Treatment with somatostatin analogues and prrt in metastatic middle ear adenoma with neuroendocrine features

SUMMARY: Middle ear adenomas with neuroendocrine features (ANEF) are rare, with an estimated 150 reported cases. They usually pursue an indolent clinical course. Four reported cases of middle ear ANEF with distant metastases were treated with surgery, external beam radiation therapy (EBRT) and chemotherapy. To date, no successful systemic treatment for malignant behaviour of this rare tumour has been reported. Long-acting somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) have been used in well-differentiated metastatic neuroendocrine tumours (NETs), but their use has never been described in cases of metastatic middle ear ANEF. We report two patients with grade 1 middle ear ANEF treated with surgery and EBRT. They had stable disease for several years, until clinical symptoms appeared and extensive metastases were detected on (68)Ga-DOTA(0)-Tyr(3)-octreotate (DOTATATE) PET/CT. Treatment with long-acting SSA was started, with stable disease for 1 year. Afterwards, despite undergoing local treatments, both patients presented progressive disease. Due to high-uptake metastases at (68)Ga-DOTATATE PET/CT, both cases underwent four cycles of PRRT with (177)Lu-DOTATATE, which secured disease control and improvement of quality of life in both. Similar to other well-differentiated NETs, SSA and PRRT could constitute efficacious therapeutic options in metastatic middle ear ANEF. Its neuroendocrine differentiation, potential to metastasize and somatostatin receptor type 2 expression prompt consideration and management of this disease as a neuroendocrine neoplasm. LEARNING POINTS: Our cases oppose the 2017 WHO classification of middle ear adenoma with neuroendocrine features as a benign disease. This entity warrants long-term follow-up, as local recurrence or persistence of disease is reported in up to 18% of surgically treated patients. PET/CT scan with (68)Ga-labelled somatostatin analogues (SSA) can be used for staging of metastatic middle ear adenoma with neuroendocrine features. Unlabelled SSA and peptide receptor radionuclide therapy (PRRT) with radiolabelled SSA can be the first systemic therapeutic options for patients with advanced middle ear adenoma with neuroendocrine features

The influence of adjuvant systemic regimens on contralateral breast cancer risk and receptor subtype

Background: An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC. Methods: This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes. Results: Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI]=3.7% to 4.0%). Overall, adjuvant chemotherapy (HR=0.70, 95% CI=0.62 to 0.80), endocrine therapy (HR=0.46, 95% CI=0.41 to 0.52), and trastuzumab with chemotherapy (HR=0.57, 95% CI=0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR=0.48, 95% CI=0.36 to 0.62) and aromatase inhibitors (HR=0.32, 95% CI=0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR=0.41, 95% CI=0.36 to 0.47) but not ER-negative CBC (HR=1.32, 95% CI=0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5years of follow-up (HR=2.84, 95% CI=1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC. Conclusion: Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction

Noise sensitivity of 89Zr-Immuno-PET radiomics based on count-reduced clinical images

PURPOSE: Low photon count in (89)Zr-Immuno-PET results in images with a low signal-to-noise ratio (SNR). Since PET radiomics are sensitive to noise, this study focuses on the impact of noise on radiomic features from (89)Zr-Immuno-PET clinical images. We hypothesise that (89)Zr-Immuno-PET derived radiomic features have: (1) noise-induced variability affecting their precision and (2) noise-induced bias affecting their accuracy. This study aims to identify those features that are not or only minimally affected by noise in terms of precision and accuracy. METHODS: Count-split (89)Zr-Immuno-PET patient scans from previous studies with three different (89)Zr-labelled monoclonal antibodies were used to extract radiomic features at 50% (S50p) and 25% (S25p) of their original counts. Tumour lesions were manually delineated on the original full-count (89)Zr-Immuno-PET scans. Noise-induced variability and bias were assessed using intraclass correlation coefficient (ICC) and similarity distance metric (SDM), respectively. Based on the ICC and SDM values, the radiomic features were categorised as having poor [0, 0.5), moderate [0.5, 0.75), good [0.75, 0.9), or excellent [0.9, 1] precision and accuracy. The number of features classified into these categories was compared between the S50p and S25p images using Fisher’s exact test. All p values < 0.01 were considered statistically significant. RESULTS: For S50p, a total of 92% and 90% features were classified as having good or excellent ICC and SDM respectively, while for S25p, these decreased to 81% and 31%. In total, 148 features (31%) showed robustness to noise with good or moderate ICC and SDM in both S50p and S25p. The number of features classified into the four ICC and SDM categories between S50p and S25p was significantly different statistically. CONCLUSION: Several radiomic features derived from low SNR (89)Zr-Immuno-PET images exhibit noise-induced variability and/or bias. However, 196 features (43%) that show minimal noise-induced variability and bias in S50p images have been identified. These features are less affected by noise and are, therefore, suitable candidates to be further studied as prognostic and predictive quantitative biomarkers in (89)Zr-Immuno-PET studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40658-022-00444-4

A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging

Background: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). Methods: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. Results: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. Conclusion: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. Trial registration: ClinicalTrials.gov, NCT02650817. Registered on 08 January 201

[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant

PURPOSE: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER+ breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant.PATIENTS AND METHODS: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES). Visual, quantitative and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS).RESULTS: The HS and PFS in the entire group did not correlate (n=16, Spearman's rho, P=0.06), but patients with a low HS (&lt;25.0%, n=4) had a PFS of &gt;5 months whereas patients with no [18F]FES uptake (HS 100.0%, n =3) had a PFS of &lt;2 months. [18F]FES uptake was not affected by ESR1 mutations. On-treatment [18F]FES PET/CT scans showed no [18F]FES uptake in any of the baseline [18F]FES positive lesions. At progression, [18F]FES uptake remained blocked in patients scanned ≤1-2 half-lives of rintodestrant whereas it restored in patients scanned ≥5 days after end of treatment.CONCLUSION: Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs.</p

Comparative biodistribution analysis across four different Zr-monoclonal antibody tracers-The first step towards an imaging warehouse

Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development. Molecular imaging with positron emission tomography (PET) can yield information in this setting. However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies. Methods: We compared the distribution of four 89Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89Zr-tracers and our delineation protocol. Results: The biodistribution patterns of 89Zr-lumretuzumab, 89Zr-MMOT0530A, 89Zr-bevacizumab and 89Zr-trastuzumab on day 4 after tracer injection were largely similar. The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines. About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney. Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain. Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion: The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways. These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions

RAS and BRAF mutations in cell-free DNA are predictive for outcome of cetuximab monotherapy in patients with tissue-tested RAS wild-type advanced colorectal cancer

In metastatic colorectal cancer, RAS and BRAF mutations cause resistance to anti-EGFR therapies, such as cetuximab. Heterogeneity in RAS and BRAF mutations might explain nonresponse in a subset of patients receiving cetuximab. Analyzing mutations in plasma-derived circulating tumor DNA (ctDNA) could provide a more comprehensive overview of the mutational landscape as compared to analyses of primary and/or metastatic tumor tissue. Therefore

Isolated Lung Metastases After Radical Nephrectomy for Clear Cell Carcinoma

Here we describe a case of a biologically indolent renal cell carcinoma. A single lung metastasis was found 1 yr after resection of a pT2bNxM0 Fuhrmann grade 2 tumor. After a further 1 yr, the patient was treated with IFN-alpha and bevacuzimab. Treatment for renal cell carcinoma should be tailored individually for each patient

Hepatosplenic candidiasis without prior documented candidemia: An underrecognized diagnosis?

Introduction. Patients with a history of chemotherapy or stem cell transplantation (SCT) and prolonged neutropenia are at risk for hepatic and/or splenic seeding of Candida. In our experience, hepatosplenic candidiasis (HSC) without documented candidemia often remains unrecognized. Case presentations.We describe three cases of HSC without documented candidemia and the challenges in establishing the diagnosis and adequately treating this condition. The first patient had a history of SCT for treatment of breast cancer and was scheduled for hemihepatectomy for suspected liver metastasis. A second opinion at our institute resulted in the diagnosis of hepatic candidiasis without prior documented candidemia, for which she was treated successfully with fluconazole. The second case demonstrates the limitations of (blood and tissue) cultures and the value of molecular methods to confirm the diagnosis. Case 3 illustrates treatment challenges, with ongoing dissemination and insufficient source control despite months of antifungal therapy, eventually resulting in a splenectomy. Literature review. A structured literature search was performed for articles describing any patient with HSC and documented blood culture results. Thirty articles were available for extraction of data on candidemia and HSC. Seventy percent (131/187) of patients with HSC did not have documented candidemia. The majority of HSC events were described in hematologic patients, although some cases were described in patients with solid tumors treated with SCT (n51) or chemotherapy and a history of leukopenia (n52). Current guidelines and practices for diagnosis and treatment are described. Conclusion. Clinicians should be aware that HSC most often occurs without documented candidemia. In case of persistent or unexplained fever or lesions in the liver and/or spleen, a history of neutropenia should place disseminated candidiasis in the differential diagnosis. HSC is not limited to hematological patients and may occur in patients with solid tumors treated with bone marrow-suppressing chemotherapy or SCT. In the latter group, HSC as alternative diagnosis for hepatic metastasis should be considered when lesions are not typical for metastasis. This might prevent unnecessary surgery or inappropriate treatment