Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Case series of docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and ado-trastuzumab emtansine (T-DM1) as second line for recurrent or metastatic HER2-positive salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) overexpresses Human Epidermal growth factor Receptor 2 (HER2) in 29-46% of cases, favoring anti-HER2 therapy. Here, we present the results of patients with recurrent or metastatic HER2-positive SDC treated with docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and subsequently ado-trastuzumab emtansine (T-DM1) in second line. Furthermore, we searched for potential biomarkers. METHODS: Retrospective case series from a tertiary hospital. First line anti-HER2 treatment consisted of DTP, after progression T-DM1 was considered for patients with an adequate performance status. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed and related to mRNA-based PI3K and MAPK signaling pathway activity scores. RESULTS: Thirteen SDC HER2 + patients received DTP. In twelve evaluable patients, one complete response (CR) and six partial responses (PR) were observed (ORR 58%), with a median PFS of 6.9 months (95%-CI 5.3-8.5). Seven patients received subsequent T-DM1 in second line, resulting in four PR (ORR 57%), with a median PFS of 4.4 months (95%-CI 0-18.8). Median OS after start of DTP was 42.0 months (95%-CI 13.8-70.1). Grade ≥ 3 toxicity on DTP was seen in 39% of patients, and 14% on T-DM1. Highest combined PI3K and MAPK signaling was seen in the patient with CR and lowest in the patient with progressive disease on DTP. CONCLUSION: In R/M HER2-positive SDC patients DTP followed by T-DM1 upon progression are promising treatments, leading to responses in the majority (58%) of the patients at an acceptable toxicity profile.

PSMA radioligand therapy for solid tumors other than prostate cancer: background, opportunities, challenges, and first clinical reports.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

Informal caregiver well-being during and after patients' treatment with adjuvant chemotherapy for colon cancer: a prospective, exploratory study.

INTRODUCTION: Caring for a significant other during cancer treatment can be demanding. Little is known about the well-being of informal caregivers of patients with colon cancer. This study aims to examine informal caregiver well-being during adjuvant chemotherapy for colon cancer. MATERIAL AND METHODS: This exploratory longitudinal, prospective study measured the course of informal caregiver burden (Self-Perceived Pressure of Informal Care), distress (Hospital Anxiety and Depression Scale), health-related quality of life (RAND-36), marital satisfaction (Maudsley Marital Questionnaire), social support (Social Support List - Discrepancies), fatigue (Abbreviated Fatigue Questionnaire), and self-esteem (Caregiver Reaction Assessment) before (T0), during (T1), and after (T2) patients' treatment. RESULTS: Baseline data of 60 out of 76 eligible dyads (79%) were analyzed. Mean levels of informal caregiver burden and distress improved significantly over time, as did their health-related quality of life and perceived social support. At baseline, 30% and 26.7% of informal caregivers reported moderate-to-high levels of burden and clinically relevant levels of distress, respectively, which changed to 20% and 18.8% at T2. Informal caregiver burden and distress at baseline were the strongest predictors of informal caregiver burden and distress during and following patients' treatment, respectively. CONCLUSION: When informal caregivers and patients experience problems before start of adjuvant chemotherapy, problems seem to improve over time. Approximately 20% of informal caregivers remain burdened and distressed after patients' end of treatment. Paying attention to baseline distress and burden seems indicated, as these were strong predictors of informal caregivers' well-being during and after treatment.

Prospective practice survey of management of cetuximab-related skin reactions.

PURPOSE: Evidence-based guidelines on how to prevent or treat cetuximab-related skin reactions are lacking and multiple care and management strategies are used. The main purpose of the present study is to gain information about the different skincare products being used against skin reactions in metastatic colorectal cancer (mCRC) and recurrent/metastatic (R/M) or locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) patients treated with cetuximab. METHODS: An open-label, prospective observational study conducted in the Netherlands. The occurrence of skin reactions and the care and management options taken were documented for 16 weeks, starting from the first administration of cetuximab. RESULTS: A total of 103 patients were included in 7 hospitals. 38 patients (37%) developed a grade ≥ 2 skin reaction. Eighty-six patients could be analysed for the primary endpoint (73.3% males, mean age 62.4 years, n = 44 LA SCCHN, n = 16 R/M SCCHN, n = 26 mCRC). The most frequently used skin products at some point during the observation period were moisturizing products (70%), systemic antibiotics (64%), topical antibiotics (58%), lipid-regenerating (28%) and other topical products (28%). The overall use of products gradually increased from baseline to week 6-10, reducing by week 16. Hospital protocols were the primary reason (> 50%) for choice of the skincare products and medications. CONCLUSION: A variety of skin care products and antibiotics were commonly used. Only few patients developed severe cutaneous reactions. For patients, the occurrence of skin reactions did not influence their willingness to continue cetuximab therapy.

STAT3 as a predictive biomarker in head and neck cancer: A validation study.

Locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment consists of radiotherapy (RT) alone or cisplatin-based concomitant chemoradiotherapy (CCRT). CCRT is accompanied by substantially more toxicity than RT alone. A previous retrospective cohort study found that LAHNSCC patients with tumors negative for nuclear expression of the signal transducer and activator of transcription 3 (STAT3) protein might not benefit from the addition of cisplatin to radiotherapy (RT) treatment. We set out to validate these results in a new cohort. We found that in patients with both STAT3 positive and negative tumors, disease-free survival (DFS) and overall survival (OS) did not differ significantly between treatment with cisplatin-based concomitant chemoradiotherapy (CCRT) and radiotherapy alone. Therefore, our validation study does not confirm that STAT3 is a potential biomarker to predict the effectiveness of the addition of cisplatin to RT in LAHNSCC patients.

[Salivary gland carcinoma]. / Het speekselkliercarcinoom.

Salivary gland cancer is a malignancy that arises in the head and neck area. It is not only rare but its clinical course is also very heterogeneous. A total of 22 different subtypes can be distinguished, the symptoms, treatment and prognosis of which may differ greatly. This means that both the diagnosis and treatment of the disease are prone to error. This is illustrated by two cases: a 62-year-old man with a salivary duct carcinoma, and a 56-year-old man with an adenoid cystic carcinoma. These cases are used to illustrate the advances that have been made in the treatment of salivary gland cancer.

Systemic therapy in the management of recurrent or metastatic salivary duct carcinoma: A systematic review.

BACKGROUND: Salivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer. Approximately half of SDC patients will develop recurrences or metastases. Therapeutic palliative therapy is therefore often needed. The majority of SDC tumors expresses the androgen receptor (AR) and one-third expresses human epidermal growth factor receptor 2 (HER2), both are potential therapeutic targets. The aim of this paper is to systematically review and summarize the evidence on systemic palliative therapy for SDC and to provide treatment recommendations. MATERIALS AND METHODS: Electronic libraries were systematically searched with a broad search strategy to identify studies where SDC patients received systemic therapy. Due to the rarity of SDC no restrictions were placed on study designs. RESULTS: The search resulted in 2014 articles of which 153 were full-text analyzed. Forty-five studies were included in the analysis, which included in total 256 SDC patients receiving systemic therapy. Two phase 2 trials primarily including SDC patients were identified. The majority of the studies were case series or case reports, resulting in an overall low quality of available evidence. Based on studies including ≥ 5 SDC patients, objective responses to HER2 targeting agents were observed in 60-70%, to AR pathway agents in 18-53% and to chemotherapy in 10-50%. CONCLUSION: For AR or HER2 positive SDC, agents targeting these pathways are the cornerstone for palliative treatment. Regarding chemotherapy, the combination of carboplatin combined with a taxane is best studied. Regarding other targeted agents and immunotherapy evidence is anecdotal, limiting formulation of treatment recommendations for these antineoplastic agents.

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

Imaging angiogenesis in patients with head and neck squamous cell carcinomas by [68Ga]Ga-DOTA-E-[c(RGDfK)]2 PET/CT.

PURPOSE: Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related αvß3 integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of 68Ga[Ga]-DOTA-E-[c(RGDfK)]2 (68Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). METHODS: Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of 68Ga-RGD (42 ± 8 µg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for αvß3 integrin to assess the expression pattern. RESULTS: 68Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUVmax ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. CONCLUSIONS: 68Ga-RGD PET/CT of αvß3 integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. TRIAL REGISTRATION: https://eudract.ema.europa.eu no. 2015-000917-31.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.

Whole-body hyperthermia in combination with systemic therapy in advanced solid malignancies.

Whole-body hyperthermia (WBH) might be beneficial for patients with metastasized solid malignancies when combined with systemic therapy. This review identified and summarized the phase I/II studies (n = 13/14) conducted using this combination of therapies. Most of the phase II studies used radiant heating methods in a thermal dose of 41.8 °C (1 h). All studies used classic chemotherapy. Great inter-study heterogeneity was observed regarding treatment regimes, included patients and reported response rates (12-89%). Ovarian cancer, colorectal adenocarcinoma, lung cancer and sarcoma have been studied most. Most reported toxicity (grade 3/4) was myelosuppression. Treatment related mortality was present (4 patients) in three out 14 phase II studies (350 evaluable patients, over 966 cycles of WBH with chemotherapy). Absence of phase III trials makes the additive value of WBH highly speculative. As modern oncology offers many less invasive treatments options, it is unlikely WBH will ever find its way in routine clinical care.

Adjuvant androgen deprivation therapy for poor-risk, androgen receptor-positive salivary duct carcinoma.

AIM: Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)-positive in 67-96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18-64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. METHODS: This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. RESULTS: Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0-82.4%) and 27.7% (95% CI 18.5-36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025-0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005-0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. CONCLUSION: Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.

Caregivers of patients receiving long-term treatment with a tyrosine kinase inhibitor (TKI) for gastrointestinal stromal tumour (GIST): a cross-sectional assessment of their distress and burden.

BACKGROUND: TKIs are a long-term treatment for GIST, and may have an impact on caregivers. MATERIAL AND METHODS: For this cross-sectional study, patients and caregivers were both included when patients had been treated with TKIs for at least six months. Caregivers completed questionnaires including demographics, distress (Hospital Anxiety and Depression scale), burden (Self-Perceived Pressure from Informal Care) general health (RAND-36), comorbidity (Self-administered Comorbidity Questionnaire), social support (Social Support List - Discrepancies) and marital satisfaction (Maudsley Marital Questionnaire). Patients completed similar questionnaires, without 'burden'. We conducted analyses to explore differences between caregivers with low/moderate versus high levels of burden and low versus high levels of distress. RESULTS: Sixty-one out of seventy-one eligible couples (84%) were included in the analysis. The median age of the caregivers was 60 years; 66% were female and 78% were the patients' spouse. The median age of the patients was 66 years; 43% were female. Caregivers experienced high levels of burden and distress in 10% and 23%, respectively. Caregivers with high levels of burden perceived significantly lower mental health, less vitality, lower general health and high levels of distress. Significantly higher levels of burden were found in non-spouses, caregivers of patients with more treatment-related side-effects, caregivers who spent more hours caring, and those caring for more than one person. For distress, caregivers with high levels of distress perceived significantly more burden, lower social functioning, more role physical and emotional problems, lower mental health, less vitality and lower general health. Furthermore, high levels of distress were found in caregivers of more dependent patients and those caring for more than one person. CONCLUSIONS: Caregivers of the patients with GIST treated with TKI are managing well. There is a small, vulnerable group of caregivers with high levels of burden and/or distress, show more health-related problems, both physical and mental, and require adequate support.

Clinicopathological characteristics and outcome of 31 patients with ETV6-NTRK3 fusion gene confirmed (mammary analogue) secretory carcinoma of salivary glands.

OBJECTIVES: In 2010, a new subtype of salivary gland cancer (SGC), (mammary analogue) secretory carcinoma (SC), was defined, characterized by the ETV6-NTRK3 fusion gene. As clinical behavior and outcome data of this histological subtype tumor are still sparse, we aimed to describe the clinicopathological course and outcome of a series of translocation positive SC patients. PATIENT AND METHODS: We re-evaluated the pathological diagnosis of a subset of SGCs, diagnosed in 4 of 8 Dutch head and neck centers. Subsequently, tumors with a morphological resemblance to SC were tested for the ETV6-NTRK3 fusion gene using RT-PCR. Furthermore, patients prospectively diagnosed with SC were included. The clinical characteristics and outcomes were retrieved from the patient files. RESULTS: Thirty-one patients with ETV6-NTRK3 fusion gene positive SC were included. The median age was 49 years, 17 patients (55%) were male. Eighteen tumors (58%) arose in the parotid gland. One patient presented with lymph node metastasis. All patients underwent tumor resection and 4 patients had a neck dissection. Four patients had re-resection and 15 patients (48%) received postoperative radiotherapy. One patient developed a local recurrence, no regional recurrences or distant metastases were observed. After a median follow-up of 49 months the 5- and 10-year overall survival were 95%, the 5- and 10-year disease free survival were 89%. CONCLUSION: The clinical course of SC is favorable with a low rate of locoregional recurrence and excellent survival. Given the low incidence of nodal metastases, elective neck treatment, i.e. surgery and/or radiotherapy, does not seem to be indicated.

Drug-drug interactions with aprepitant in antiemetic prophylaxis for chemotherapy.

In the current guidelines to prevent hemotherapyinduced nausea and vomiting, multiple antiemetic drugs are administered simultaneously. In patients who receive highly emetogenic chemotherapy, aprepitant, an NK1-receptor antagonist, is combined with ondansetron and dexamethasone. Aprepitant can influence the pharmacokinetics of other drugs, as it is an inhibitor and inducer of CYP3A4. Some anticancer drugs and other co-medication frequently used in cancer patients are CYP3A4 or CYP29C substrates. We give an overview of the metabolism and current data on clinically relevant drug-drug interactions with aprepitant during chemotherapy. Physicians should be aware of the potential risk of drug-drug interactions with aprepitant, especially in regimens with curative intent. More research should be performed on drug-drug interactions with aprepitant and their clinical consequences to make evidence-based recommendations.