype and 56% patients had unmutated IGHV status. Median Beta 2 microglobulin was 3.6 mg/L (1.5-7.5) and median GFR (Cockroft) was 81 mL/min (42-173). At Month 9, 92% patients had received the 8 planned infusions of obinutuzumab. Ibrutinib dosage was reduced in 4 patients and definitively discontinued in 3 of them (3.9%) due to AE (atrial fibrillation, atrial flutter and neutropenia). Fifty seven percent of the patients presented at least a grade (G) 3 toxicity during the first 9 months of treatment (neutropenia 24%, anemia 6% and thrombocytopenia 31%). One hundred and thirty patients were evaluable for response at M9 and 5 not evaluable (2 deaths: one sudden at M7 and one accidental at M8; one acute coronary syndrome; one listeria meningitidis and one acute pulmonary edema at day 1 cycle 1). In intention to treat (ITT), ORR was 100% with 41% of patients reaching CR (42% for evaluable patients) but only 12% had BM MRD At month 16, 115 patients were evaluable for response. In ITT, the CR rate was 69% (78% for evaluable patients) and 79% of patients had BM MRD During the trial second period (M9 to M16), 38% patients presented at least a G3 toxicity: neutropenia 24%, thrombocytopenia 15%, anemia 1.5%, febrile neutropenia 3%, gastrointestinal disorders 9.5% and cardiac events 2.4%. A total of 41 serious AEs were observed throughout the entire treatment duration: 9 cardiac events including 1 atrial flutter and 3 atrial fibrillations, 4 hemorrhagic events, 7 infections, 3 second cancers (2 basocellular carcinoma, 1 renal adenocarcinoma) and 2 deaths. In conclusion, this MRD-driven strategy given for a definite period of time leads to a very high rate of uMRD CR in previously untreated CLL fit patients without TP53 aberration and displays an acceptable security profile. To our knowledge, these results are superior to standard FC + rituximab (FCR) or any chemo-free regimen. We hypothesize that this very high rate of bone marrow undetectable MRD will translate in a prolonged PFS while discontinuing treatment. Disclosures Laribi:Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Teva: Other: Grant; Gilead: Other: Personal fees; Sandoz: Other: Grant; Roche: Other: Grant; Amgen: Other: Personal fees; Hospira: Other: Grant. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria. Cartron:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cymbalista:Gilead: Honoraria; AbbVie, Inc: Honoraria; Janssen: Honoraria; Sunesis: Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.

DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers. Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. Dutch Cancer Society.

Femoral nerve palsy is a mythic complication of Pavlik harness treatment for developmental dysplasia of the hip

Introduction Femoral nerve palsy (FNP) is reported as a potential complication of Pavlik harness treatment for developmental dysplasia of the hip (DDH). It is known to be transient, as it often resolves following strap adjustment to decrease hip flexion, which may jeopardize the treatment success. The purpose of this study was to report the incidence of this potential complication, to identify any possible associated risk factors and to evaluate its outcome without any specific strap release. Materiel et methodes A retrospective chart review was conducted on all DDH patients who underwent Pavlik harness treatment for DDH between August 1997 and June 2015 by a single physician. Our treatment protocol includes biweekly visits to the clinic for strap adjustment and evaluation of bilateral active knee extension as an indirect indicator of femoral nerve palsy during the entire treatment duration, 3 months in average. Femoral nerve palsy (FNP) was defined as a partial or total deficit in active knee extension anytime during or following the completion of Pavlik harness treatment. All cases of femoral nerve palsy were identified and reviewed. In unilateral cases, the DDH hip was compared to the non-affected side. All hips with femoral nerve palsy were compared to the remaining hips of the series and any possible risk factor for paralysis was recorded, including age, patient's size, severity according to Tonnis and hip flexion angle in the harness. Statistical analysis was undertaken. Resultats Fifty-three cases of femoral nerve palsy of various severity were identified from a group of 473 children with 527 hips treated for DDH (10%) at an average age of 3.9 months. Ninety-three percent of them presented during the first 2 weeks of treatment. FNP was more common in older and larger children with the most severe Tonnis type and a hip flexion angle in the harness above 90 degrees (P Discussion FNP is a fairly common complication of Pavlik harness treatment for DDH. It is most observed in higher Tonnis types, but its presence by itself is not predictive of treatment failure. The most significant risk factors for FNP seem to be DDH severity and hip flexion angle in the harness. FNP resolves spontaneously before completion of treatment without any specific measures and therefore does not require any strap release or harness discontinuation.

Effect of Penile Traction and Vacuum Erectile Device for Peyronie’s Disease in an Animal Model

BackgroundPenile traction therapy with the use of a traction device (TD) or vacuum erectile device (VED) has been studied as local modalities for Peyronie’s disease (PD). AimTo identify changes of penile curvature, erectile function, and possible cellular and molecular mechanisms between the TD and VED in a rat model of PD. MethodsPeyronie’s plaque was induced in 30 adult male rats. Then, rats were randomly divided into control (PD without treatment), VED, and TD groups. In the VED group, vacuum pressure was applied to the cylinder to induce penile engorgement inside the cylinder for 1 minute. The penis was allowed to deflate completely for another 1 minute. This was repeated for five cycles (inflate and deflate). In the TD group, the rat penis was straightened by a suspended tension gauge at the same tension by clamping the prepuce. This was performed three times per day at 20 minutes per session, with 5-minute intervals between sessions. The entire treatment duration was 4 weeks. OutcomesPenile curvature, intracavernosal pressure, and mean arterial pressure were measured. Immunohistochemistry for α-smooth muscle actin, transforming growth factor-β1 and mothers against decapentaplegic homolog 2/3 were performed. ResultsThe TD and VED groups had less penile curvature compared with the control group (15.3 ± 5.3° for TD, 28.4 ± 6.8° for VED, 38.6 ± 10.5° for control; P < .001 for TD vs control, P < .05 for VED vs control). The TD group also had less penile curvature compared with the VED group (P < .05). The VED group had a higher ratio of intracavernosal pressure to mean arterial pressure compared with the two other groups (0.56 ± 0.10 for VED, 0.38 ± 0.06 for TD, 0.32 ± 0.07 for control; P < .001). The immunohistochemistry results showed the VED group had more preserved α-smooth muscle actin with less transforming growth factor-β1 and mothers against decapentaplegic homolog 2/3 than the TD and control groups in the corpus cavernosa. Clinical TranslationVarious benefits can be observed with the TD and VED for the treatment of PD. Strengths and LimitationsThis study explored the mechanism and benefits of TD and VED therapies for the treatment of PD. The rat model might not represent the human condition. ConclusionPenile traction therapy with the TD or VED is beneficial to decrease penile curvature in animal models of PD. The underlying mechanism could be related to antiapoptosis, antifibrosis, and smooth muscle preservation.Lin H, Liu C, Wang R. Effect of Penile Traction and Vacuum Erectile Device for Peyronie’s Disease in an Animal Model. J Sex Med 2017;14:1270–1276.

Pathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer.

577 Background: Inclusion of H with chemotherapy has increased pathologic complete response (pCR) rates in HER2 positive breast cancer, and dual HER2 blockade involving H + P further increased efficacy. With dual HER2 blockade and taxane-based (+/-carboplatin followed by anthracycline) chemotherapies, pCR rates reach, 75% in estrogen receptor (ER) negative and 45% in ER+ patients. HER2 targeted therapies also increase the efficacy of anthracyclines but are not routinely combined due to potential cardiotoxicity. The goal of this phase II study was to assess pCR rate when H+P is administered during the entire treatment duration, including the anthracycline phase, of weekly T (80 mg/m2) x 12 followed by FE(75 mg/m2)C x 4 neoadjuvant chemotherapy. Methods: pCR (ypT0/is and ypN0) rate was assessed separately in ER+ and ER- cancers following Simon’s two-stage design to detect improvement in pCR rates to 90% and 70% in the ER- and ER+ cohorts, respectively. Eligibility included age &lt;65, stage I-III, HER2+ disease, and normal cardiac function. Results: The ER- cohort completed full accrual of 25 patients: 23 completed therapy and surgery, 2 patients are still receiving treatment. The pCR rate is 78% (n=18, 95% CI:58-90%). The ER+ cohort was closed after 23 patients were accrued to the first stage due to lower than expected pCR of 26% (n=6, 95% CI:13-46%) at interim analysis. The incidence of grade 3/4 adverse events was 48% (n=24/50), the most common being neutropenia (n=12) and diarrhea (n=7). No patient experienced symptomatic congestive heart failure, one patient had a drop in LVEF to &lt; 50% following completion of chemotherapy. Thirteen patients (27%) had a &gt;10% asymptomatic drop in their LVEF but remained above 50%, LVEF returned to baseline by the next assessment in half of these cases. Conclusions: Neoadjuvant P and H administered concomitantly with weekly T followed by FEC resulted in 78% pCR rate in ER-/HER2+ cancers. This pCR rate is among the highest reported in the literature. The pCR rate was substantially lower in ER+ cancers. Clinical trial information: NCT01855828.

Direct Observation (DO) for Drug-Resistant Tuberculosis: Do We Really DO?

IntroductionDirectly-observed therapy (DOT) is recommended for drug-resistant tuberculosis (DR-TB) patients during their entire treatment duration. However, there is limited published evidence on implementation of direct observation (DO) in the field. This study aims to detail whether DO was followed with DR-TB patients in a Médecins Sans Frontières (MSF) tuberculosis program in Mumbai, India.MethodsThis was a cross-sectional, mixed-methods study. Existing qualitative data from a purposively-selected subset of 12 patients, 5 DOT-providers and 5 family members, were assessed in order to determine how DO was implemented. A questionnaire-based survey of DR-TB patients, their DOT-providers and MSF staff was completed between June and August 2014. Patients were defined as”following Strict DO” and “following DO” if a DOT-provider had seen the patient swallow his/her medications “every day” or “most of the days” respectively. If DO was not followed, reasons were also recorded. The qualitative data were analysed for theme and content and used to supplement the questionnaire-based data.ResultsA total of 70 DR-TB patients, 65 DOT-providers and 21 MSF health staff were included. Fifty-five per cent of the patients were HIV-co-infected and 41% had multidrug-resistant-TB plus additional resistance to a fluoroquinolone. Among all patients, only 14% (10/70) and 20% (14/70) self-reported “following Strict DO” and “following DO” respectively. Among DOT-providers, 46% (30/65) reported that their patients “followed DO”. MSF health staff reported none of the patients “followed DO”. Reasons for not implementing DO included the unavailability of DOT-provider, time spent, stigma and treatment adverse events. The qualitative data also revealed that “Strict DO” was rarely followed and noted the same reasons for lack of implementation.ConclusionThis mixed-methods study has found that a majority of patients with DR-TB in Mumbai did not follow DO, and this was reported by patients and care-providers. These data likely reflect the reality of DO implementation in many high-burden settings, since this relatively small cohort was supported and closely monitored by a skilled team with access to multiple resources. The findings raise important concerns about the necessity of DO as a “pillar” of DR-TB treatment which need further validation in other settings. They also suggest that patient-centred adherence strategies might be better approaches for supporting patients on treatment.

On-line MR imaging for dose validation of abdominal radiotherapy

For quality assurance and adaptive radiotherapy, validation of the actual delivered dose is crucial.Intrafractional anatomy changes cannot be captured satisfactorily during treatment with hitherto available imaging modalitites. Consequently, dose calculations are based on the assumption of static anatomy throughout the treatment. However, intra- and interfraction anatomy is dynamic and changes can be significant.In this paper, we investigate the use of an MR-linac as a dose tracking modality for the validation of treatments in abdominal targets where both respiratory and long-term peristaltic and drift motion occur.The on-line MR imaging capability of the modality provides the means to perform respiratory gating of both delivery and acquisition yielding a model-free respiratory motion management under free breathing conditions.In parallel to the treatment, the volumetric patient anatomy was captured and used to calculate the applied dose. Subsequently, the individual doses were warped back to the planning grid to obtain the actual dose accumulated over the entire treatment duration. Ultimately, the planned dose was validated by comparison with the accumulated dose.Representative for a site subject to breathing modulation, two kidney cases (25 Gy target dose) demonstrated the working principle on volunteer data and simulated delivery. The proposed workflow successfully showed its ability to track local dosimetric changes. Integration of the on-line anatomy information could reveal local dose variations −2.3–1.5 Gy in the target volume of a volunteer dataset. In the adjacent organs at risk, high local dose errors ranging from −2.5 to 1.9 Gy could be traced back.

An Open-Label, Phase 2, Multicenter Study Of The Safety Of Long-Term Treatment With Siltuximab (an Anti-Interleukin-6 Monoclonal Antibody) In Patients With Multicentric Castleman's Disease

▪Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disease driven by interleukin (IL)-6 overproduction. There is no established standard of care for MCD, and patients are usually managed by a variety of strategies with only modest success. Treatment with siltuximab, an anti-IL-6 mAb, demonstrated clinical and radiologic responses in MCD patients in a phase 1 study (Kurzrock et al. Clin Cancer Res 2013;19:3659-70). A phase 2 extension study to assess the safety of long-term treatment with siltuximab in MCD patients is currently ongoing.We report the interim analysis results based on 19 patients who had sustained disease control on siltuximab in the phase 1 study and continued to receive siltuximab 11 mg/kg q3w IV in the phase 2 extension study. Safety monitoring focused on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, and liver function based on the potential risks from the mechanism of action of IL-6 blockade. Investigator assessed disease control and survival status were also collected.When these 19 patients started the phase 1 study, median age was 44 (range 18, 76) yrs, 63% were male, median disease duration was 4.8 mos (37% newly diagnosed), 53% had hyaline vascular and 47% had plasmacytic histological type, all were HIV- and HHV-8-negative, 32% were therapy-naïve, and 68% had prior therapy (including 21% with prior cancer-related surgery and 63% with prior systemic therapy for MCD). At the data cutoff for this interim analysis of the extension study (January 2013), patients had received in total a median of 81 doses (maximum 129) of siltuximab during a median treatment duration of 5.1 (range 3.4, 7.2) yrs, with 74% of patients treated >4 yrs. All 19 patients are alive and continuing siltuximab treatment.Over the entire treatment duration (ie, both studies), upper respiratory tract infection (89%); nausea (63%); vomiting (58%); diarrhea (53%); hypercholesterolemia (47%); hypertriglyceridemia, pain in extremities, headache, rash, and hepatic function abnormal (each 42%) were most commonly reported. The incidence of AEs reported in the different system-organ classes was similar or lower in the treatment periods of 2 to 4 yrs and more than 4 yrs compared with the treatment period of 0 to 2 yrs. 63% of patients reported at least one grade ≥3 AE (mostly grade 3, none grade 5) during the entire treatment period, most commonly in the following system-organ classes: gastrointestinal (32%); infections (26%); and blood/lymphatic system disorders or general disorders/administration-site conditions (each 21%). Grade ≥3 hypertension was reported in 3 patients; grade ≥3 nausea, cellulitis, and fatigue in 2 patients each; other grade ≥3 AEs were reported in single patients.Two patients had at least one serious infection during phase 1, and none were reported during phase 2 extension study (overall incidence 0.0226 per pt-yr). Eight patients had low-grade hypertriglyceridemia in phase 1, with no additional cases reported during extension study (overall incidence 0.1250 per pt-yr). No patient had grade ≥3 thrombocytopenia, and only 1 patient had grade ≥3 neutropenia during the entire treatment period (overall incidence 0.0103 per pt-yr). Only 1 case of grade ≥3 abnormal hepatic function was reported (in phase 1). No GI perforations occurred. No patient developed infusion-related reactions during the extension study. Only 3 patients had SAEs during the extension study, including unrelated syncope and dyspnea. One patient developed grade 3 polycythemia (Hb 18.8 g/dL), which was controlled without complications.Based on independent radiologic review of images from the phase 1 study, 1 patient had CR, 11 had PR, and 7 had SD at initiation of extension study. All 19 patients have sustained disease control (SD or better) by investigator assessment, including 8 patients who had their dosing interval increased to q6w after established prolonged PR/CR (median q6w treatment duration 11 mos). After a median follow-up of 5.1 yrs, the OS rate in these 19 patients is 100%.In conclusion, the 19 patients with MCD in this extension study have received siltuximab for a prolonged period of time (median 5.1 yrs, up to 7.2 yrs). All patients are alive and maintain disease control. Prolonged siltuximab treatment is well tolerated, with no evidence of new or cumulative toxicity or treatment discontinuations and with a low rate of serious adverse events including serious infections. Disclosures:Van Rhee:Janssen Research & Development: Research Funding. Casper:Janssen Research & Development: Research Funding. Voorhees:Janssen Research & Development: Research Funding; Abbott: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qin:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Tromp:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Kurzrock:Janssen Research & Development: Research Funding.

Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI) therapy in accelerated-phase CML (CML-AP).

6587 Background: For patients (pts) presenting with CML-AP, TKIs are recommended. Although generally well tolerated, dose reductions and/or interruptions are often required. The impact of TKI dose intensity (DI) on CML-AP outcome has not been described. Aim: To determine impact of TKI dose interruptions and/or reductions on outcome in de novo CML-AP. Methods: Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or parallel clinical trials with TKIs as initial therapy: imatinib (n=36), dasatinib (n=5), or nilotinib (n=17). CML-AP features included: blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets &lt;100x109/L (n=3), cytogenetic clonal evolution (n=22), or &gt;1 feature (n=3). We examined the impact of dose reductions, treatment interruptions, and DI (ratio of the dose received vs. the intended dose for the entire treatment duration) on event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: Among 58 pts, 37 required treatment interruptions and/or dose reductions (29 required dose reductions). 12 pts required dose reductions and/or interruptions due to hematologic toxicity and 23 for non-hematologic toxicities. Pts were divided into 3 DI tiers: 100% (n= 21), 90-99%, (n=10), and &lt;90% (n=27). Outcomes were analyzed based on DI tiers and presence or absence of dose reductions as shown in the table. Pts with dose reductions and/or interruptions for hematologic toxicities vs. non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100% (p=0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo or later were 100% and 91%, respectively (p =0.7). Conclusions: DI has no significant impact on de novo CML-AP outcome. However, dose interruptions and/or reductions for hematologic toxicities are associated with worse 24-mo EFS, suggesting myelosuppression may in some patients be more a feature of the disease than toxicity from therapy. [Table: see text]