Pre-therapeutic dihydropyridimidine dehydrogenase (DPD) deficiency screening: Impact on fluoropyrimidine dose reduction at the second chemotherapy cycle and on early severe toxicity.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3096-3096
Author(s):  
Côme De Metz ◽  
Benjamin Hennart ◽  
Marie-Cecile Le Deley ◽  
Pierre-Yves Cren ◽  
Christophe Desauw ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Screening Method ◽  
Chemotherapy Cycle ◽  
Severe Toxicity ◽  
Dose Adaptation ◽  
Kappa Test ◽  
Grade 5 ◽  
Phenotype Analysis ◽  
Grade 3 ◽  
Deficiency Screening

3096 Background: DPD deficiency screening before fluoropyrimidine is a matter of debate. To avoid lethal toxicity, French authorities impose DPD screening before fluoropyrimidine-based chemotherapy by dosing uracilemia since April 2019. Methods: We have included all consecutive adult patients receiving 5-fluorouracil (5-FU) or capecitabin from April 2019 to January 2020 in 6 cancer centers. During the study period, different methods for screening had been applied: DPYD complete sequencing, phenotype (uracilemia and/or dihydrouracilemia/uracilemia ratio - UH2/U -) or both. All sceening tests were conducted in the same laboratory. Association between the method of DPD screening and fluoropyrimidine dose reduction at second chemotherapy cycle or on severe ≥grade 3 early toxicity (between first and second cycle) was evaluated using multivariate logistic regression. Concordance between genotype and phenotype for DPD deficiency was explored using Cohen Kappa test. Results: We included 597 patients, the median age was 63 (range, 55-77). The most prevalent cancers were digestive (68.3%), head and neck (19.4%) and breast (9.2%). 12.3% of patients received capecitabine and 87.3% received polychemotherapy. DPD deficiency screening was done for most of patients (n=519, 86.9%). DPD screening method consisted in full sequencing of DPYP (n=41; 7.9%), phenotype analysis (n=44, 8.5%) or both (n=424, 83.6%). We did not identify any complete DPD deficiency. Uracilemia was dosed for 467 patients, the median was 6.5 ng/mL and for 21 patients (4.5%) uracilemia was > 16 ng/mL and/or UH2/U <6, suggesting DPD deficiency. Severe early toxicities were observed for 82 patients (14%), with two patients presenting grade 5 toxicity. Overall DPD screening and method of DPD screening were not associated with fluoropyrimidine dose reduction at second cycle or early severe toxicity. In multivariate analysis, the only predictor for fluoropyrimidine reduction at second cycle (n = 125 patients) was polychemotherapy (OR=2.8; p=0.012). Kappa between uracilemia and UH2/U was 0.23 (poor concordance). Kappa between DPYP sequencing and uracilemia or UH2/U was 0.09 (very poor concordance). Conclusions: No DPD deficiency screening method was associated with dose adaptation at second cycle or early severe toxicity. The optimal strategy for DPD screening requires further clinical evaluation.

Prevention of 5-FU-induced health-threatening toxicity by pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3601-3601
Author(s):  
Michele Boisdron-Celle ◽  
Olivier Capitain ◽  
Jean-Philippe Metges ◽  
Roger Faroux ◽  
Christophe Borg ◽  
...  
Keyword(s):  
Economic Assessment ◽  
Economic Benefits ◽  
Severe Toxicity ◽  
Safe Treatment ◽  
Dose Adaptation ◽  
Screening Cost ◽  
Group A ◽  
Group B ◽  
Partial Deficiency ◽  
Deficiency Screening

3601 Background: While 5-FU is the foundation of many in GI oncology treatments, pts with DPD deficiency can experience early-onset severe (5%) even fatal (0.3%) toxicities. This study aimed to confirm the pharmaco-economic benefits of pre-therapeutic screening for DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (NCT01547923). Methods: Two parallel cohorts of pts treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD deficiency screening; Group B: no evaluation. Enrollment was based on 5-FU administration guidelines of each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) (1,2,3). The 2 groups were to be compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed in the case of proven 5-FU-related toxic death. Results: 1,130 pts were included from 06/01/2008 to 07/31/2012. Group A: no severe toxicity despite 1 pt with complete deficiency (pt not treated with 5-FU), 20 pts with partial deficiency had safe PK-monitored 5-FU (ODPM Protocol) with only one hospitalization due to toxicity. Group B: One death due to complete DPD deficiency, confirmed retrospectively. Enrollment prematurely closed after experts’ unanimous decision citing ethical concerns. 21 pts with partial DPD deficiency. 5 reported toxicity-related hospitalizations. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A pt had safe treatment whereas Group B pt died due to 5-FU toxicity. Pre-therapeutic DPD deficiency screening using this multi-parametric approach should be performed before 5-FU-based treatment and PK-guided dose adaptation allows for safe treatment of even partially DPD deficient patients. Clinical trial information: NCT01547923. [Table: see text]

Pharmacokinetics and Pharmacodynamics of High Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and down Syndrome: a Case Cohort Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1626-1626
Author(s):  
T. Buitenkamp ◽  
R. Mathot ◽  
A. Vulto ◽  
A. Veerman ◽  
E. van Wering ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Lymphoblastic Leukemia ◽  
Serum Levels ◽  
High Dose ◽  
Severe Toxicity ◽  
Treatment Protocols ◽  
Dose Methotrexate ◽  
Increased Risk ◽  
Grade 3 ◽  
Dose Reductions

Abstract Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid, as well as acute lymphoblastic leukemia (DS-ALL). DS ALL patients have a poorer tolerance for high-dose methotrexate (HD-MTX), which is one of the key components of ALL treatment. There are no specific dosing guidelines for HD-MTX in DS-ALL. As a result doses are frequently reduced. In this study the pharmacokinetics (PK) and pharmacodynamics of HD-MTX were studied retrospectively in DS-ALL patients in order to develop specific dosing guidelines. Only one study addressed MTX-pharmacokinetics (PK) in DS children (Garre et al, J Pediatrics 1987). They found that median MTX plasma concentrations, 42 hours after infusion, were significantly higher in 5 DS-ALL patients compared to 3 non-DS controls. A retrospective case-cohort study was performed with DS-ALL patients enrolled in treatment protocols DCOG ALL-8, -9 or -10 in 8 Dutch medical centers during the period Nov 1991-Dec 2006. MTX dosages varied from 2.0–5.0 gr/m2 in the different treatment protocols. Forty-four DS and 87 non DS-ALL patients were included. The latter were matched for treatment protocol, sex and body surface area. All DS-ALL patients had B-cell-precursor ALL, and the median diagnostic WBC was 8,8*109/L. MTX serum levels and toxicity data were collected from patient files. Toxicity was graded according to CTCAE v3.0. Population PK-models were fitted to data from all individuals simultaneously, using non-linear mixed effect modeling (NONMEM). The PK of MTX was described according to a two-compartment model with a first order elimination from the central compartment. A total of 468 HD-MTX courses were given to 44 DS and 87 non-DS children. In 20% of the DS-ALL patients doses were reduced, comprising 26/152 (17.1%) of MTX courses. In 18/26 courses, dose-reduction was electively initiated from the 1st course onwards, whereas in 8/26 courses dose-reductions were applied from the 2nd course onwards because of documented toxicity in the 1st course. Dose reductions did not occur in non DS-ALL patients (p&lt;0.001). The cumulative frequency of grade 3/4 gastro-intestinal toxicity (mucositis) was significantly higher in DS versus non-DS children (27.6% of courses vs. 4.1%; p&lt;0.001), including courses in which MTX was dose-reduced. Hemoglobin and WBC were significantly lower in DS-patients, but probably not clinically relevant, as the differences were small. The methotrexate clearance for DS-ALL patients was 5% lower than for non DS-ALL patients (p&lt;0.001). Area under the curve (AUC) and MTX serum levels at various time-points after HD-MTX infusion were not different between DS and non-DS children. Moreover, there was no correlation between AUC (range 276–2603 μmol/L*hr) and grade 3 and 4 gastro-intestinal toxicity (rs 0.17; p=0.15). In fact grade 3/4 toxicity occurred at the lowest AUC of 276 μmol/L*hr. Hence no safe AUC could be defined. To summarize, DS-ALL patients suffer from increased risk of severe mucositis, which could not be explained by differences in PK, but are most likely due to pharmacodynamic effects of MTX. Given that only one patient needed a dose-reduction after severe toxicity when being treated with MTX dosages of 1–3 gr/m2, it seems safe to treat DS children with moderately high dosages of MTX and adjust dose in individual cases in case of severe toxicity. However, in case of 5 gr/m2, 8 patients needed dose-reduction, and hence this dose is probably too high for DS patients.

Prevention of 5-FU-induced toxicities using pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 351-351 ◽  
Author(s):  
Michele Boisdron-Celle ◽  
Olivier Capitain ◽  
Roger Faroux ◽  
Christophe Borg ◽  
Jean-Philippe Metges ◽  
...  
Keyword(s):  
Economic Assessment ◽  
Patient Characteristics ◽  
Severe Toxicity ◽  
Screening Cost ◽  
Grade 5 ◽  
Group A ◽  
Multicenter Prospective Cohort Study ◽  
Group B ◽  
Partial Deficiency ◽  
Deficiency Screening

351 Background: 5-FU is the backbone of most chemotherapy regimens in GI oncology. Patients with DPD deficiency can experience early onset severe (5%) even fatal (0.3%) toxic side-effects. We decided to confirm the medical and economic interest of pre-therapeutic screening of DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (Eudract n°2008-000026-39). Methods: Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD activity evaluation; Group B: no evaluation. Enrollment in either group was based on 5-FU administration guidelines at each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) as well as other patient characteristics (1,2,3). The 2 groups were compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed if 5-FU-induced toxic death occurred. Results: 1,130 patients were included from to 16/06/2008 to 07/31/2012. Group A: no severe toxicity despite 1 patient with complete deficiency (5-FU replaced by another TS inhibitor), 17 patients with partial deficiency safely received PK-monitored 5-FU (ODPM Protocol). Group B: 1 death: 65 y.o. patient, adjuvant FOLFOX 4, 5-FU-induced SAE at day 6: grade 4 febrile neutropenia, septicemia, diarrhoea, mucositis and secondary dehydration, renal failure, then death. 5-FU imputable Grade 5 SAE declared by investigator. Complete DPD deficiency retrospectively confirmed. The enrollment was prematurely closed after unanimous experts’ decision for ethical reasons. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A patient had safe treatment whereas Group B patient died due to 5-FU grade 5 toxicity. DPD deficiency screening by a multiparametric approach (ODPM Tox) should be performed before 5-FU treatments. Clinical trial information: 2008-000026-39. [Table: see text]

Incidence, Predictors, and Significance of Severe Toxicity in Patients with HIV-Associated Hodgkin Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2587-2587 ◽  
Author(s):  
Hatoon Ezzat ◽  
Matthew C Cheung ◽  
Lisa K Hicks ◽  
Kevin C Murphy ◽  
Chantal S Leger ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Hodgkin Lymphoma ◽  
Opportunistic Infections ◽  
Infectious Complications ◽  
Hematologic Toxicity ◽  
Severe Toxicity ◽  
Hiv Viral Load ◽  
Ct Dose ◽  
Increased Risk ◽  
Grade 3

Abstract Hodgkin lymphoma (HL) occurs in HIV-infected individuals more frequently than in the HIV-negative population and the incidence is rising. Patients (pts) with non-Hodgkin’s lymphoma in HIV appear to have improved outcomes if they receive HAART with chemotherapy (CT). ABVD is standard CT for HL and is frequently administered with HAART in pts with HIV-HL. However, some components of the ABVD regimen may interact with antiretroviral (ARV) medications to alter metabolism and increase toxicity. In particular, vinblastine (VBL) is metabolized by CYP3A4 and protease inhibitors, particularly ritonavir (RTV), appear to inhibit this cytochrome potentially leading to higher VBL exposure. Little definitive information is available regarding how interactions might affect clinical outcome. We conducted a retrospective review of 36 pts with HIV-related HL to identify the frequency of neurotoxicity (NT), hematologic toxicity (HT), and lung toxicity (LT), to identify risk factors for severe (grade III–IV) toxicity, and to determine its clinical significance. Clinical data were collected from the CFE database and by chart review from 3 centers. The median age at HL diagnosis (dx) was 41 (range 29–66) years and 34 (94%) were male. HL was advanced stage in 28 (78%). Hasenclever score could be calculated in 23 pts and was 0–4 and ≥5 in 15 and 8 pts respectively. ECOG PS was 0–1 in 13 and ≥2 in 8 (n=21). HIV risk factor was: sexual, n=21 and other, n=5 (n=26). Median CD4 count at HL dx was 210 (2–660) cells/ul (n=31). Median HIV viral load (VL) was undetectable (&lt;50; range &lt;50-&gt;500,000) copies/ml (n=25). Hepatitis B and C coinfection was present in 8 and 7 pts respectively (n=29). Prior AIDS was present in 23, all opportunistic infections. Twenty-four pts received HAART with CT. Primary HL CT was: ABVD, n=29 (81%); MOPP/ABV, n=4 (11%); palliative, n=3 (8%). G-CSF was used in 22 pts. All pts received prophylaxis for PCP and 3 for HSV/VZV. HAART included 17 Arts in numerous combinations. Infectious complications were: bacterial infection, n=6; febrile neutropenia, n=4; HSV, n=3; PCP, n=1. HT occurred in 21 (75%) of 28 assessable pts and was grade 3–4 in 18 (64%; 18 and 15 were on HAART, respectively). NT occurred in 14 (50%) pts and was grade 3–4 in 6 (21%; 13 and 5 on HAART respectively, n=28). Of 6 cases of severe NT, 3 were autonomic neuropathy with pseudobowel obstruction that in 1 pt resulted in perforation. Bleomycin LT occurred in 3 pts (n=26). CT dose reduction (DR) of ≥25% in ≥1 agent was required in 9 pts (n=26). Factors associated with grade 3–4 HT were: receiving RTV, p=0.04, HR 2.9 (95% CI 1.1–7.4); and receiving lopinovir (LPV), p=0.02, HR 7.0 (2.3–21.3) and for any HT were: RTV, p=0.004, HR 3.1 (1.3–7.3); emtricitabine, p=0.01, HR 4.8 (1.4–11.6); and LPV, p=0.04, HR 4.4 (1.6–12.1). Factors for grade 3–4 NT were: LPV, p=0.05, HR 10.8 (2.0–59.5) and for any NT was: RTV, p=0.01, HR 4.0 (1.3–12.1). Fourteen pts received RTV and of 8 receiving LPV, 7 received LPV with RTV (p=0.007). At a median follow-up of 15.3 (0.1–154.8) months (mo) 25 pts (69%) are alive. The median overall survival (OS) for all pts was 44.5 (2–154.8) mo and there was no difference in OS by baseline features or the occurrence of HT or NT. However, CT dose reduction was associated with inferior OS (p=0.04, HR 3.9 [1.0–15.7]); although only 1 of 9 deaths was from HL progression; others were: infectious, n=6; and unrelated, n=2. In conclusion, pts with HIV-HL appear to experience a significantly increased incidence of NT compared to rates reported in non-HIV HL pts. In contrast, rates of HT and LT appear to be similar to those in non-HIV HL. The use of RTV or LPV during CT appeared to be associated with an increased risk of NT, suggesting a clinically significant interaction between these ARV agents and CT, particularly VBL. Prospective studies to devise a rational dosing strategy using measurements of ARV and/or CT levels are warranted.

scholarly journals Adenosine-induced Asystole during AVM Embolization

2021 ◽  
Author(s):  
V. Hellstern ◽  
P. Bhogal ◽  
M. Aguilar Pérez ◽  
M. Alfter ◽  
A. Kemmling ◽  
...  
Keyword(s):  
Demographic Data ◽  
Clinical Results ◽  
Endovascular Embolization ◽  
Neurological Deficits ◽  
Residual Shunt ◽  
Grade 5 ◽  
Martin Grade ◽  
Grade 3 ◽  
Brain Avms

Abstract Background Adenosine induced cardiac standstill has been used intraoperatively for both aneurysm and arteriovenous malformation (AVM) surgery and embolization. We sought to report the results of adenosine induced cardiac standstill as an adjunct to endovascular embolization of brain AVMs. Material and Methods We retrospectively identified patients in our prospectively maintained database to identify all patients since January 2007 in whom adenosine was used to induce cardiac standstill during the embolization of a brain AVM. We recorded demographic data, clinical presentation, Spetzler Martin grade, rupture status, therapeutic intervention and number of embolization sessions, angiographic and clinical results, clinical and radiological outcomes and follow-up information. Results We identified 47 patients (22 female, 47%) with average age 42 ± 17 years (range 6–77 years) who had undergone AVM embolization procedures using adjunctive circulatory standstill with adenosine. In total there were 4 Spetzler Martin grade 1 (9%), 9 grade 2 (18%), 15 grade 3 (32%), 8 grade 4 (18%), and 11 grade 5 (23%) lesions. Of the AVMs six were ruptured or had previously ruptured. The average number of embolization procedures per patient was 5.7 ± 7.6 (range 1–37) with an average of 2.6 ± 2.2 (range 1–14) embolization procedures using adenosine. Overall morbidity was 17% (n = 8/47) and mortality 2.1% (n = 1/47), with permanent morbidity seen in 10.6% (n = 5/47) postembolization. Angiographic follow-up was available for 32 patients with no residual shunt seen in 26 (81%) and residual shunts seen in 6 patients (19%). The angiographic follow-up is still pending in 14 patients. At last follow-up 93.5% of patients were mRS ≤2 (n = 43/46). Conclusion Adenosine induced cardiac standstill represents a viable treatment strategy in high flow AVMs or AV shunts that carries a low risk of mortality and permanent neurological deficits.

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7505-7505
Author(s):  
Tycel Jovelle Phillips ◽  
Alexey Valeryevich Danilov ◽  
David Alan Bond ◽  
Alex Francisco Herrera ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Data ◽  
Standard Of Care ◽  
Primary Objective ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Grade 5 ◽  
Unrelated Condition ◽  
Mantle Cell ◽  
Grade 3

7505 Background: MCL is a rare lymphoma without a standard of care but several regimens have demonstrated clinical activity, the majority based on traditional chemotherapy. We hypothesized that adding venetoclax (V) to R2 would be safe and effective in MCL pts irrespective of age, morphology or stage. Here we present safety and efficacy data from the on-going phase 1b study of R2 + V in pts with newly diagnosed MCL. Methods: This multi-center phase 1 study (NCT03523975) enrolled pts aged ≥18 yrs with untreated MCL. The primary objective was to characterize the safety and tolerability of R2 + V and determine the MTD. During induction (12 months (m)) pts received lenalidomide (L) 20 mg daily on day 1-21, Rituximab (R) was given weekly during c1 then on day 1 of every even cycle, V was escalated over 4 weeks to 400 mg beginning day 8. Each cycle is 28 days (d). The DLT period was 42 d beginning C1D8. In maintenance, R every 8 weeks for 36m, L at 10 mg or half of last dose during induction for 24 m and V for minimum 12 m. No pts have been transplanted. Pts with progression (PD) came off study. MRD was analyzed in parallel with scans during induction by clonoSEQ assay (Adaptive Biotechnologies). Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts on study. Pt characteristics/responses are summarized in Table. Among the 28 pts who have received at least one dose, the median treatment duration so far is 278d (IQR 170-560), with 24 pts still on treatment (Tx). 1 pt is off from a unrelated condition. All pts escalated to V 400 mg w/o any DLTs noted. Treatment-emergent adverse events (TEAEs) were reported in 100% of pts, and grade 3+ TEAEs were reported in 26 (93%) patients. The most common all-grade TEAEs (≥50% of pts), regardless of relationship to study Tx, were fatigue, neutropenia and diarrhea. Grade ≥3 TEAEs reported in ≥50% pts were neutropenia (68%) and thrombocytopenia (50%). No pts have withdrawn or d/c Tx due to AEs. There was one grade 5 event, in a non-evaluable pt, related to a PE that occurred prior to DLT period. In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing was successful in all pts. At time of submission 20 of 28 (71%) were MRD - at 10-6. Conclusions: Interim results show that at the MTD the combination of V 400 mg daily, L 20 mg, with R is safe with a manageable toxicity profile and a high ORR and MRD - in pts with newly diagnosed MCL. Safety data is consistent with the AE profile noted for each drug without any unexpected or unique AEs. Updated results including BH3 profiling will be presented at the meeting. Clinical trial information: NCT03523975. [Table: see text]

Phase I INSIGHT platform trial: Advanced safety and efficacy data from stratum D evaluating feasibility and safety of eftilagimod alpha (soluble LAG-3 protein) combined with avelumab in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2518-2518
Author(s):  
Thorsten Oliver Goetze ◽  
Daniel Wilhelm Mueller ◽  
Mohammad-Reza Rafiyan ◽  
Dragan Kiselicki ◽  
Timursah Habibzade ◽  
...  
Keyword(s):  
Adverse Events ◽  
Renal Insufficiency ◽  
Diffuse Myocardial Fibrosis ◽  
Pleural Mesothelioma ◽  
Advanced Solid Tumors ◽  
Clinical Progression ◽  
Grade 5 ◽  
Common Grade ◽  
Acute Renal Insufficiency ◽  
Grade 3

2518 Background: Stratum D of the INSIGHT platform trial evaluates s.c. eftilagimod alpha (efti, IMP321) combined with avelumab in advanced solid tumors. Efti is an MHC class II agonist which activates antigen-presenting cells followed by CD8 T-cell activation. Combination with PD-1/PD-L1 blockade aims at enhanced efficacy. Methods: This IIT platform trial consists of 5 strata: intratumoral (A) or intraperitoneal efti (B); s.c. efti with SOC (C) or with PD-L1 inhibition (D). Strat E is currently under development and starts soon with a new efti combination. This abstract focuses on preliminary data of Strat D. Patients (pts) received 800mg avelumab i.v. q2w along with s.c. efti: 6mg in cohort 1 (coh 1, 6 pts), 30mg in cohort 2 (coh 2, 6 pts). Primary endpoint: safety. Results: Recruitment has been completed with 12 pts (coh 1: gastric, gallbladder, colon cancer, pleural mesothelioma; coh 2: gastric, gastroesophageal, anal, rectum, cervix uteri). No dose limiting toxicities (DLTs) occurred. 10 serious adverse events (SAEs) were reported, none of them considered causally related (4 in 3 pts of coh 1 [1 acute renal insufficiency grade 5 in 1 pt, 2 preileus grade 3 in 1 pt, hearing impaired grade 4 in 1 pt] and 6 in 4 pts of coh 2 [1 anal hemorrhage and 1 gallbladder obstruction in 1 pt, 1 eye pain and 1 surgery to replace the feeding tube in 1 pt, each grade 3, 1 skin infection grade 2, 1 diffuse myocardial fibrosis grade 5]. 1 AE of special interest (AESI) possibly related with avelumab (sarcoidosis grade 1) occurred in coh 1. 2 pts completed max treatment duration with 24 cycles. In coh 1, 47 adverse events (AEs; grade 1-2, 29; grade 3, 14; grade 4, 3; grade 5, 1) occurred in 5 pts. Most common grade 1-2 AEs were nausea, pain in 33%, 33% of the pts. Most common grade 3 AEs were ileus, vomiting in 33%, 33% of the pts. 2 AEs grade 4 (hearing impaired, sepsis) and 1 AE grade 5 (acute renal insufficiency) were reported. All AEs grade 3-5 were considered causally unrelated. In coh 2, 51 adverse events (AEs; grade 1-2, 29; grade 3, 19; grade 4, 2; grade 5, 1) occurred in 5 pts. The most common grade 1-2 AE was hypothyroidism in 33% of the pts. 1 AE grade 5 (diffuse myocardial fibrosis) was reported. Only 1 AE grade 3-5 was considered causally related (urinary tract infection grade 3 related with avelumab). 5 pts showed partial response as best response (2 coh 1: colon, pleural mesothelioma; 3 coh 2: gastric, anal, cervical), 1 stable disease with clinical progression (coh 2) (all but one of these pts still alive), 5 disease progressions acc. to RECIST 1.1 (3 coh 1, 2 coh 2), 1 clinical progression (coh 1). Signals of activity were also observed in pre-treated MSS/PD-L1low pts. Conclusions: Combined treatment with avelumab 800mg and efti 6mg (coh 1) or 30 mg efti (coh 2) seems feasible and safe. No unexpected AEs occurred. Signals of efficacy with CPI combination were seen (DCR 50%). Clinical trial information: NCT03252938.

Abstract TP467: Effects of the Tortuosity of the Cervical Internal Carotid Artery on Procedural Outcomes of Stent Placement

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Iqra N Akhtar ◽  
Raza S Hyder ◽  
Vamshi Balasetti ◽  
Nitish Kumar ◽  
Jacqueline J Kraus ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Stent Placement ◽  
Internal Carotid ◽  
Consecutive Series ◽  
Complication Rates ◽  
Grade 5 ◽  
Vessel Tortuosity ◽  
Grade 3 ◽  
Cervical Internal Carotid Artery

Introduction: Severe tortuosity of the cervical internal carotid artery distal to the stenosis may prevent successful placement of distal protection device and increase the risk of dissection and/or ischemic stroke. Objective: To assess and categorize the effects of tortuosity of the cervical internal carotid artery distal on procedural times, and peri-procedural complications in patients treated with carotid artery stent placement. Material and Methods: We analyzed the angiographic images and clinical data for a consecutive series of patients treated with stent placement over an 18-month period and graded the tortuosity as follows: Grade 0 is no vessel turns; Grade 1 (MILD) is 1 vessel turn, >90 degrees; Grade 2 (MODERATE) is 1 vessel turn, ≤90 degrees; Grade 3 (SEVERE) is 2 vessel turns, any angle; Grade 4 (SEVERE) is two vessel segments which are parallel to due to interspersed loop; Grade 5 (SEVERE) is a complete vessel loop (360 degrees). Technical complications including unsuccessful attempts to cross the stenosis with interventional devices, unutilized distal embolic protection, iatrogenic dissection, and ischemic events were ascertained. Results: A total of 80 patients were identified who underwent stent placement; mean (SD) 67.4 (8), 60 (75%) were men. Forty-three patients (53.8%) had evidence of stroke on non-invasive imaging prior to stent placement. In sixty-five cases, stent placement was performed electively (81.3%), emergently in fifteen cases (18.8%). The tortuosity was graded as 1 (46.2%), 2 (11.3%), 3 (15%), 4 (6.3%), and 5 (2.5%). Of the 80 patients, eighteen (22.5%) had severe tortuosity of grade 3 or higher. Mean procedural time (SD) was significantly greater with severe vessel tortuosity compared to mild to moderate vessel tortuosity (51.6 (6.2) versus 42.3 (5.2) minutes, p=.042). Technical complication rates were not significantly different with severe vessel tortuosity compared with mild to moderate vessel tortuosity (7% vs 9% p=.53). One intra-procedural dissection occurred in a case of severe tortuosity (grade 5). Conclusions: Severely tortuous internal carotid arteries distal to the stenosis can be seen in one fifth of patients undergoing carotid stent placement and is associated with increased procedural times.

Orthodontic Treatment Need at Nishter Institute of Dentistry

2021 ◽  
Vol 15 (8) ◽  
pp. 1903-1905
Author(s):  
Muhammad Azeem ◽  
Zubair Hassan Awaisi ◽  
Sohaib Hassan ◽  
Farhan Ahmad ◽  
Saadia Ata ◽  
...  
Keyword(s):  
Orthodontic Treatment ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Treatment Need ◽  
Grade 5 ◽  
Present Cross Sectional Study ◽  
Grade 3 ◽  
Keywords Treatment ◽  
Plaster Models ◽  
Orthodontic Need

Background: The Index of Orthodontic Treatment Need (IOTN) is one of the important index to find out orthodontic need of patients. Aim: To find out the need of orthodontic treatment in patients visiting Nishter Institute of Dentistry, Multan (NID). Method: The index was applied using plaster models and intraoral examination. The measurements of various components of IOTN index was taken with the help of digital vernier calliper. Results: The results of various measurements of IOTN index was taken, recorded and analyzed statistically. Result of the present cross-sectional study showed that 65% patients were in grade 4 and 5 of IOTN. The analysis showed that 13% were in grade 4 of IOTN, 52% were in grade 5, 15% were in grade 3, 16% were in grade 2 and 4% patients was in grade 1 of IOTN index. Conclusion: No significant sex differences were shown for the need of orthodontic therapy in any category of IOTN. The need of orthodontic treatment is very high in patients of Southern Punjab, Pakistan. Keywords: Treatment Need; IOTN; Orthodontics.

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