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Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5–7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

BACKGROUND: The prognostic value of preoperative fluorine-18-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) scan for determining overall survival (OS) in breast cancer (BC) patients is controversial. AIM: To evaluate the OS predictive value of preoperative PET positivity after 15 years. METHODS: We performed a retrospective search of the Universitair Ziekenhuis Brussel patient database for nonmetastatic patients who underwent preoperative PET between 2002-2008. PET positivity was determined by anatomical region of interest (AROI) findings for breast and axillary, sternal, and distant sites. The prognostic role of PET was examined as a qualitative binary factor (positive vs negative status) and as a continuous variable [maximum standard uptake value (SUVmax)] in multivariate survival analyses using Cox proportional hazards models. Among the 104 identified patients who received PET, 36 were further analyzed for the SUVmax in the AROI. RESULTS: Poor OS within the 15-year study period was predicted by PET-positive status for axillary (P = 0.033), sternal (P = 0.033), and combined PET-axillary/sternal (P = 0.008) nodes. Poor disease-free survival was associated with PET-positive axillary status (P = 0.040) and combined axillary/sternal status (P = 0.023). Cox models confirmed the long-term prognostic value of combined PET-axillary/sternal status [hazard ratio (HR): 3.08, 95% confidence interval: 1.42-6.69]. SUVmax of ipsilateral breast and axilla as continuous covariates were significant predictors of long-term OS with HRs of 1.25 (P = 0.048) and 1.54 (P = 0.029), corresponding to relative increase in the risk of death of 25% and 54% per SUVmax unit, respectively. In addition, the ratio of the ipsilateral axillary SUVmax over the contralateral axillary SUVmax was the most significant OS predictor (P = 0.027), with 1.94 HR, indicating a two-fold relative increase of mortality risk. CONCLUSION: Preoperative PET is valuable for prediction of long-term survival. Ipsilateral axillary SUVmax ratio over the uninvolved side represents a new prognostic finding that warrants further investigation.

PD-1 Immune checkpoint inhibitors, such as Pembrolizumab, can have a durable beneficial therapeutic effect in patients with advanced melanoma. However, not all patients will benefit equally from these therapies, and (potentially life-threatening) immune-related adverse events may occur. In this study, we investigate the value of early response assessment by FDG-PET/CT as a biomarker for predicting survival. We identified all patients with advanced melanoma who were treated with Pembrolizumab in our medical center and underwent a baseline and at least one follow-up FDG-PET/CT. The total metabolic tumor volume (TMTV) was calculated, and the evolution was compared to survival parameters. A total of 77 patients underwent a baseline and at least one follow-up FDG-PET/CT, 36 patients had follow-up imaging within 2–4 months, and 21 patients an FDG-PET/CT 5–6 months after baseline. When the TMTV evolution was categorized into two subgroups (stable/decrease versus increase), an association was found between stability or decrease in TMTV and better PFS and OS. A similar trend, however non-significant, was observed at 5–6 months. The evolution in TMTV as assessed by FDG-PET/CT 2–4 months after treatment initiation is associated with long-term outcomes in patients with advanced melanoma treated with Pembrolizumab.

BACKGROUND Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021). METHODS Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w. RESULTS 20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing. CONCLUSION Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.

BACKGROUND: The objective of this study was to evaluate if 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)-derived parameters are useful in predicting response and survival after programmed cell death protein 1 (PD-1) blocking immunotherapy in patients with advanced NSCLC characterized by a high programmed death-ligand 1 (PD-L1) expression (≥50%) on immunohistochemistry. PATIENTS AND METHODS: In 30 patients with advanced stage IV non-small-cell lung cancer (NSCLC) and high PD-L1 expression, 18F-FDG PET/CT parameters before start of treatment with PD-1 blocking immunotherapy were evaluated retrospectively. In 24 out of the 30 patients, 18F-FDG PET/CT was available 8 to 9 weeks after start of the treatment. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and metabolic responses assessed on 18F-FDG PET/CT were compared. RESULTS: Median follow-up was 20 months (range, 4.2-37.6). Median PD-L1 expression was 80%. The objective response rate with RECIST 1.1 was 53.3%. Median progression-free survival (PFS) was 12.4 months (95% confidence interval [CI], 1.0-37.8), and median overall survival (OS) was 14.9 months (95% CI, 2.4-38.2). Baseline 18F-FDG PET/CT parameters did not differ between responders and non-responders (all P > .05). The maximum standardized uptake value (SUVmax) was the only 18F-FDG PET/CT parameter associated with PFS (P = .04), with a trend for OS (P = .06). At first evaluation, response according to total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were associated with PFS and OS (both P < .0001). This was not the case for RECIST 1.1 (P = .29 for PFS and P = .38 for OS). CONCLUSION: Clinical response and survival were independent from metabolic tumor volume at baseline. Reduction of metabolic tumor volume after 8 to 9 weeks of treatment was a better predictor for prolonged survival than RECIST 1.1.

Introduction:131I-GMIB-Anti-HER2-VHH1 is a targeted radionuclide theranostic agent directed at HER2 expressing cancers. VHH1 is a single domain antibody fragment covalently linked to therapeutic radio-iodine 131I via the linker SGMIB. The Phase I study presented was aimed at evaluating the safety, biodistribution, radiation dosimetry and tumor imaging potential of 131I-GMIB-Anti-HER2-VHH1 in healthy volunteers and breast cancer patients. Methods: In a first cohort, six healthy volunteers were included. The biodistribution of 131I-GMIB-Anti-HER2-VHH1 was assessed using whole body (anterior and posterior) planar images obtained at 40 min., 2, 4, 24 and 72 h following i.v. administered (38 ± 9 MBq) 131I-GMIB-VHH1. Imaging data were analyzed using OLINDA/EXM software 1.0 to determine the dosimetry. Blood and urine samples were obtained over 72h. In the second cohort, three patients with metastatic HER2 positive breast cancer were included. Planar whole-body imaging was performed at 2 h and 24 h after injection. Additional SPECT/CT images were obtained following the whole body images at 2 and 24 h in case of relevant uptake in known cancer lesions Results: No drug related adverse events (AEs) were observed throughout the study. The biological half-life of 131I-GMIB-Anti-HER2-VHH1 in healthy subjects was about 8 h. After i.v. administration, the compound is eliminated from the blood with a 2.5 h half-life. The drug is primarily eliminated via the kidneys. The drug was stable in circulation and there was no increased accumulation in thyroid or stomach. The absorbed dose to the kidneys was 1.54 ± 0.25 mGy/MBq, while to bone marrow 0.03 ± 0.01 mGy/MBq. SPECT/CT imaging in patients with advanced breast cancer showed focal uptake of 131I-GMIB-Anti-HER2-VHH1 in metastatic lesions. Conclusion: No AEs were observed after iv administration of 131I-GMIB-Anti-HER2-VHH1 at low activity. Unbound drug is rapidly eliminated via the kidneys. In patients with stage IV HER2 positive breast cancer accumulation of 131I-GMIB-Anti-HER2-VHH1in metastatic sites was observed. Dosimetry predicts kidneys as the dose limiting organ upon dose escalation, but kidney toxicity should only occur at very high injected activities. Dose escalation is planned in a subsequent phase I/II study to assess the therapeutic window of this compound (NCT04467515).

Purpose: To evaluate the overall survival prognostic value of preoperative 18F-fluorodeoxyglucose positron emission tomography (PET) in breast cancer, as compared with the lymph node ratio (LNR). Methods: Data were abstracted at a median follow-up 14.7 years from a retrospective cohort of 104 patients who underwent PET imaging before curative surgery. PET-Axillary|Sternal was classified as PET-positive if hypermetabolism was visualized in ipsilateral nodal axillary and/or sternal region, else as PET-negative. The differences of 15 years restricted mean survival time ∆ RMST according to PET and LNR were computed from Kaplan–Meier overall survival. The effect of PET and other patients' characteristics was analyzed through rankit normalization, which provides with Cox regression the Royston–Sauerbrei D measure of separation to compare the characteristics (0 indicating no prognostic value). Multivariate analysis of the normalized characteristics used stepwise selection with the Akaikeinformation criterion. Results: In Kaplan–Meier analysis, LNR > 0.20 versus ≤ 0.20 showed ∆ RMST = 3.4 years, P = 0.003. PET-Axillary|Sternal positivity versus PET-negative showed a ∆ RMST = 2.6 years, P = 0.008. In Cox univariate analyses, LNR appeared as topmost prognostic separator, D = 1.50, P < 0.001. PET ranked below but was also highly significant, D = 1.02, P = 0.009. In multivariate analyses, LNR and PET-Axillary|Sternal were colinear and mutually exclusive. PET-Axillary|Sternal improved as prognosticator in a model excluding lymph nodes, yielding a normalized hazard ratio of 2.44, P = 0.062. Conclusion: Pathological lymph node assessment remains the gold standard of prognosis. However, PET appears as a valuable surrogate in univariate analysis at 15-year follow-up. There was a trend towards significance in multivariate analysis that warrants further investigation.

Simple Summary MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. We hypothesized that a low dose of the BRAF-inhibitor dabrafenib can mitigate the skin toxicity associated with a full dose of the MEK-inhibitor trametinib in patients with advanced NRASQ61R/K/L mutant melanoma who progressed after treatment with immune checkpoint inhibitors. The results of this two-stage phase 2 trial show that addition of a low dose of dabrafenib effectively mitigates the skin toxicity associated with trametinib. This combination is, however, insufficiently active in patients with advanced NRASQ61R/K/L mutant melanoma. The combination of low-dose dabrafenib plus full-dose trametinib can be of further interest for the treatment of MEK-inhibitor-sensitive tumors. Abstract Background: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma. Methods: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. Results: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. Conclusions: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.

The objective of this study was to evaluate ifIn 30 patients with advanced stage IV non-small-cell lung cancer (NSCLC) and high PD-L1 expression,Median follow-up was 20 months (range, 4.2-37.6). Median PD-L1 expression was 80%. The objective response rate with RECIST 1.1 was 53.3%. Median progression-free survival (PFS) was 12.4 months (95% confidence interval [CI], 1.0-37.8), and median overall survival (OS) was 14.9 months (95% CI, 2.4-38.2). BaselineClinical response and survival were independent from metabolic tumor volume at baseline. Reduction of metabolic tumor volume after 8 to 9 weeks of treatment was a better predictor for prolonged survival than RECIST 1.1.

Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. Results: 183 patients were included (stage IV 85.2%, WHO performance status &ge, 1 31.1%, pembrolizumab first-line 25.7%), of whom 112 underwent baseline 18F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) &ge, 2ULN (upper limit of normal), CRP &ge, 10ULN, or ALC &lt, 750/mm3 delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV &ge, 80 mL encompassed 17/21 patients with LDH &ge, 2ULN, CRP &ge, 750/mm3. No significant associations were observed between baseline GEP scores and survival. Conclusion: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

We report a case of anti-protein death 1-induced sarcoid-like reaction in a 63-year-old Caucasian male who was diagnosed with stage IV-M1a melanoma. He was initially treated with pembrolizumab monotherapy (Q3W) and had a complete response after 14 cycles. However, relapse was suspected 3 months later with appearance of hilar, mediastinal and hepatic hilar lymph nodes as well as a skin lesion. Biopsy of both the hilar lymph nodes and the skin lesion demonstrated sarcomatoid granulomatosis. Pembrolizumab was discontinued temporarily. While on F-FDG-PET/CT, all sarcoid-like lesions regressed in size and activity, a new hypermetabolic solitary skeletal lesion was detected in a lumbar vertebra, suspicious for metastasis. However, since the patient was asymptomatic, a watchful-waiting attitude was taken. During this period, a spontaneous and complete resolution of the metabolic activity was observed of the skeletal lesion. Until today, the patient remains in complete remission. Current case presents an atypical presentation and evolution of anti-PD-1-induced sarcoid-like reaction, illustrating the difficulty of differentiating it from disease progression. Before considering (re-)initiation of anti-melanoma therapy, a tissue biopsy of one of the suspected lesions may be performed to confirm diagnosis. Physicians treating patients with ICI should be aware of this difficulty and critically assess the nature of lesions suspect of progression in patients responding to ICI and presenting with a sarcoid-like reaction.

To evaluate the overall survival prognostic value of preoperativeData were abstracted at a median follow-up 14.7 years from a retrospective cohort of 104 patients who underwent PET imaging before curative surgery. PET-Axillary|Sternal was classified as PET-positive if hypermetabolism was visualized in ipsilateral nodal axillary and/or sternal region, else as PET-negative. The differences of 15 years restricted mean survival time ∆In Kaplan-Meier analysis, LNR 0.20 versus ≤ 0.20 showed ∆Pathological lymph node assessment remains the gold standard of prognosis. However, PET appears as a valuable surrogate in univariate analysis at 15-year follow-up. There was a trend towards significance in multivariate analysis that warrants further investigation.

This retrospective-observational study hypothesizes that preoperative 18FDG-PET for breast cancer has significant prognostic value for the prediction of survival. Data from patients who had breast surgery and had a preoperative FDG-PET examination at the UZ Brussel in 2002-2008 and in 2009-2015 will be analyzed without restriction on age or sex. Data collection for the cohort 2002-2008 has been finalized and will be shared on Mendeley (Reserved DOI: 10.17632/sfvtmrd8z9.1 ). Data for the cohort 2009-2015 will be collected by end of 2020. Detailed and referred to in: # Breast cancer preoperative 18FDG-PET, overall survival prognostic separation compared with the lymph node ratio. # Vinh-Hung V, Everaert H, Gorobets O, Van Parijs H, Verfaillie G, Vanhoeij M, Storme G, Fontaine C, Lamote J, Perrin J, Farid K, Nguyen NP, Verschraegen C, De Ridder M. # Breast Cancer. 2021 Jul;28(4):956-968. doi: 10.1007/s12282-021-01234-z # PMID: 33689151 https://link.springer.com/article/10.1007%2Fs12282-021-01234-z # Is there a utility of [18F]FDG-PET before surgery in breast cancer? A 15-years overall survival analysis. # Perrin, Farid K, Van Parijs H, Gorobets O, Vinh-Hung V, Nguyen NP, Djassemi N, De Ridder M, Everaert H. # World J Clin Oncol. Pending. Study registration: https://www.isrctn.com/ISRCTN17962845

2534 Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has low activity in recurrent glioblastoma (rGB). Intratumoral (IT) and intracavitary (IC) administration of IPI and NIVO is under evaluation in the GlITIpNi phase I clinical trial. Methods: Patients (pts) with resectable rGB were recruited to cohorts C1, C2 and C4; pts with non-resectable rGB were recruited in C3 (biopsy only). IT administration (brain tissue lining the resection cavity during surgery) of IPI (10 mg)(C1), or IPI (5 mg) plus NIVO (10 mg)(C2, C3 and C4), was followed by IC administration of NIVO at escalating doses of 1, 5 or 10 mg Q2w in both C3 and C4 (via an Ommaya reservoir). In all cohorts, pts received 10 mg NIVO IV Q2w (6x in C1/C2, and 12x in C3/C4). Corticosteroids were contraindicated. Results: Forty-six pts (31 male; median age 56y (38-74); IDH1 R132H mutation in 2 pts in C1/C2; NGS somatic mutation analysis for C3/C4 ongoing) with rGB following resection, RT and temozolomide were enrolled (3, 24, 13 and 6 pts in C1, C2, C3 and C4, respectively). All pts received IT administrations. Pts in C1/C2 received a median of 5 IV NIVO administrations. Study treatment has been completed in all pts in C1/C2, in 9 pts in C3, and in 3 pts in C4; pts received a median of 4 (0-10) and 3 (0-7) postoperative IC/IV administrations in C3 and C4, respectively. Two pts in C2 and 1 pt in C3 had an increased perilesional cerebral edema (G3) with neurological deterioration after surgery/IT-injection, that was reversible with steroids. Most frequent AE were fatigue (32 pts, 64%), fever (20 pts, 44%), and headache (25 pts, 50%). In 4 pts from C3, the Ommaya was removed because of bacterial colonization (asymptomatic). There were no G5 AE. There was no dose/AE correlation with increasing IC NIVO doses in C3/C4. Repetitive CSV analysis during therapy (C3/C4) revealed increased lymphocyte counts in 4 pts; scRNA- and TCR-sequencing is ongoing. Gene expression profiling for C1/C2, and pharmacokinetic analysis of NIVO and IPI in CSV for C3/C4 are ongoing. After a median FU of 62w (16-165) for pts in C1/C2, 16 pts have died; median OS is 71w (95% CI 8-134), 1- and 2y-OS% are respectively 51% (95% CI 31-71), and 34% (95% CI 10-59). OS compares favorably to a historical cohort of Belgian rGB pts (n = 469; Log-Rank p .001). After a median FU of 10w (1-37) for pts in C3/C4, 2 pts have died; median OS has not been reached. One pt in C3 achieved a PR that is ongoing at 12m. Conclusions: IT/IC administration of NIVO and IPI is feasible and sufficiently safe to warrant further investigation in pts with rGB. Clinical trial information: NCT03233152 .

A 49-year-old male with Ewing sarcoma and bone, pleural, lung and mediastinal lymph node metastasis was treated with cabozantinib after four lines of previous systemic treatments. He responded objectively and subjectively well for 8 months. In this heavily pretreated patient, the daily starting dose of 60 mg had to be reduced to 30 mg because of adverse events. We conclude that treatment with cabozantinib administered in further-line was active in this particular patient with metastatic Ewing sarcoma. The underlying mechanism of action remains unclear. Because of a stable disease on a long-term treatment with pazopanib targeting an anti-angiogenic pathway common to both drugs previously administered in this patient, it is hypothesized that the action of cabozantinib could be ascribed to its action on the non-common receptors AXL and c-Met. The potential of cabozantinib should be further investigated more upfront in this disease either alone or in combination with other systemic treatments.

e22041 Background: Pembrolizumab (PEMBRO) improves survival in advanced melanoma (MEL). This research investigates baseline (BL) biomarkers that predict long-term benefit on PEMBRO monotherapy. Methods: Outcome data on patients (pts) with advanced cutaneous/mucosal MEL treated with PEMBRO in our institution were collected after pt consent. Responses were evaluated using the immune-related response criteria. Total metabolic tumor volume (TMTV), assessed by 18-fluorodeoxyglucose positron emission tomography/computed tomography, was calculated as the sum of all tumor-associated voxels with a standardized uptake value (SUV) above the mean SUV measured in a reference region in normal liver tissue plus 3 standard deviations using Syngo.via software (Siemens Healthcare). The NanoString PanCancer IO360 panel was used for gene expression profiling (GEP). Results: A total of 196 pts was included in this analysis (median age 60; cutaneous 86%, mucosal 3%, unknown primary 12%; stage III 14%, IV-M1a/b/c 60%, IV-M1d 26%; first-line 24%). Median progression-free survival (PFS) in the population was 20.4 w (95% CI 10.2-30.7); median overall survival (OS) was 143.6 w (95% CI NR-NR). BL WHO Performance Status (PS) > 0 (HR 1.63 [95% CI 1.13-2.37]), C-reactive protein (CRP) > ULN (HR 1.92 [95% CI 1.33-2.77]), absolute lymphocyte count (ALC) < 750/mm³ (HR 2.45 [95% CI 1.32-4.55]) and > 1 metastatic site (HR 1.84 [95% CI 1.23-2.77]) were associated (P≤0.01) with worse PFS in multivariate analysis (Cox regression); BL WHO PS > 0 (HR 2.77 [95% CI 1.82-4.24]), lactate dehydrogenase (LDH) > ULN (HR 1.80 [95% CI 1.16-2.79]) and > 1 metastatic site (HR 1.95 [95% CI 1.16-3.25]) were associated with worse OS (P≤0.011). BL TMTV data were available in 118 pts (60%): BL CRP > ULN (HR 1.83 [95% CI 1.13-2.96]), ALC < 750/mm³ (HR 2.49 [95% CI 1.02-6.08]), > 1 metastatic site (HR 1.71 [95% CI 1.04-2.82]) and BL corticosteroid use (HR 4.62 [95% CI 1.38-15.45]) were associated with worse PFS (P < 0.05). BL WHO PS > 0 (HR 2.82 [95% CI 1.57-5.08]), ALC < 750/mm³ (HR 2.62 [95% CI 1.06-6.51]), history of brain metastases (HR 2.59 [95% CI 1.37-4.91]) and TMTV > 80 mL (HR 3.56 [95% CI 1.82-6.95]) were all associated with worse OS (P≤0.038). GEP data on a representative BL tumor sample were available in 27 pts (14%). Higher apoptosis signature scores were associated with increased probability of OS (HR 0.45 [95% CI 0.33-0.73], P < 0.01). Conclusions: BL TMTV > 80 mL identifies a subgroup of advanced MEL pts with worse outcome on PEMBRO. Increased apoptosis gene signature scores in a subset of patients predict increased OS.

Background: Human epidermal growth factor receptor 2 (HER2) status is an important predictive biomarker in breast cancer (BC). Tumor heterogeneity has been described, with changes in HER2 expression levels between lesions and over the disease course. HER2 expression is assessed on tissue biopsies, at primary diagnosis and in metastatic lesions. A whole-body imaging technique such as PET/CT could help understand expression levels in different lesions. A 68Ga-labeled single domain antibody (sdAb) targeting the HER2 receptor has been developed and proven safe (Keyaerts et al., 2016). Imaging is performed at 90 min post-injection (pi). We report results of a phase II trial to assess the repeatability of the technique in 20 patients and the correlation of tracer uptake with HER2 tissue expression of the lesions present at the time of imaging. Methods: Twenty patients (pts) with a locally advanced or metastatic BC with at least one lesion of minimum 12 mm were included. Pts were injected intravenously with a typical protein mass of 100 µg and a radioactive dose ranging from 98-168 MBq 68GaNOTA-anti-HER2 sdAb. PET/CT images were obtained at 90 min pi. A second tracer injection followed by PET/CT was done with a maximal interval of 8 days. To assess repeatability, up to 5 lesions per pt were selected, with no more than 2 in a single organ. Peak Standard Uptake Values (SUVpeak) of the lesions were measured on both scans and compared with a t-test and Bland-Altman Plots. Images were compared to other available medical or imaging data and interpreted considering the subject’s disease course. Serum and plasma samples were collected before injection and between 60 and 365 days pi and stored for future detection of anti-drug antibodies (ADA) and liquid biopsies analysis for the presence of HER2 amplification. Tissue samples were assessed by central labs using mass spectrometry, immunohistochemistry and in fluorescence situ hybridization. Results: Twenty women with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81) were included. Three pts were scanned only once (2 due to withdrawal of consent, 1 due to covid pandemic). Repeatability of the technique was visually scored as excellent. For quantification, 50 lesions were compared on both scans in 17 pts without significant differences between the two measurements (p=0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentage difference (MAPD) was 13.6%, comparable to repeat values reported for 18F-FDG. In 3 out of 6 HER2-positive (HER2+) patients, lesions showed high uptake, even better visible than using 18F-FDG in 2 of them. In 2 HER2+ subjects with a negative scan, lesions were confirmed to be true negatives: one patient did not relapse from BC but had tuberculosis; the other was confirmed to have a radiopneumonitis after radiotherapy and no relapse. In 1 HER2+ patient, the uptake was unexpectedly low. However, the HER2 status was also not reconfirmed in the metastatic setting for this subject. In 1 HER2-negative patient, the tumor HER2 status was changed from negative to positive based on a subsequent image-guided biopsy performed in this study. High tracer uptake was also seen in many of the patients presenting with HER2-low BC (IHC 1+ or 2+), indicating the potential of the tracer to detect low-level HER2 expression. Additional correlation to centrally performed tissue and blood analysis is ongoing. Conclusion: 68GaNOTA-Anti-HER2 PET/CT shows high uptake in HER2-expressing BC lesions but also in HER2-low lesions. The technique shows good repeatability and, in some cases, even better sensitivity than 18F-FDG PET/CT. Specificity was confirmed in relapse-free lesions such as tuberculosis and radiopneumonitis. Its sensitivity makes it a promising technique to assess HER2+ and HER2-low lesions in BC patients. Citation Format: Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, Marleen Keyaerts. Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-05.

BACKGROUND: Intracerebral (iCE) administration of nivolumab (NIVO) and ipilimumab (IPI) after resection of recurrent glioblastoma (rGB), followed by repeated intravenous(IV) NIVO was recently shown to be feasible, safe and associated with encouraging survival. Subsequent cohorts were defined to investigate the addition of biweekly intracavitary (iCA) or intrathecal (iTH) NIVO +/- IPI administrations. METHODS Four groups were defined according to rGB resectability and postoperative treatment schedule. Group A and D underwent biopsy, B and C maximal safe resection. All patients received iCE injections of 10 mg/1ml NIVO + 5 mg/1ml IPI at the end of surgery, after which an Ommaya catheter was implanted iCA (A, B and C) or iTH (D). Following surgery, all patients received biweekly IV low-dose NIVO(10mg) combined with iCA/iTH 10 mg NIVO (A and B) + 1, 5 or 10 mg IPI (C and D) for up to 24 weeks. NIVO/IPI concentrations were dosed in the cerebrospinal fluid (CSF). Gene sequencing and RNA gene expression profiling were performed on all tissue samples RESULTS 39pts(27 male; 16 in A, 16 in B, 4 in C, 3 in D; recruitment ongoing in C+D) were enrolled. All patients received the predefined dose of iCE IPI/NIVO. Most frequent AEs were fatigue (n=30), headache (n=19), confusion (n=14), dysphasia (n=13), and fever (n=10). Ommaya infection occurred in 5patients, subacute neurological deterioration requiring corticosteroids in 6patients. There were no G5 AEs. irAEs were infrequent and mild. Median PFS and OS were 5w(95% CI 1-8) and 23w(95% CI 0-53) in A and 13w(95% CI 7-19) and 42w(95% CI 30-54) in B, respectively. >90% of CSF samples had elevated protein levels and lymphocytic pleocytosis. There was no evidence for accumulation of NIVO/IPI in the CSF. CONCLUSION Repeated intracavitary or intrathecal administration of NIVO +/- IPI in rGB is feasible and safe. Favourable survival outcome is seen in patients amenable to surgical resection.

INTRODUCTION Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing. METHODS Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively. RESULTS 21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%). CONCLUSION This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.

Purpose: Macrophage mannose receptor (MMR, CD206) expressing tumor-associated macrophages (TAM) are protumorigenic and was reported to negatively impact therapy responsiveness and is associated with higher chances of tumor relapse following multiple treatment regimens in preclinical tumor models. Since the distribution of immune cells within the tumor is often heterogeneous, sampling Berrors^ using tissue biopsies will occur. In order to overcome this limitation, we propose positron emission tomography (PET)/X-ray computed tomography (CT) imaging using 68Ga-labeled anti-MMR single-domain antibody fragment (sdAb) to assess the presence of these protumorigenic TAM. Procedures: Cross-reactive anti-MMR-sdAb was produced according to good manufacturing practice (GMP) and conjugated to p-SCN-Bn-NOTA bifunctional chelator for 68Ga-labeling. Biodistribution and PET/CT studies were performed in wild-type and MMR-deficient 3LL-R tumor-bearing mice. Biodistribution data obtained in mice were extrapolated to calculate radiation dose estimates for the human adult using OLINDA software. A 7-day repeated dose toxicity study for NOTA-anti-MMR-sdAb was performed in healthy mice up to a dose of 1.68 mg/kg. Results: [68Ga]Ga-NOTA-anti-MMR-sdAb was obtained with 76 ± 2 % radiochemical yield, 99 ± 1 % radiochemical purity, and apparent molar activity of 57 ± 11 GBq/μmol. In vivo biodistribution analysis showed fast clearance via the kidneys and retention in MMR-expressing organs and tumor, with tumor-to-blood and tumor-to-muscle ratios of 6.80 ± 0.62 and 5.47 ± 1.82, respectively. The calculated effective dose was 0.027 mSv/MBq and 0.034 mSv/MBq for male and female, respectively, which means that a proposed dose of 185 MBq in humans would yield a radiation dose of 5.0 and 6.3 mSv to male and female patients, respectively. In the toxicity study, no adverse effects were observed. Conclusions: Preclinical validation of [68Ga]Ga-NOTA-anti-MMR-sdAb showed high specific uptake of this tracer in MMR-expressing TAM and organs, with no observed toxicity. [68Ga]Ga- NOTA-anti-MMR-sdAb is ready for a phase I clinical trial.

Background: Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. Methods: Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAF V600 and NRAS Q61/G12/G13 mutations. Results: After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. Conclusions: Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Macrophage mannose receptor (MMR, CD206) expressing tumor-associated macrophages (TAM) are protumorigenic and was reported to negatively impact therapy responsiveness and is associated with higher chances of tumor relapse following multiple treatment regimens in preclinical tumor models. Since the distribution of immune cells within the tumor is often heterogeneous, sampling "errors" using tissue biopsies will occur. In order to overcome this limitation, we propose positron emission tomography (PET)/X-ray computed tomography (CT) imaging usingCross-reactive anti-MMR-sdAb was produced according to good manufacturing practice (GMP) and conjugated to p-SCN-Bn-NOTA bifunctional chelator for[Preclinical validation of [

Background Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30-39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated. Methods Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue. Results Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1-4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2-152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029). Conclusion IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS. Trial registration NCT03233152., SCOPUS: ar.j, info:eu-repo/semantics/published

9529 Background: The mitogen-activated protein kinase (MAPK) pathway can be activated by alternative driver mutations in BRAFV600/ NRASQ61R/K/L wild-type (wt) melanoma. MEK-inhibitor monotherapy has activity in BRAFV600/ NRASQ61R/K/L wt melanoma, but is associated with considerate skin toxicity. Skin toxicity associated with the MEK-inhibitor trametinib (T) can be effectively mitigated by adding a low dose (50 mg BID) of the BRAF-inhibitor dabrafenib (LD-D) (Awada et al. Ann Oncol 2020). Methods: This two-stage, single-center phase 2 trial investigated T 2 mg QD in patients (pts) with advanced BRAFV600/ NRASQ61R/K/L wt melanoma who previously progressed on treatment with checkpoint inhibitors. In case of dose-limiting T-related skin toxicity, LD-D (50 mg BID) was added to T (pre-amend). The trial was amended in June 2019 to administer T upfront with LD-D (post-amend). Objective response rate (ORR, by RECIST v1.1) served as the primary endpoint. A Simon’s two-stage optimal design was used (p0 0.10; p1 0.30; alpha 0.05; power 0.80): in case of > 1 OR in the first 10 pts, 19 additional pts would be included in stage 2. The trial is considered positive if > 5 OR are observed. Results: As of February 9, 2021, 16 pts (3 pre-amend; 13 post-amend) were included (median age 56.5; male 56.3%; stage IIIB 6.3%, IV-M1a-c 68.8%, IV-M1d 25.0%; ECOG performance status 0-1 93.8%; normal lactate dehydrogenase 56.3%). Median duration of follow-up is 17.9 weeks (wks; range 1.9-90.1). The ORR in 14 evaluable pts is 42.9% (5 confirmed and 1 unconfirmed partial response), the disease control rate is 71.4%. Four OR are ongoing after a median follow-up of 8.0 wks (range 0.0-77.0), 2 responding pts progressed on therapy after respectively 16.6 and 24.0 wks. Four out of 6 OR are observed in pts with MAPK-pathway activating mutations (3 class II BRAF and 1 GNAQ mutation). Eight pts (50.0%) have progressed (median progression-free survival 16.4 wks [95% confidence interval [CI] 6.9-25.9]); 4 pts (25.0%) have died (median overall survival 54.7 wks [95% CI 37.6-71.8]). Adverse events (AE) are observed in all pts (grade [G] 3-4 9 [56.3%]). Two pre-amend pts added on LD-D due to dose-limiting T-related skin toxicity; no clinically relevant T-related skin toxicity was observed post-amend with the upfront addition of LD-D. The most frequent AE were creatine kinase increase (G1-2 11 [68.8%]; G3-4 1 [6.3%]), and anemia and acneiform rash (both G1-2 7 [43.8%]; G3-4 0). Therapy was temporarily interrupted due to AE in 11 pts (68.8%) and permanently interrupted in 1 pt (6.3%) due to recurrent pneumonitis. Conclusions: In this two-stage phase 2 trial, T plus LD-D was found to have promising antitumor activity and acceptable toxicity in pts with advanced pretreated BRAFV600/ NRASQ61R/K/L wt melanoma, especially in the presence of identifiable somatic MAPK-pathway activating mutations. Clinical trial information: NCT04059224.

Background: Intravenous (IV) administration of IPI and NIVO has low activity in patients (pts) with recurrent glioblastoma (rGB). IT administration of IPI and NIVO was safe in cohort C1 and C2 of the GlITIpNi phase I clinical trial (Schwarze et al. ASCO 2020, abstract #2534). In C3 and C4, IT administration of IPI and NIVO was followed by repeated IC and IV administrations of NIVO. Method(s): Pts with resectable rGB were recruited in C4; pts with non-resectable rGB in C3 (biopsy only). IT administration (in the brain tissue lining the resection cavity) of IPI (5 mg) plus NIVO (10 mg), was followed by IC-NIVO (through an Ommaya reservoir) at a dose of 1, 5 or 10 mg Q2w plus IV-NIVO (10mg) Q2w (max 12x). Cerebrospinal fluid (CSF) was collected prior to each drug administration for biochemical/cytological analysis, and concentration measurements of IPI and NIVO. NGS (RNA/DNA) was performed on resected tissue. Result(s): 32 pts (23 male; med age 55y [38-77]; IDH1 R132H mutation [n=2], 1p/19q LOH [n=1]) diagnosed with rGB were enrolled (C3 [n=17], C4 [n=15]). After a median FU of 37w (1-82w), study treatment is ongoing in 2 pts. All pts received the predefined IT dose of IPI and NIVO. Median number of IC/IV NIVO administrations in C3 and C4 were respectively 5 [1-12] and 4 [1-12]. Most frequent AEs were fatigue (n=27), headache (n=17), fever (n=9), and seizures (n=5). Bacterial colonization of the Ommaya reservoir requiring removal and antibiotic therapy occurred in 4 pts. There were no G5 AEs. In C3, 1 pt has an ongoing PR after 83w (best response was PD in all other 15 evaluable pts); 11 pts have died (due to PD; median OS is 38w [95% CI 9-61]). In C4, 3 pts remain relapse-free after 30, 31 and 32w; 5 pts have died (all due to PD; median OS not reached). In 5 (C3) and 6 (C4) pts, elevated protein levels as well as lymphocytic pleocytosis were documented. There was no evidence for accumulation of NIVO in the CSF during therapy. Cytokine, cfDNA analysis of CSF and NGS on tumor tissue are ongoing. Conclusion(s): IT administration of NIVO and IPI followed by IC/IV administration of NIVO was feasible and sufficiently safe to warrant further investigation in pts with rGB. Clinical trial identification: NCT03233152. Legal entity responsible for the study: Department of Medical Oncology, Universitair Ziekenhuis Brussel. Funding(s): Stichting Tegen Kanker. Disclosure: J.K. Schwarze: Travel/Accommodation/Expenses: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Amgen. G. Awada: Research grant/Funding (institution): Pfizer; Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Astellas. B. Neyns: Research grant/Funding (institution): Roche; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: EtheRNA; Advisory/Consultancy: CryoStorage; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck-Serono. All other authors have declared no conflicts of interest.Copyright © 2020 European Society for Medical Oncology

PURPOSE: To explore the preoperative utility of FDG PET for the diagnosis and prognosis in a retrospective breast cancer case series. METHODS: In this retrospective study, 104 patients who had undergone a preoperative FDG PET scan for primary breast cancer at the UZ Brussel during the period 2002-2008 were identified. Selection criteria were: histological confirmation, FDG PET performed prior to therapy, and breast surgery integrated into the primary therapy plan. Patterns of increased metabolism were recorded according to the involved locations: breast, ipsilateral axillary region, internal mammary chain, or distant organs. The end-point for the survival analysis using Cox proportional hazards was disease-free survival. The contribution of prognostic factors was evaluated using the Akaike information criterion and the Nagelkerke index. RESULTS: PET positivity was associated with age, gender, tumour location, tumour size >2 cm, lymphovascular invasion, oestrogen and progesterone receptor status. Among 63 patients with a negative axillary PET status, 56 (88.9 %) had three or fewer involved nodes, whereas among 41 patients with a positive axillary PET status, 25 (61.0 %) had more than three positive nodes (P < 0.0001). In the survival analysis of preoperative characteristics, PET axillary node positivity was the foremost statistically significant factor associated with decreased disease-free survival (hazard ratio 2.81, 95% CI 1.17-6.74). CONCLUSION: Preoperative PET axillary node positivity identified patients with a higher burden of nodal involvement, which might be important for treatment decisions in breast cancer patients.

INTRODUCTION Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing. METHODS Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively. RESULTS 21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%). CONCLUSION This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.

Background: Although one of the most frequent diagnosed mental illnesses worldwide, it appears to be challenging to successfully treat major depressive disorder (MDD). Although the phenomenon of treatment-resistant depression (TRD) still remains unclear, the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible neurobiological marker to evaluate clinical effects of a variety of antidepressant treatments, including repetitive transcranial magnetic stimulation (rTMS). Accelerated high-frequency (HF)-rTMS may have the potential to rapidly result in beneficial clinical outcomes in TRD. No studies yet examined the clinical effects of such accelerated stimulation treatment paradigms on sgACC regional glucose metabolism (CMRglc), nor the predictive value of the latter for clinical outcome. Objective: First, we investigated the predictive value of baseline sgACC metabolic activity for clinical outcome. Second, we hypothesized that in clinical responders only accelerated HF-rTMS treatment would result in significant metabolic decreases. Methods: We recruited right-handed antidepressant-free unipolar melancholic TRD patients to participate in a two-week randomized sham-controlled crossover HF-rTMS treatment study. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). Fifteen patients underwent 18FDG PET (CMRglc) at baseline (T0), after the first week (T1) of accelerated HF-rTMS and at the end of the treatment after the second week (T2). Results: Higher baseline sgACC metabolic activity may indicate beneficial clinical outcome to this kind of accelerated HF-rTMS treatment. Moreover, clinical response resulted in a significant decrease in sgACC CMRglc. Non-response did not affect sgACC CMRglc. Conclusions: Our results add to the sgACC as a specific neurobiological marker for anti-depressive response in accelerated HF-rTMS treatment paradigms. Such protocols may not only have the ability to result in fast clinical responses but they may also have potential to acutely modulate a dysfunctional sgACC.

Purpose: To compare using immuno-PET/CT the distribution of 89Zr-labelled rituximab without and with a preload of unlabelled rituximab to assess the impact of preloading with unlabelled rituximab on tumour targeting and radiation dose of subsequent radioimmunotherapy with 90Y-labelled rituximab in CD20+ B-cell lymphoma. Methods: Five patients with CD20+ B-cell lymphoma and progressive disease were prospectively enrolled. All patients underwent three study phases: initial dosimetric phase with baseline 89Zr-rituximab PET/CT imaging without a cold preload, followed 3 weeks later by a second dosimetric phase with administration of a standard preload (250 mg/m2) of unlabelled rituximab followed by injection of 89Zr-rituximab, and a therapeutic phase 1 week later with administration of unlabelled rituximab followed by 90Y-rituximab. PET/CT imaging and tracer uptake by organs and lesions were assessed. Results: With a cold rituximab preload, the calculated whole-body dose of 90Y-rituximab was similar (mean 0.87 mSv/MBq, range 0.82–0.99 mSv/MBq) in all patients. Without a preload, an increase in whole-body dose of 59 % and 87 % was noted in two patients with preserved circulating CD20+ B cells. This increase in radiation dose was primarily due to a 12.4-fold to 15-fold higher dose to the spleen without a preload. No significant change in whole-body dose was noted in the three other patients with B-cell depletion. Without a preload, consistently higher tumour uptake was noticed in patients with B-cell depletion. Conclusion: Administration of the standard preload of unlabelled rituximab impairs radioconjugate tumour targeting in the majority of patients eligible for radioimmunotherapy, that is patients previously treated with rituximab-containing therapeutic regimens. This common practice may need to be reconsidered and further evaluated as the rationale for this high preload has its origin in the “prerituximab era”. Clinical Trial Application: CTA 2011-005474-38 Trial Registry: EudraCT, SCOPUS: ar.j, info:eu-repo/semantics/published

Recurrent glioblastoma is a devastating disease for which no treatment has demonstrated to improve overall survival in a randomized clinical trial. Anti-tumor Cytolytic T-cell (CTL) activity is suppressed by the CTLA4 and PD-1 immune-checkpoint receptors. Nivolumab(NIVO) is an IgG-4 mAb that blocks PD-1, and ipilimumab(IPI) an IgG-1 mAb that blocks CTLA-4. In a clinical trial for recurrent glioblastoma (BMS CheckMate143), combination of NIVO and IPI administered IV caused unacceptable toxicity. Animal models showed that intratumoral administration of CTLA-4-blocking mAb at a ratio of [1:100] compared to IV-dosing had equivalent anti-tumor effect and was associated with improved tolerability. An ongoing phase I clinical trial for patients with recurrent glioblastoma (rGB) has currently recruited 5 patients: 2M, 3F, median age 60 (range 38-72). Study treatment consists of surgical resection of rGB with injection of IPI (10mg:2ml) (cohort 1 = first 3 patients) or IPI (5mg:1ml) plus NIVO (10mg:1ml) (cohort 2 = 2 patients at present) in the walls of the resection cavity, concomitant with biweekly IV-administration of 10 mg of NIVO x6. Grade 3 AE consisted of epileptic seizures (1pt in cohort 2) and hemiplegia due to accumulation of serosanguinous fluid in the resection cavity (1pt in cohort 2). Additionally, 4/5 patients developed transient grade 1 pyrexia during the postoperative period. Lymphopenia gr 3 was seen in 4/5 patients. All patients have persisting rim-contrast enhancement on MRI. After median follow-up of 22weeks, two patients have progression of disease (after respectively 13 and 19 weeks). All patients are alive. We conclude from these early results that surgical resection of rGB combined with direct intracerebral injection of IPI alone/with NIVO followed by IV administration of NIVO at the doses administered in this trial is feasible and safe. Updated results of this ongoing clinical trial will be presented at the meeting.

We describe a finding of unilaterally decreased binding of 123I-ioflupane in the basal ganglia in a 78-year-old woman that could be attributed to an underlying developmental venous anomaly.

Background: To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC ( 68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. Methods: A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. Results: A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1–29.0 ng/mL). A median dose of 43.5 Gy (range 30–64 Gy) was delivered by IMRT-IGRT in 12–27 fractions. At a median follow-up of 7 months (range 2–17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8–83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p

AIM: To investigate rates of distant metastases (DM) detected with [18]fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT) in early stage invasive breast cancer. METHODS: We searched the English language literature databases of PubMed, EMBASE, ISI Web of Knowledge, Web of Science and Google Scholar, for publications on DM detected in patients who had (18)FDG-PET/CT scans as part of the staging for early stages of breast cancer (stage I and II), prior to or immediately following surgery. Reports published between 2011 and 2017 were considered. The systematic review was conducted according to the PRISMA guidelines. RESULTS: Among the 18 total studies included in the analysis, the risk of DM ranged from 0% to 8.3% and 0% to 12.9% for stage I and II invasive breast cancer, respectively. Among the patients with clinical stage II, the rate of occult metastases diagnosed by (18)FDG-PET/CT was 7.2% (range, 0%-19.6%) for stage IIA and 15.8% (range, 0%-40.8%) for stage IIB. In young patients (< 40-year-old), (18)FDG-PET/CT demonstrated a higher prevalence of DM at the time of diagnosis for those with aggressive histology (i.e., triple-negative receptors and poorly differentiated grade). CONCLUSION: Young patients with poorly differentiated tumors and stage IIB triple-negative breast cancer may benefit from (18)FDG-PET/CT at initial staging to detect occult DM prior to surgery.

AIM OF THE STUDY: The aim of the study was to analyze the evolution of perfusion (Q)-defects in patients treated for acute pulmonary embolism (PE), correlation with baseline parameters and evaluation of recurrence risk. METHODS: This is a single-center prospective observational cohort study in symptomatic normotensive PE. Comparison of the ventilation/perfusion single-photon emission computed tomography (V/Q-SPECT) acquired at baseline with a quantified SPECT (Q-SPECT) repeated at 1 week and 6 months. The Q-defect extent (percentage of total lung volume affected) was measured semiquantitatively. Data collected at baseline were age, gender, body mass index (BMI), history of previous venous thromboembolism (HVTE), Charlson′s Comorbidity Score (CcS), plasma troponin-T and D-dimer levels, PE Severity Index, and tricuspid regurgitation jet (TRJ) velocity. RESULTS: Forty-six patients (22 men/24 women, mean age 61.7 years (± standard deviation 16.3)) completed the study. At 1 week, 13/46 (28.3 %) and at 6 months 22/46 (47.8%) patients had completely normalized Q-SPECT. Persistence of Q-defects was more frequent in female patients in univariate and multivariate analysis. We found no correlation between the persistence of Q-defects on Q-SPECT and HVTE, BMI, plasma troponin-T, and CcS. However, lower TRJ and younger age were statistically significantly linked to normalization of Q-scans after 6 months of treatment only in univariate analysis. There is no difference in the frequency of recurrent PE in relation to the persistence of Q-defects. CONCLUSION: Acute PE patients of female, older age, and higher TRJ in univariate analysis and patients of female in multivariate analysis seem to have a higher risk of persistent Q-defects after 6 months treatment. The presence of residual Q-abnormalities at 6 months was not associated with an increased risk for recurrent PE.

Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein which is frequently overexpressed on prostate cancer cells. Ga-PSMA PET/CT plays an increasing role in prostate cancer management. However, growing evidence suggests increased PSMA uptake in a variety of other malignant tumor entities and in some benign lesions. This report describes PSMA uptake in numerous thoracic lymph nodes in a patient with known mediastinal sarcoidosis. Knowledge and recognition of these possibilities are important to avoid scan misinterpretation.

BACKGROUND AND AIMS: 18F-fluoro-ethyl-tyrosine (FET) is a radiopharmaceutical used in positron emission tomography (PET)-computed tomography in patients with glioma. We propose an original approach combining a radiotracer-pharmacokinetic exploration performed at the voxel level (three-dimensional pixel) and voxel classification to identify tumor tissue. Our methodology was validated using the standard FET-PET approach and magnetic resonance imaging (MRI) data acquired according to the current clinical practices. METHODS: FET-PET and MRI data were retrospectively analyzed in ten patients presenting with progressive high-grade glioma. For FET-PET exploration, radioactivity acquisition started 15 min after radiotracer injection, and was measured each 5 min during 40 min. The tissue segmentation relies on population pharmacokinetic modeling with dependent individuals (voxels). This model can be approximated by a linear mixed-effects model. The tumor volumes estimated by our approach were compared with those determined with the current clinical techniques, FET-PET standard approach (i.e., a cumulated value of FET signal is computed during a time interval) and MRI sequences (T1 and T2/fluid-attenuated inversion recovery [FLAIR]), used as references. The T1 sequence is useful to identify highly vascular tumor and necrotic tissues, while the T2/FLAIR sequence is useful to isolate infiltration and edema tissue located around the tumor. RESULTS: With our kinetic approach, the volumes of tumor tissue were larger than the tissues identified by the standard FET-PET and MRI T1, while they were smaller than those determined with MRI T2/FLAIR. CONCLUSION: Our results revealed the presence of suspected tumor voxels not identified by the standard PET approach.

Ipilimumab, a CTLA-4-blocking monoclonal antibody, improved the overall survival (OS) of advanced melanoma patients treated in prospective clinical trials. We here report a study on the outcome of patients with pretreated advanced melanoma offered ipilimumab (at its licensed dose of 3 mg/kg, every 3 wk for a total of 4 doses) in an expanded access program at a single-center university hospital. Of the 50 patients initiating ipilimumab, 31 patients completed induction therapy and 9 patients were offered reinduction therapy. Most immune-related adverse events were mild and reversible. The best objective response rate by mWHO-criteria included 1 complete response and 4 partial responses (best objective response rate of 10%). Two additional patients obtained a partial response by immune-related response criteria. Median OS was 7 months, with a 1- and 2-year survival rate of 45.2% and 28.8%, respectively. Long-term disease control with ipilimumab was observed in 7 patients of which 4 received reinduction. Baseline serum C-reactive protein (CRP) and the absolute lymphocyte count (ALC) measured on week 6 significantly correlated with OS. In conclusion, in this single-center experience with ipilimumab for advanced pretreated melanoma patients, clinical outcome was comparable with the results of published prospective studies. Reinduction therapy was of importance for maintaining long-term disease control in the majority of responding patients. Baseline CRP and ALC at week 6 deserve further prospective evaluation as prognostic and/or predictive (surrogate) markers.

Ga-PSMA plays an increasing role in prostate cancer management, but several instances of false positivity have now been recognized. We present a patient with metastatic prostatic carcinoma who also showed overexpression of PSMA in Paget disease of the humerus on Ga-PSMA PET. This probably relates to bone remodeling and increased vascularity. It is important to be aware of this aspecific uptake because its recognition may avoid overstaging and may alter the therapeutic choice.