Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which can be administered intralesionally in patients with stage IIIB/C‐IVM1a unresectable melanoma (EMA label). ...The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET‐CT and histological biopsies for response evaluation. Median follow‐up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1–2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza‐like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T‐VEC. Best ORR for T‐VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T‐VEC in early metastatic (stage IIIB/C‐IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.
What's new?
Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which is registered for the treatment of stage IIIB/C‐IVM1a unresectable locally advanced melanoma. Here the authors evaluated the response to this drug in 26 patients with a follow up longer than 6 months. They demonstrate promising response rates, with 61.5% of their treated patients achieving a CR. This indicates a strong potential of this novel drug in the rapidly developing field of immunotherapeutic treatment of melanoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Merkel cell carcinoma (MCC) is a cutaneous tumor with a high tendency to metastasize, and a significant proportion of patients have metastases at first presentation. This study aims to ...determine the value of baseline ultrasound (US) and 18fluorodeoxyglucose‐positron emission tomography/computed tomography (18FDG‐PET/CT) imaging in both patients with clinically localized MCC (Stage I/II) and patients who present with palpable lymph nodes (Stage III).
Methods
This retrospective cohort included 135 MCC patients who underwent baseline US (with fine needle aspiration cytology (FNAC)) and/or FDG‐PET/CT imaging between 2015 and 2021.
Results
Of the 104 patients with clinically localized disease, 48% were upstaged to Stage III and 3% to Stage IV by imaging or sentinel lymph node biopsy (SLNB). FDG‐PET/CT imaging identified regional metastases in 23%, while US with FNAC identified regional metastases in 19%. SLNB was performed in 56 patients, of whom 57% were upstaged to Stage III. Of the 31 patients who presented with palpable lymph nodes, 16% were upstaged to Stage IV by FDG‐PET/CT imaging.
Conclusion
Baseline imaging frequently upstages Stage I/II MCC patients to Stage III, both by US and FDG‐PET/CT, Stage IV disease is rarely identified. Patients who present with palpable nodes are frequently upstaged to Stage IV by FDG‐PET/CT imaging.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The role of surveillance imaging in high‐risk stage III melanoma patients after complete surgical resection remains controversial, and with the advent of adjuvant therapy, it may also be ...expanded. Therefore, we evaluated two fluorine‐18 fluorodeoxyglucose‐positron emission tomography/computed tomography (FDG‐PET/CT) protocols in two cohorts.
Methods
Cohort 1 (n = 35) focused on surveillance in asymptomatic patients (before approval and reimbursement of adjuvant therapy) and was assigned to 5x FDG‐PET/CT's after surgery: one every 6 months for 2 years, with one final scan after 3 years. Cohort 2 (n = 42) was assigned to one screening FDG‐PET/CT, which took place in between surgery and the start of adjuvant treatment.
Results
In cohort 1 (median follow‐up: 33 months), 12 patients (34.3%) developed recurrence detected by FDG‐PET/CT, of which 7 (20.0%) were detected with the first scan. Sensitivity and specificity were 92.3% and 100%, respectively. In cohort 2, recurrence was suspected on nine scans (21.4%) and four (9.5%) were true positive. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort 1 and 2, respectively.
Conclusions
FDG‐PET/CT is a valuable imaging tool to detect recurrence in stage III melanoma, even shortly after surgery. A surveillance FDG‐PET/CT protocol after surgery or a screening PET/CT before adjuvant therapy should be considered.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal ...melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy.
Methods
Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016–12 and 2020–01 with a follow-up time > 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR.
Results
A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting > 6 months) was 51%. Grade 1–2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions.
Conclusions
This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
The aim of the current study was to evaluate the relationship between the site of latest mechanical activation as assessed with gated myocardial perfusion SPECT (GMPS), left ventricular (LV) ...lead position and response to cardiac resynchronization therapy (CRT).
Methods
The patient population consisted of consecutive patients with advanced heart failure in whom CRT was currently indicated. Before implantation, 2-D echocardiography and GMPS were performed. The echocardiography was performed to assess LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). The site of latest mechanical activation was assessed by phase analysis of GMPS studies and related to LV lead position on fluoroscopy. Echocardiography was repeated after 6 months of CRT. CRT response was defined as a decrease of ≥15% in LVESV.
Results
Enrolled in the study were 90 patients (72% men, 67±10 years) with advanced heart failure. In 52 patients (58%), the LV lead was positioned at the site of latest mechanical activation (concordant), and in 38 patients (42%) the LV lead was positioned outside the site of latest mechanical activation (discordant). CRT response was significantly more often documented in patients with a concordant LV lead position than in patients with a discordant LV lead position (79% vs. 26%,
p
<0.01). After 6 months, patients with a concordant LV lead position showed significant improvement in LVEF, LVESV and LVEDV (
p
<0.05), whereas patients with a discordant LV lead position showed no significant improvement in these variables.
Conclusion
Patients with a concordant LV lead position showed significant improvement in LV volumes and LV systolic function, whereas patients with a discordant LV lead position showed no significant improvements.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Purpose
The aim of the current study was to evaluate the feasibility of phase analysis on gated myocardial perfusion SPECT (GMPS) for the assessment of left ventricular (LV) diastolic dyssynchrony in ...a head-to-head comparison with tissue Doppler imaging (TDI).
Methods
The population consisted of patients with end-stage heart failure of New York Heart Association functional class III or IV with a reduced LV ejection fraction of ≤35%. LV diastolic dyssynchrony was calculated using TDI as the maximal time delay between early peak diastolic velocities of two opposing left ventricle walls (diastolic mechanical delay). Significant LV diastolic dyssynchrony was defined as a diastolic mechanical delay of >55 ms on TDI. Furthermore, phase analysis on GMPS was performed to evaluate LV diastolic dyssynchrony; diastolic phase standard deviation (SD) and histogram bandwidth (HBW) were used as markers of LV diastolic dyssynchrony.
Results
A total of 150 patients (114 men, mean age 66.0 ± 10.4 years) with end-stage heart failure were enrolled. Both diastolic phase SD (
r
= 0.81,
p
< 0.01) and diastolic HBW (
r
= 0.75,
p
< 0.01) showed good correlations with LV diastolic dyssynchrony on TDI. Additionally, patients with LV diastolic dyssynchrony on TDI (>55 ms) showed significantly larger diastolic phase SD (68.1 ± 13.4° vs. 40.7 ± 14.0°,
p
< 0.01) and diastolic HBW (230.6 ± 54.3° vs. 129.0 ± 55.6°,
p
< 0.01) as compared to patients without LV diastolic dyssynchrony on TDI (≤55 ms). Finally, phase analysis on GMPS showed a good intra- and interobserver reproducibility for the determination of diastolic phase SD (ICC 0.97 and 0.88) and diastolic HBW (ICC 0.98 and 0.93).
Conclusion
Phase analysis on GMPS showed good correlations with TDI for the assessment of LV diastolic dyssynchrony.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Background
The role of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the ...correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS).
Methods
Patients with the above histological subtypes in three participating institutions with preoperative 18F‐FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse‐free survival (RFS) and overall survival (OS) were also studied.
Results
Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2–33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003).
Conclusion
There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
Sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive technique for nodal staging. Since associated morbidity is not negligible, it is highly relevant to pursue a more ...minimally invasive alternative. The purpose of this study was to prospectively evaluate the sensitivity of fine needle aspiration cytology (FNAC) with combined gamma probe and ultrasound (US) guidance in comparison with the gold standard histology of the sentinel node (SN) after SLNB for detecting metastasis.
Methods
The study was designed as a prospective, multicentre, open-label, single-arm trial enrolling patients with newly diagnosed cutaneous melanoma or breast cancer between May 2015 and August 2017. Sample radioactivity was measured using a Mini 900 scintillation monitor. After FNAC, all patients underwent SLNB. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated.
Results
Accrual was terminated early following an unplanned interim analysis indicating that a FNAC sensitivity of at least 80% could not be achieved. In total 58 patients of the originally planned 116 patients underwent FNAC with gamma probe and US guidance. There were no true-positive FNAC results, 14 false-negative results and one false-positive result, and thus the sensitivity, specificity, PPV and NPV of FNAC were 0%, 98%, 0% and 75%, respectively. At least 75% of the FNAC samples had a radioactivity signal higher than the background signal.
Conclusion
FNAC with gamma probe and US guidance is not able to correctly detect metastases in the SN and is therefore not able to replace SLNB. Gamma probe-guided US is a highly accurate method for correctly identifying the SN, which offers possibilities for future research.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Purpose
Vascular stiffness may potentially be used as a screening tool to identify asymptomatic patients with diabetes with abnormal myocardial perfusion. The purpose of this study was therefore to ...determine the association between vascular stiffness, measured in term of pulse wave velocity (PWV) and augmentation index (AIx), and abnormal myocardial perfusion imaging (MPI) in asymptomatic patients with diabetes.
Methods
Prospectively, 160 asymptomatic patients with diabetes (mean age 51 years, 87 men) underwent MPI with adenosine stress. The summed stress score (SSS) was determined in each patient according to a 17-segment and five-point score. Abnormal MPI (SSS ≥3) was classified as moderate (SSS 3–7) or severe (SSS ≥8) MPI defects. Using applanation tonometry, the carotid–femoral PWV and the radial AIx corrected to 75 beats per minute were determined noninvasively.
Results
MPI was abnormal in 61 patients (38%), with severe MPI defects in 22 patients (14%). Mean PWV increased with deteriorating MPI from 8.4 ± 2.2 m/s in normal MPI to 9.0 ± 2.2 m/s in moderate MPI defects (
p
= 0.11) and to 11.1 ± 2.5 m/s in severe MPI defects (
p
< 0.01). Likewise, mean AIx increased from 18.4 ± 13.4% to 19.4 ± 10.7% (
p
= 0.66) and to 25.4 ± 9.0% (
p
= 0.03). After adjustment for age and other risk factors, PWV remained a significant predictor of severe MPI defects (
p
= 0.01, OR 1.50, 95% CI 1.11–2.00), whereas AIx was no longer significant (
p
= 0.20).
Conclusion
Vascular stiffness measured by PWV is associated with severe MPI defects in asymptomatic patients with diabetes.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly ...improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with
F-Fluorodeoxyglucose (
F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of
F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment.
F-Fluoro-3'-deoxy-3'L-fluorothymidine (
F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than
F-FDG.
This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo
F-FDG PET/CT and in 25 patients additional
F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.
The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both
F-FDG and
F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment.
Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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