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Invasive lobular carcinoma (ILC) is the most common histologic subtype of breast cancer after invasive ductal carcinoma (i.e., no special type [NST]). ILC differs from NST in clinical presentation, site-specific metastases and response to conventional therapies. Loss of E-cadherin protein expression, due to alterations in its encoding geneBreast cancer is the most common cancer among women worldwide. Breast cancer is not a unique disease, but rather a heterogeneous disease, with different subtypes. Lobular breast cancer is the second most common histologic subtype of breast cancer after ductal breast cancer. Lobular breast cancer has some peculiar characteristics that make it a distinct entity in the context of breast cancer. Nevertheless, few clinical studies so far have focused specifically on this subtype. ROSALINE is a clinical study aimed to test entrectinib, a new drug that showed promising activity in preliminary research studies, in combination with endocrine therapy in women with lobular breast cancer before surgery. Trial Registration Number: NCT04551495 (ClinicalTrials.gov).

Background: Antitumor activity of ipilimumab or BRAF +/- MEK inhibitors (BRAFi +/- MEKi) following pembrolizumab administration in melanoma is poorly characterized. Patients and methods: In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi +/- MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. Results: At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi +/- MEKi for 59 (10.6%) [33 received BRAFi thorn MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi +/- MEKi naive]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi +/- MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi +/- MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi +/- MEKi initiation was 12.9 months. ORR for BRAFi +/- MEKi-naive patients who received subsequent BRAFi +/- MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). Conclusions: Ipilimumab and BRAFi +/- MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

BackgroundImmune-related adverse events are increasingly prevalent in the oncologist’s practice. Cardiac adverse events are rare but can be life-threatening. Case reports of immune checkpoint inhibitor (ICI)–related pericarditis are scarce and so is the scientific evidence for its management. This is the first report of a steroid-dependent pericarditis.Case summaryWe present a case of a woman with lung metastatic melanoma who developed pericarditis after two infusions of pembrolizumab. The initial response to steroids and colchicine was favourable, and steroids were successfully tapered, after which the immunotherapy was reintroduced. A complete metabolic remission was achieved after six cycles of pembrolizumab, but pericarditis symptoms recur each time the steroid dose is lowered below 10 mg. After introduction of azathioprine, steroids were successfully tapered over the course of 6 months.DiscussionBecause of the chronicity of the pericarditis, it was hypothesized that an underlying auto-immune pericarditis was triggered by the checkpoint inhibitor and the general guidelines for recurrent idiopathic pericarditis were followed, successfully adding azathioprine to taper steroids to stop.

Background Immune checkpoint inhibition with anti-PD(L)1 and anti-CTLA4 antibodies has significantly changed cancer treatment during the last 10 years. Nevertheless, boosting the immune system with immune checkpoint inhibition can result in immune-related adverse events, affecting different organ systems, among which the endocrine system is the most affected. However, there are few descriptions of the association of immune-related adverse events, and the pathophysiology of some is still lacking. Case summary Here, we report a 70-year-old Caucasian patient treated with nivolumab (anti-PD1 monoclonal antibody) after resection of a unique relapse of melanoma in the neck region who presented with sicca syndrome, extreme fatigue, and weight loss 6 months after the start of anti-PD1 therapy. Blood tests revealed hypoglycemia and secondary hypocortisolism due to isolated adrenocorticotrophic hormone deficiency. Interestingly, brain methionine positron emission tomography/magnetic resonance revealed physiological metabolism of the pituitary gland, which was not increased in size, and no hypophyseal metastasis was detected. The sicca syndrome investigation revealed the absence of anti-SSA/SSB antibodies, while the labial salivary gland biopsy showed lymphoplasmatocytic infiltrates with a focus score of 1. To provide new insights into the physiopathology of the anti-PD1-related sialadenitis, we investigated the distribution of aquaporins 5 by immunostaining on the labial salivary gland acini, and compared this distribution with the one expressed in the primary Sjögren’s syndrome. Contrary to patients with primary Sjögren’s syndrome (in whom aquaporins 5 is mainly expressed at the basolateral side), but similar to the patients with no sialadenitis, we observed expression of aquaporins 5 at the apical pole. This new finding deserves to be confirmed in other patients with anti-PD1-related sialadenitis. Owing to these immune-related adverse events, anti-PD1 was stopped; nevertheless, the patient developed a new relapse 1 year later (March 2020) in the neck region, which was treated by radiotherapy. Since then, no relapse of melanoma was seen (1.5 years after radiotherapy), but the patient still requires hypophyseal replacement therapy. The sialoadenitis resolved partially. Conclusion We report a combination of sialoadenitis and hypophysitis explaining extreme fatigue in a patient who was treated in the adjuvant setting with anti-PD1 for a melanoma relapse.

Background Falls and fall-related injuries are a major public health problem. Data on falls in older persons with cancer is limited and robust data on falls within those with a frailty profile are missing. The aim of this study is to investigate the incidence and predictive factors for falls and fall-related injuries in frail older persons with cancer. Methods This study is a secondary data analysis from data previously collected in a large prospective multicenter observational cohort study in older persons with cancer in 22 Belgian hospitals (November 2012–February 2015). Patients ≥70 years with a malignant tumor and a frailty profile based on an abnormal G8 score were included upon treatment decision and evaluated with a Geriatric Assessment (GA). At follow-up, data on falls and fall-related injuries were documented. Results At baseline 2141 (37.2%) of 5759 included patients reported at least one fall in the past 12 months, 1427 patients (66.7%) sustained an injury. Fall-related data of 3681 patients were available at follow-up and at least one fall was reported by 769 patients (20.9%) at follow-up, of whom 289 (37.6%) fell more than once and a fall-related injury was reported by 484 patients (62.9%). Fear of falling was reported in 47.4% of the patients at baseline and in 55.6% of the patients at follow-up. In multivariable analysis, sex and falls history in the past 12 months were predictive factors for both falls and fall-related injuries at follow-up. Other predictive factors for falls, were risk for depression, cognitive impairment, dependency in activities of daily living, fear of falling, and use of professional home care. Conclusion Given the high number of falls and fall-related injuries and high prevalence of fear of falling, multifactorial falls risk assessment and management programs should be integrated in the care of frail older persons with cancer. Further studies with long-term follow-up, subsequent impact on cancer treatment and interventions for fall prevention, and integration of other important topics like medication and circumstances of a fall, are warranted. Trial registration B322201215495.

Although pituitary adenomas (PAs) account for 15% of intracranial tumors, pituitary carcinomas (PCs) are a rare entity. Most commonly, PCs evolve from aggressive PAs invading the surrounding structures and eventually leading to metastatic lesions. Due to the low incidence, the diagnosis and treatment remains challenging. We report a case series of five patients with pituitary carcinoma (PC) treated in our center. At first diagnosis 3 patients had an ACTH-producing adenoma, 1 a prolactinoma and 1 a double secreting adenoma (GH and prolactin). The mean time interval from initial diagnosis to diagnosis of PC was 10.7 years (range 5-20 years). All patients underwent multiple surgical resections and radiotherapy. Four patients were treated with temozolomide for metastatic disease. One patient with concomitant radiochemotherapy for local recurrence. Temozolomide led to a stable disease in 2 patients. One patient had a progressive disease after 9 cycles of temozolomide. In absence of standard treatment, immunotherapy was initiated, resulting in a stable disease.We report five cases of PCs. Three patients obtained a stable disease after tailored multidisciplinary treatment. Additionally, one patient was treated with immunotherapy, opening a new treatment option in PCs. Overall, PCs are rare intracranial neoplasms occurring several years after the initial diagnosis of aggressive PAs. Currently, the absence of predictive factors for an aggressive clinical course, provokes a challenging management.

Malignant melanoma is a type of cancer that most commonly originates from the skin, less frequently from mucosal surfaces, the eye, or meninges [Annu Rev Pathol. 2014;9(1):239-71]. In 2019, this type of malignancy was the third most frequent cancer to be diagnosed in males and the fifth most in females according to the American Cancer Society and the National Cancer Institute [CA Cancer J Clin. 2019;69(5):363-85]. The majority of the malignant melanomas in the head and neck region (85-90%) are cutaneous lesions, most often arising in the skin of the face [Head Neck. 2016;38:147-155]. In sharp contrast are the histological findings of metastatic melanoma with an unknown primary site: they are much more scarce and histologically difficult to diagnose. The literature is limited to case studies or small cohorts. In 2-6% of all patients suffering from metastatic melanoma, after clinical examination of the skin and mucosa, imaging, and other diagnostic examination, a primary tumor cannot be found [Eur J Cancer. 2004;40(9):1454-5]. A very small subgroup (0.5%) presents with a single focus of melanoma within the dermis or subcutaneous tissues [Arch Dermatol. 2000;136(11):1397-9]. We hereby report a case in this subgroup of a solitary melanoma metastasis found in the submandibular gland in a 59-year-old male. The tumor was discovered incidentally after surgical excision of this gland because of nodular enlargement. ispartof: Case Reports in Oncology vol:14 issue:2 pages:957-962 ispartof: location:Switzerland status: published

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients.

BACKGROUND AND OBJECTIVE: In oncology, 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) / computed tomography (CT) is widely used to identify and analyse metabolically-active tumours. The combination of the high sensitivity and specificity from 18F-FDG PET and the high resolution from CT makes accurate assessment of disease status and treatment response possible. Since cancer is a systemic disease, whole-body imaging is of high interest. Moreover, whole-body metabolic tumour burden is emerging as a promising new biomarker predicting outcome for innovative immunotherapy in different tumour types. However, this comes with certain challenges such as the large amount of data for manual reading, different appearance of lesions across the body and cumbersome reporting, hampering its use in clinical routine. Automation of the reading can facilitate the process, maximise the information retrieved from the images and support clinicians in making treatment decisions. METHODS: This work proposes a fully automated system for lesion detection and segmentation on whole-body 18F-FDG PET/CT. The novelty of the method stems from the fact that the same two-step approach used when manually reading the images was adopted, consisting of an intensity-based thresholding on PET followed by a classification that specifies which regions represent normal physiological uptake and which are malignant tissue. The dataset contained 69 patients treated for malignant melanoma. Baseline and follow-up scans together offered 267 images for training and testing. RESULTS: On an unseen dataset of 53 PET/CT images, a median F1-score of 0.7500 was achieved with, on average, 1.566 false positive lesions per scan. Metabolically-active tumours were segmented with a median dice score of 0.8493 and absolute volume difference of 0.2986 ml. CONCLUSIONS: The proposed fully automated method for the segmentation and detection of metabolically-active lesions on whole-body 18F-FDG PET/CT achieved competitive results. Moreover, it was compared to a direct segmentation approach which it outperformed for all metrics.

Immune checkpoint inhibitors (ICI) and targeted therapies form the therapeutic mainstay for v-Raf murine sarcoma viral oncogene homolog B V600-mutated metastatic melanoma. Both treatment regimens can cause inflammatory arthritis. The reported incidence of treatment-induced inflammatory arthritis is low, though presumably underestimated due to lack of awareness, clear definitions and uniform grading systems. Nevertheless, recognition is important as inflammatory arthritis can become chronic and thus affect the quality of life beyond treatment. In this short communication, we present two patients with metastatic melanoma treated with ICI and targeted therapies who develop severe polyarthritis. Based on their clinical discourse we describe standard inflammatory arthritis treatment modalities and more advanced immunomodulatory treatment options with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). Long-term immunosuppressive treatment with glucocorticoids or DMARDs in this setting raises concerns about antitumour response and potential carcinogenic risk. Current literature on this topic is scarce, heterogeneous and retrospective. Prospective analysis of cancer patients treated with DMARDs is needed to clearly address these concerns.

Background Finding new therapeutic uses for existing medicines could lead to safe, affordable and timely new treatment options for patients with high medical needs. However, due to a lack of economic incentives, pharmaceutical developers are rarely interested to invest in research with approved medicines, especially when they are out of basic patent or regulatory protection. Consequently, potential new uses for these medicines are mainly studied in independent clinical trials initiated and led by researchers from academia, research institutes, or collaborative groups. Yet, additional financial support is needed to conduct expensive phase III clinical trials to confirm the results from exploratory research. Methods In this study, scientific and grey literature was searched to identify and evaluate new mechanisms for funding clinical trials with repurposed medicines. Semi-structured interviews were conducted with 16 European stakeholders with expertise in clinical research, funding mechanisms and/or drug repurposing between November 2018 and February 2019 to consider the future perspectives of applying new funding mechanisms. Results Traditional grant funding awarded by government and philanthropic organisations or companies is well known and widely implemented in all research fields. In contrast, only little research has focused on the application potential of newer mechanisms to fund independent clinical research, such as social impact bonds, crowdfunding or public-private partnerships. Interviewees stated that there is a substantial need for additional financial support in health research, especially in areas where there is limited commercial interest. However, the implementation of new funding mechanisms is facing several practical and financial challenges, such as a lack of expertise and guidelines, high transaction costs and difficulties to measure health outcomes. Furthermore, interviewees highlighted the need for increased collaboration and centralisation at a European and international level to make clinical research more efficient and reduce the need for additional funding. Conclusions New funding mechanisms to support clinical research may become more important in the future but the unresolved issues identified in the current study warrant further exploration.

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.

PURPOSE: The present study investigates by optical coherence tomography angiography (OCTA) the retinal capillary plexus and choriocapillaris flow voids and their possible correlation with MEKAR. METHODS: 34 eyes of 17 patients (61.5 years [30.4-77.4]) with stage IV cutaneous melanoma were included prospectively. All patients showed disease progression under treatment with Nivolumab/Ipilimumab and were subsequently treated with the MEK-inhibitor Trametinib 2 mg once daily. At the start and every 6 weeks during follow-up of 4 months, patients underwent a complete ophthalmologic exam, OCTA and when needed fluorescein angiography. RESULTS: Statistical analysis was performed on 17 eyes of 9 patients. Eight patients were excluded due to missing OCTA images or due to drop-out because of decease or change of treatment. Comparing vessel area density (P = .625 and 0.681, respectively), vessel skeleton density (P = .996 and 0.766, respectively) of the superficial and deep capillary plexus, flow void number and total flow void area (mm2 and %) (P = .495; 0.197 and 0.298, respectively) of choriocapillaris slab, before and after treatment, revealed no significant difference. The evolution of choriocapillaris flow void parameter did not significantly differ in patients, who developed MEKAR compared to patients who did not. CONCLUSION: In patients receiving MEK-inhibitor with and without MEKAR, no significant different characteristics of the retinal capillary plexus and choriocapillaris were found. These data suggest that the development of MEKAR, has no correlation with vascular alteration.

Purpose:Women with hormone receptor–positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk.Experimental Design:In a secondary analysis of Study of Letrozole Extension trial, a case-cohort–like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.Results:Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48–6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61–7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors.Conclusions:Postmenopausal women with hormone receptor–positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Recently, a paradigm shift has been established for oncolytic viruses (OVs) as it was shown that the immune system plays an important role in the specific killing of tumor cells by OVs. OVs have the intrinsic capacity to provide the right signals to trigger anti-tumor immune responses, on the one hand by delivering virus-derived innate signals and on the other hand by inducing immunogenic cell death (ICD), which is accompanied by the release of various damage-associated molecules from infected tumor cells. Here, we determined the ICD-inducing capacity of Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1 based OV, and benchmarked this to other previously described ICD (e.g., doxorubicin) and non-ICD inducing agents (cisplatin). Furthermore, we studied the capability of T-VEC to induce the maturation of human BDCA-1+ myeloid dendritic cells (myDCs). We found that T-VEC treatment exerts direct and indirect anti-tumor effects as it induces tumor cell death that coincides with the release of hallmark mediators of ICD, while simultaneously contributing to the maturation of BDCA-1+ myDCs. These results unequivocally cement OVs in the category of cancer immunotherapy.

Cancers affecting the gastrointestinal system are highly prevalent and their incidence is still increasing. Among them, gastric and pancreatic cancers have a dismal prognosis (survival of 5–20%) and are defined as difficult-to-treat cancers. This reflects the urge for novel therapeutic targets and aims for personalised therapies. As a prerequisite for identifying targets and test therapeutic interventions, the development of well-established, translational and reliable preclinical research models is instrumental. This review discusses the development, advantages and limitations of both patient-derived organoids (PDO) and patient-derived xenografts (PDX) for gastric and pancreatic ductal adenocarcinoma (PDAC). First and next generation multicellular PDO/PDX models are believed to faithfully generate a patient-specific avatar in a preclinical setting, opening novel therapeutic directions for these difficult-to-treat cancers. Excitingly, future opportunities such as PDO co-cultures with immune or stromal cells, organoid-on-a-chip models and humanised PDXs are the basis of a completely new area, offering close-to-human models. These tools can be exploited to understand cancer heterogeneity, which is indispensable to pave the way towards more tumour-specific therapies and, with that, better survival for patients.

Gini's mean difference (GMD, mean absolute difference between any two distinct quantities) of the restricted mean survival times (RMSTs, expectation of life at a given time limit) has been proposed as a new metric where higher GMD indicates better prognostic value. GMD is applied to the RMSTs at 25 years time-horizon to evaluate the long-term overall survival of women with breast cancer who received neoadjuvant chemotherapy, comparing a classification based on the number (pN) versus a classification based on the ratio (LNRc) of positive nodes found at axillary surgery. A total of 233 patients treated in 1980–2009 with documented number of positive nodes (npos) and number of nodes examined (ntot) were identified. The numbers were categorized into pN0, npos = 0; pN1, npos = [1,3]; pN2, npos = [4,9]; pN3, npos ≥ 10. The ratios npnx = npos/ntot were categorized into Lnr0, npnx = 0; Lnr1, npnx = (0,0.20]; Lnr2, npnx = (0.20,0.65]; Lnr3, npnx > 0.65. The GMD for pN-classification was 5.5 (standard error: ± 0.9) years, not much improved over a simple node-negative vs. node-positive that showed a GMD of 5.0 (± 1.4) years. The GMD for LNRc-classification was larger, 6.7 (± 0.8) years. Among other conventional metrics, Cox-model LNRc's c-index was 0.668 vs. pN's c = 0.641, indicating commensurate superiority of LNRc-classification. The usability of GMD-RMSTs warrants further investigation.

Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Methods: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. Results: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39–72), and 85.7% (95% CI, 70–100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Conclusions: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

Medical writing and editorial assistance were provided by Tim Ibbotson, PhD, of ApotheCom (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Statistical analysis was done by Herbert Thijs, Sofie Van Waes, and Filip Deforce (DICE). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The authors thanks to Hermine Leroi for the operational support and assistance during this project. The authors thank Katrien Willaert for the initiation of the study and its study design.

Background : The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of an unprecedented scale, with an ever-growing impact on healthcare systems. The clinical presentation of coronavirus disease 2019 (COVID-19) is diverse, ranging from asymptomatic illness to respiratory failure requiring admission to the intensive care unit (ICU). Risk factors for severe presentation include old age, male gender, underlying comorbidities such as metabolic syndrome, chronic lung diseases, heart-, liver- and kidney diseases, malignancy, immunodeficiency, and pregnancy (1). Little is known about the risk of COVID-19 in patients with rare endocrine malignancies, such as pituitary carcinoma. Case presentation: We describe the case of a 43-year-old man with ACTH-secreting pituitary carcinoma (with cerebellar and cervical drop metastases) who experienced a severe COVID-19 pneumopathy. He had previously received multiple lines of treatment including surgery, radiotherapy, ketoconazole, pasireotide,cabergoline, bilateral (subtotal) adrenalectomy, and temozolomide chemotherapy, as described elsewhere (2). His most recent therapy was a combination of immune checkpoint inhibitors with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) (anti-CTLA-4 and anti-PD-1, respectively) every 3 weeks for 4 cycles, after which maintenance therapy with nivolumab (240 mg) every 2 weeks was continued. Residual endogenous cortisol production was suppressed with ketoconazole 800mg daily. He had disease stabilisation with a decrease in 08:00h plasma ACTH, urinary free cortisol, and stable radiographic findings. Surgical resection of the left adrenal remnant was planned, but could not proceed due to the development of COVID-19 infection. In March 2021, he consulted our emergency department with respiratory exhaustion due to SARS-CoV-2 infection requiring urgent endotracheal intubation. He was commenced on high dose dexamethasone for 10 days together with broad-spectrum antibiotics for positive sputum cultures containing Serratia,methicillin-susceptible S. aureus and H. Influenzae. He developed multiple organ involvement, including metabolic acidosis, acute renal failure requiring continuous veno-venous hemofiltration, acute coronary syndrome type 2, septic thrombophlebitis of the right jugular vein, and critical illness polyneuropathy. He was readmitted twice to the ICU, for ventilator-associated pneumonia and central line-associated bloodstream infection respectively. He was eventually discharged from the hospital and able to continue his rehabilitation. Regarding his endocrine treatment, a "block-replace" regimen was adopted with the continuation of ketoconazole (restarted on day 11), and the supplementation of hydrocortisone at a dose depending on the current level of stress. The consecutive daily dose of hydrocortisone and ketoconazole is demonstrated in Figure 1. Discussion: The learning points of this case are twofold. Firstly, this case illustrates the presence of many of the comorbidities for COVID-19 mortality in patients with Cushing’s disease, such as the cardiovascular risk factors of obesity, arterial hypertension, impaired glucose metabolism, as well as increased thromboembolic risk and increased susceptibility to bacterial infections. Patients with endogenous glucocorticoid excess may therefore be particularly susceptible to severe COVID-19. Secondly, a « block-replace » therapy might be preferred in this patient population, to avoid adrenal insufficiency and reduce the need for biochemical monitoring (as suggested by Newell-Price et al.) (3). References: 1. Gao Y dong, Ding M, Dong X, Zhang J jin, Kursat Azkur D, et al. Risk factors for severe and critically ill COVID-19 patients : A review. Allergy : European Journal of Allergy and Clinical Immunology. 2021. 2. Sol B, de Filette JMK, Awada G, Raeymaeckers S, Aspeslagh S, Andreescu CE, et al. Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma : A new emerging treatment ? Eur J Endocrinol.2021. 3. Newell-Price J, Nieman LK, Reincke M, Tabarin A. ENDOCRINOLOGY in the TIME of COVID-19 : Management of Cushing’s syndrome. Eur J Endocrinol.2020

Background: Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) are the current standard-of-care for many advanced cancers (1). This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE). The underlying mechanisms are not yet fully understood. We explore the role of HLA in endocrinopathy related to ICI therapy using an interesting patient. Case presentation: A 63-year-old woman was diagnosed in May 2019 with stage IIIB non-small cell lung carcinoma of the right superior lobe with PD-L1 expression > 50%. The patient had a partial therapeutic response on two cycles of radio-chemotherapy with carboplatin and vinorelbine, with persistence of mild hypermetabolism in pulmonary nodules. She was started on consolidation immunotherapy with durvalumab (anti-PD-L1), 10 mg/kg every two weeks, with the intended treatment duration of one year. A routine blood sampling performed before the first chemotherapy showed normal thyroid function with a TSH 1.37 mU/L (reference range: 0.27-4.20) and free T4 19.0 pmol/l (reference range: 12.0-22.0). The thyroid function was not rechecked before the first durvalumab dosing. In December 2019, after three cycles, the patient presented herself at the pneumology department with fatigue, weight loss (2 kg in two months) and increased shortness of breath. Laboratory analysis showed a mild hyperthyroidism with decreased TSH (0.23 mU/L) and increased free T4 (29.4 pmol/l). Approximately 6 weeks later, levothyroxine 50 mg daily was started because of an evolution towards hypothyroidism (with TSH 37.90 mU/L; free T4 5.8 pmol/l), as shown in Figure 1. Thyroperoxidase antibodies were positive (216 kUI/L, reference range: < 34), while the TSH receptor antibodies (TRAb, analysis of stimulating and blocking) were negative. Ultrasound examination of the thyroid was normal. Thyroid scintigraphy was not performed. HLA analysis showed A*02, -; B*15,*40; C*03,*07; the DR haplotypes: DRB1*04,*13, and the DQ haplotypes: DQB1*03,*06. Discussion: This case report illustrates that more attention should be given to the immunogenetic background of oncology patients treated with immunotherapy (2). HLA polymorphisms have been implicated for ‘conventional’ autoimmune thyroid disease (AITD), such as DR4 (susceptible), DR7 and DR13 (protective) for Hashimoto, and DR3 (susceptible) for Graves’ disease. Our patient has a mixed HLA susceptibility, with the presence of both HLA-DR4 (susceptible) and DR13 (protective). A variety fo other HLA associations have been described in patients with endocrinopathy related to immune therapy, such as DR4 in diabetes mellitus; DR4-DQ4 and DR9-DQ9 in diabetes mellitus of Asian origin (3); HLA-A2, A24, B7, DR1 and DR4 (lymphocytic hypophysitis) in two cases of nivolumab-induced hypophysitis, DRB1*04 : 05-DQA1*03 :03-DQB1*04 :01 (autoimmune polyglandular syndrome with pituitary disorder in a Japanese population) in a patient with isolated adrenocorticotropin deficiency by nivolumab-induced hypophysitis. Conclusion: In summary, our case of patient with thyroiditis associated with the PD-L1 inhibitor durvalumab highlights not only the need for proactive monitoring of thyroid function, but also identifying biomarkers associated with an increased risk of ICI-induced side effects for better patient selection, optimal management and improved understanding of the mechanisms involved. References: 1. Sammamed MF, Chen L. A Paradigm Shift in Cancer Immunotherapy : From Enhancement to Normalization. Cell. 2018. 2. Correale P, Saladino RE, Nardone V, Giannicola R, Agostino R, Pirtoli L, et al. Could PD-1/PDL1 immune checkpoints be linked to HLA signature ? Immunotherapy. 2019. 3. De Filette JMK, Pen JJ, Decoster L, Vissers T, Bravenboer B, Van Der Auwera BJ, et al. Immune checkpoint inhibitors and type 1 diabetes mellitus : A case report and systematic review. European Journal of Endocrinology. 2019.

The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating type of cancer. While many studies have shed light into the pathobiology of PDAC, the nature of PDAC's cell of origin remains under debate. Studies in adult pancreatic tissue have unveiled a remarkable exocrine cell plasticity including transitional states, mostly exemplified by acinar to ductal cell metaplasia, but also with recent evidence hinting at duct to basal cell transitions. Single cell RNA sequencing has further revealed intrapopulation heterogeneity among acinar and duct cells. Transcriptomic and epigenomic relationships between these exocrine cell differentiation states and PDAC molecular subtypes have started to emerge, suggesting different ontogenies for different tumor subtypes. This review sheds light on these diverse aspects with particular focus on studies with human cells. Understanding the 'masked ball' of exocrine cells at origin of PDAC and leaving behind the binary acinar versus duct cell classification may significantly advance our insights in PDAC biology.

Breast cancer; Second-line treatment Cáncer de mama; Tratamiento de segunda línea Càncer de mama; Tractament de segona línia Patients with triple-negative breast cancer (TNBC) who relapse early after (neo)adjuvant chemotherapy have more aggressive disease. In the ASCENT trial, sacituzumab govitecan (SG), an antibody-drug conjugate composed of an anti-Trop–2 antibody coupled to SN-38 via a hydrolyzable linker, improved outcomes over single-agent chemotherapy of physician’s choice (TPC) in metastatic TNBC (mTNBC). Of 468 patients without known baseline brain metastases, 33/235 vs 32/233 patients (both 14%) in the SG vs TPC arms, respectively, received one line of therapy in the metastatic setting and experienced disease recurrence ≤12 months after (neo)adjuvant chemotherapy. SG prolonged progression-free survival (median 5.7 vs 1.5 months [HR, 0.41; 95% CI, 0.22–0.76]) and overall survival (median 10.9 vs 4.9 months [HR, 0.51; 95% CI, 0.28–0.91]) vs TPC, with a manageable safety profile in this subgroup consistent with the overall population. In this second-line setting, as with later-line therapy, SG improved survival over conventional chemotherapy for patients with mTNBC. This study was sponsored by Gilead Sciences, Inc.

Background: Cancer-related cognitive impairment (CRCI) is a prevalent source of comprised quality of life in cancer survivors. This study evaluated the efficacy of Emotional Freedom Techniques (EFT) on self-reported CRCI (sr-CRCI). Methods: In this prospective multicentre randomised wait-list controlled study (ClinicalTrials.gov Identifier: NCT02771028), eligible cancer survivors had completed curative treatment, were 18 years or older and screened positive for sr-CRCI with > 43 on the Cognitive Failures Questionnaire (CFQ). Participants were randomised to the immediate treatment group (ITG) or wait-list control (WLC) group, based on age (< or > 65 years), gender, treatment (chemotherapy or not), and centre. The ITG started to apply EFT after inclusion and performed this for 16 weeks. The WLC group could only start the application of EFT after 8 weeks of waiting. Evaluations took place at baseline (T0), 8 weeks (T1) and 16 weeks (T2). The primary outcome was the proportion of patients with sr-CRCI according to the CFQ score. Findings: Between October 2016 and March 2020, 121 patients were recruited with CFQ > 43 indicating sr-CRCI. At T1, the number of patients scoring positive on the CFQ was significantly reduced in the ITG compared to the WLC group (40.8% vs. 87.3% respectively; p

Background: Immune-related Adverse Events (IrAEs) present a new challenge to patient safety. The use of Patient-Reported Outcomes (PROs) to monitor adverse events is increasing. Existing measures like the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) do not offer clear guidance how to select the symptoms to monitor in different populations. The wide spectrum of toxicities of more recent treatments such as Immune Checkpoint Inhibitors (ICIs) is not fully covered. We aimed to a) reach expert consensus on PRO-CTCAE symptom to be monitored in cancer patients treated with ICIs; b) gather expert opinion on additional symptom terms that could be used to broaden its reach in the ICI toxicity spectrum; and c) reach expert consensus on a set of priority symptom terms to monitor symptomatic IrAEs in this population. Methods: We conducted a Delphi study with an international panel of eleven experts across four rounds. In round 1, experts assessed the relevance of PRO-CTCAEsymptom terms and suggested additional terms. Subsequent rounds aimed at consensus on the importance-to-monitor on three levels (level1 ¼ highest; level 3 ¼ lowest) of all relevant symptom terms. Results: All (n¼80) PRO-CTCAE Symptom terms were considered relevant. By round 4, consensus on the importance-to-monitor was reached for 82% (n¼65). Thirty terms reached consensus on level 1 importance, followed by 33 on level 2 and 2on level 3. Experts agreed on a set of 54 additional symptom terms to be considered to monitor ICI-related toxicities. Consensus on the importance-to-monitor was reached for 87% (n¼47) of these terms. Conclusions: To our knowledge, this is the first consensus of a prioritized list of symptom terms that should be considered for prospective surveillance of ICI-related toxicities. Additionally, they reveal the need to improve existing PRO measures to address the complex nature of IrAEs, and provide a first consensus on what symptom terms should be targeted by future work.

Immunotherapy has become the standard of care for various cancer types. The widespread use of immune checkpoints inhibitors confronts us with a whole range of novel immune-related adverse events. Skin toxicity is one of the most frequent adverse events. In this article, we report a case of anti-PD-1 induced late bullous pemphigoid (BP) with mucosal erosions and associated with a troublesome neurological disorder of undetermined origin in a patient with metastatic melanoma. Skin biopsy was essential to make the diagnosis and rapid initiation of systemic prednisolone played a role in favorable clinical outcome of BP. We will discuss the difficulty of early diagnosis of BP, its unusual association with neurological disorders, and the specific management of this particular dermatological entity.

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.

T-VEC, a HSV-1 derived oncolytic virus, is approved for the treatment of advanced melanoma. The mechanisms that underly the systemic anti-tumor effect that is seen following intratumoral injection have not yet been studied but are likely to be mediated by myeloid dendritic cells (myDC) that initiate an adaptive immune response. In this study we could demonstrate that T-VEC is non-toxic for human myDC. T-VEC and a T-VEC oncolysate of melanoma cell lines were able to mature human myDC. myDC were able to take up lysed melanoma cells and cross-present melanoma-derived tumor antigens to antigen-specific T cells. Our results support the possible role of myDC as mediators of an adaptive anti-tumor effect and intratumoral co-administration of T-VEC plus autologous myDC could be a complementary treatment option. A clinical trial that investigates this hypothesis is currently ongoing. ispartof: FRONTIERS IN IMMUNOLOGY vol:12 ispartof: location:Switzerland status: published

Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd–5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.

The objective of this study was to evaluate the utility of serum C-reactive protein (CRP) as biomarker for the early diagnosis of immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitors (ICIs) in the adjuvant setting, and its potential correlation with relapse-free survival (RFS). Prospectively collected data from 72 melanoma patients treated with adjuvant ICIs were pooled. CRP values at diagnosis of 10 irAEs were descriptively analysed. Correlations between RFS and the occurrence of irAEs, the grade of the irAE, the extent of CRP-elevation and the use of corticosteroids for irAE treatment were investigated. A total of 191 irAEs (grade 1/2, n = 182; grade 3/4, n = 9) occurred in 64 patients [skin toxicity (n = 70), fatigue (n = 50), thyroiditis (n = 12), musculoskeletal toxicity (n = 11), sicca syndrome (n = 10), other (n = 23), pneumonitis (n = 6), colitis (n = 4), hepatitis (n = 3) and hypophysitis (n = 2)]. In pneumonitis and hypophysitis, the median CRP levels at diagnosis exceeded the upper limit of normal (ULN, 5 mg/L). After a median follow-up of 26.5 months, 28 patients (39%) had been diagnosed with a melanoma relapse. Patients who experienced no irAE were at the highest risk for relapse (P = 0.008). A trend was observed for patients diagnosed with an irAE that was associated with an elevated CRP (>2xULN) to be at higher risk for relapse as compared to those diagnosed with an irAE and CRP

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. METHODS: The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. RESULTS: The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37–0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1 were abrogated. CONCLUSIONS: The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.

Background We examined 15 years of key performance indicators (KPIs) of the population-based mammography screening programme (PMSP) in Flanders, Belgium. Methods Individual screening data were linked to the national cancer registry to obtain oncological follow-up. We benchmarked crude KPI results against KPI-targets set by the European guidelines and KPI results of other national screening programmes. Temporal trends were examined by plotting age-standardised KPIs against the year of screening and estimating the Average Annual Percentage Change (AAPC). Results PMSP coverage increased significantly over the period of 15 years (+ 7.5% AAPC), but the increase fell to + 1.6% after invitation coverage was maximised. In 2016, PMSP coverage was at 50.0% and opportunistic coverage was at 14.1%, resulting in a total coverage by screening of 64.2%. The response to the invitations was 49.8% in 2016, without a trend. Recall rate decreased significantly (AAPC -1.5% & -5.0% in initial and subsequent regular screenings respectively) while cancer detection remained stable (AAPC 0.0%). The result was an increased positive predictive value (AAPC + 3.8%). Overall programme sensitivity was stable and was at 65.1% in 2014. In initial screens of 2015, the proportion of DCIS, tumours stage II+, and node negative invasive cancers was 18.2, 31.2, and 61.6% respectively. In subsequent regular screens of 2015, those proportions were 14.0, 24.8, and 65.4% respectively. Trends were not significant. Conclusion Besides a suboptimal attendance rate, most KPIs in the Flemish PMSP meet EU benchmark targets. Nonetheless, there are several priorities for further investigation such as a critical evaluation of strategies to increase screening participation, organising a biennial radiological review of interval cancers, analysing the effect that preceding opportunistic screening has on the KPI for initial screenings, and efforts to estimate the impact on breast cancer mortality.

Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010-August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.8%) had stage IV disease at dabrafenib initiation and 39.9% had brain metastases (BMs). Dabrafenib was used first line in 67.7% of patients, and median treatment duration was 6.4 months. Dabrafenib was well tolerated. Common grade 2/3 adverse events were hyperkeratosis (7.6%), pyrexia/fever (6.6%), fatigue (5.1%), hand-foot syndrome (5.4%) and nausea (3.6%). Overall response rate was 45.9%, median progression-free survival was 5.2 months (95% confidence interval, 4.2-6.1 months), and median overall survival was 12.4 months (95% confidence interval, 10.2-15.0 months). In patients with known brain metastases (n = 132) versus patients without (n = 199), overall response rate was 42.4% versus 48.2%, progression-free survival was 3.9 months (95% confidence interval, 3.8-5.5 months) versus 5.9 months (95% confidence interval, 4.8-7.8 months) and overall survival was 9.5 months (95% confidence interval, 6.7-12.4 months) versus 15 months (95% confidence interval, 11.1-20.5 months), respectively. Safety and effectiveness of dabrafenib in patients with unresectable advanced BRAF V600-mutant melanoma treated in an Named Patient Program was similar to the clinical trial experience, demonstrating effectiveness of dabrafenib in a nontrial setting.

Objectives: This study evaluated the effect of lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, used as primary (PP) or secondary prophylaxis (SP) on chemotherapy (CT) treatment modifications, as well as the incidence of CT-induced neutropenic events in adult patients receiving cytotoxic CT with or without biological therapy (BT) for solid and hematological tumors, in routine clinical practice. Other objectives were to characterize the population of lipegfilgrastim-treated cancer patients and safety assessment. Methods: This phase 4, prospective, observational study was conducted at 15 centers from Belgium and Luxembourg, between 2015 and 2017. Results: Of 139 patients, 82.7% had breast cancer and 54.7% were treated with dose-dense regimens. Most received lipegfilgrastim as PP (82.0%) and were at high-risk of febrile neutropenia (FN) (68.3%). FN and grade III/IV neutropenia were reported for 7.9% and 22.3% patients. Among 123 evaluated patients, CT/BT dose modifications were recorded for 33.3% (PP) and 52.4% (SP) of patients receiving lipegfilgrastim; dose reductions, followed by dose delays, were more frequent than omissions. Among 45 patients with dose modifications, FN was reported for 8.8% and 9.1% patients and grade IV neutropenia for 17.6% and 18.2% of patients when lipegfilgrastim was applied for PP and SP, respectively. Adverse events related to lipegfilgrastim occurred for 55 (39.6%) patients; bone pain and back pain were more frequent. Lipegfilgrastim-related serious adverse events were reported for 9 (6.5%) patients. Conclusion: Use of lipegfilgrastim in real-world settings resulted in limited CT dose modifications and low incidences of neutropenic events, with no new safety concerns arising.

Objectives Cachexia is an important outcome-modulating parameter in patients with cancer. In the context of a randomized controlled trial on cachexia and nutritional therapy, the TiCaCONCO (Tight Caloric Control in the Cachectic Oncologic Patient) trial, the contacts between patients with cancer and health care practitioners and oncologists were screened. The aim of this retrospective study was to identify in the charts the input of data on body weight (necessary to identify cachexia stage), relevant nutritional data, and nutritional interventions triggered or implemented by oncologists and dietitians. Methods In a tertiary, university oncology setting, over a time span of 8 mo (34 wk), the charts of patients admitted to an oncology, gastroenterology, or abdominal surgery unit were screened for the presence of information contributing to a cancer cachexia diagnosis. Data (patient characteristics, tumor type, and location) was gathered. Results We analyzed 9694 files. Data on body weight was present for >90% of patients. Of the 9694 screening, 118 new diagnoses of cancer were present (1.22% of patient contacts). Information on weight evolution or nutritional status was absent for 54 patients (46%). In contacts between oncologists and patients with cancer, at the time of diagnosis, cachexia was present in 50 patients (42%). In 7 of these patients (14%), no nutritional information was present in the notes. Of the 50 patients with cachexia, only 8 (16%) had a nutritional intervention initiated by the physician. Nutritional interventions were documented in the medical note in 11 patients (9%) in the overall study population. Dietitians made notes regarding nutrition and weight for 49 patients (42%). We could not demonstrate a difference in mortality between cachectic and non-cachectic patients, although numbers are small for analysis. Conclusion Patients newly diagnosed with cancer are not systematically identified as being cachectic and if they are, interventions in the field of nutrition therapy are largely lacking. Important barriers exist between oncologists and dietitians, the former being mandatory to the success of a nutrition trial in cancer.

Adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) is adopted worldwide as a valuable option for elderly patients with high-risk early breast cancer. Some studies suggest that paclitaxel may have a better therapeutic ratio than docetaxel. Therefore we have implemented an adjuvant chemotherapy in which docetaxel was replaced by paclitaxel. We report here the retrospective analysis of that cohort and make a safety comparison with an earlier TC cohort in the same target population. This retrospective analysis demonstrates the feasibility of paclitaxel/cyclophosphamide as an alternative, better tolerated adjuvant regimen for elderly patients. Further evaluation and assessment of noninferiority to TC is warranted.

The combination of BRAF and MEK inhibitors is a standard therapeutic option for patients with metastatic melanoma with BRAF-mutated tumors. This type of targeted therapy improved patient survival, having a manageable toxicity profile. Nevertheless, potentially life-threatening severe toxicity as anaphylaxis-like reactions was observed in two reported cases. No confirmatory testing was performed for these two patients. We report a case of anaphylactic reaction to the BRAF inhibitor dabrafenib administered as a first-line treatment. The clinical picture is different compared with the reported cases, with the main life-threatening symptom being severe hypotension. An important feature of our case report is the diagnostic assessment by drug provocation test, which is considered the 'gold standard' investigation for the diagnosis of drug hypersensitivity. Additionally, serum tryptase levels were assessed, and the basophil activation test has been performed as an in-vitro diagnostic test. Elements in favor of both IgE-mediated and non-IgE-mediated reaction were observed, which is suggestive of a complex pathomechanism. This can be evocative for the heterogenous clinical manifestation of the immediate hypersensitivity reactions to BRAF inhibitors. The mechanisms responsible for the reactions should be investigated in future molecular and cellular studies.

BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population.PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397).RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib.CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.

PURPOSE: Using the EORTC Global Health Status (GHS) scale, we aimed to determine minimal clinically important differences (MCID) in health-related quality of life (HRQOL) changes for older cancer patients with a geriatric risk profile, as defined by the geriatric 8 (G8) health screening tool, undergoing treatment. Simultaneously, we assessed baseline patient characteristics prognostic for HRQOL changes. METHODS: Our analysis included 1424 (G8 ≤ 14) older patients with cancer scheduled to receive chemotherapy (n = 683) or surgery (n = 741). Anchor-based methods, linking the GHS score to clinical indicators, were used to determine MCID between baseline and follow-up at 3 months. A threshold of 0.2 standard deviation (SD) was used to exclude MCID estimates too small for interpretation. Logistic regressions analysed baseline patient characteristics prognostic for HRQOL changes. RESULTS: The 15-item Geriatric Depression Scale (GDS15), Visual Analogue Scale (VAS) for Fatigue and ECOG Performance Status (PS) were selected as clinical anchors. In the surgery group, MCID estimates for improvement and deterioration were ECOG PS (5*, 11*), GDS15 (5*, 2) and VAS Fatigue (3, 9*). In the chemotherapy group, MCID estimates for improvement and deterioration were ECOG PS (8*, 7*), GDS15 (5, 4) and VAS Fatigue (5, 5*). Estimates with * were > 0.2 SD threshold. Patients experiencing pain or malnutrition (surgery group) or fatigue (chemotherapy group) at baseline showed a significantly stable or improved HRQOL (p

The dabrafenib plus trametinib (dab + tram) combination has demonstrated durable long-term efficacy in patients with BRAF V600–mutant metastatic melanoma. However, real-world data characterizing patients with long-term benefit are limited. DESCRIBE III was a global, observational, retrospective, chart review study in patients with unresectable or metastatic melanoma treated with dab monotherapy and/or dab + tram combination therapy as part of the Named Patient Program or Individual Patient Program. Overall, 509 patients were enrolled. Patients were categorized into three groups based on their observed treatment duration: long-term (on therapy ≥12 months), intermediate (on therapy ≥6 months and &lt, 12 months), and short-term (on therapy &lt, 6 months) duration of benefit. More patients in the short-term duration of benefit group had baseline characteristics associated with poor prognosis compared with the other two groups. Median lactate dehydrogenase (LDH) levels (368 U/L) at baseline were also higher in the short-term duration of benefit group. No new safety signals were identified. DESCRIBE III identified baseline characteristics associated with long-term benefit of dab + tram. Lower LDH level and &lt, 3 metastatic sites at baseline were associated with a longer duration of benefit, confirming that the findings from COMBI-d and COMBI-v are relevant to patients treated in a real-world setting.

Treatment with combined BRAF and MEK inhibition is widely accepted as a first-line treatment option for patients with advanced BRAF V600E mutant melanoma. It is generally well-tolerated and has limited side-effects. However, we report a case of a sarcoid-like syndrome induced by treatment with dabrafenib/trametinib (D/T) in a patient with stage IV-M1d melanoma. Sarcoid-like syndrome is a known side-effect of immune checkpoint-inhibition therapy but has only rarely been described in BRAF/MEK inhibition. However, recognizing this side-effect is important because of potential misinterpretation as progressive disease and influence on treatment. We describe a 48-year-old female patient who initially presented with solitary brain metastasis and diffuse lung lesions. She was treated with D/T to which she had an initial response in all lesions. One year later, new hilar and mediastinal lymphadenopathies were detected. Imaging was suggestive of the sarcoid-like syndrome. An endoscopic biopsy of the enlarged lymph node showed no melanoma cells. Treatment was continued. Three months later, the patient experienced a drop in hemoglobin, which prompted further investigations into possible occult intestinal metastasis. Video capsule examination revealed a metastatic lesion in the small intestine. A treatment switch to the combination of checkpoint inhibitors nivolumab and ipilimumab successfully treated both lung and small intestine lesions. After the third dose of this combination therapy, she developed an immune-related pneumonitis. Treatment with corticosteroids resolved the pneumonitis and decreased metabolism in the sarcoid-like syndrome. The treatment was not restarted afterward. She remains free of the disease up to today, 2.5 years after diagnosis.

Background: Rapidly evolving treatment options for advanced NSCLC can lead to difficulties in implementing those changes in daily practice. Insight into real-world treatment choices might help identify needs for better patient care. Methods: 215 consecutive metastatic treatment-naïve NSCLC patients were prospectively enrolled in BEPACT Lung (NCT03959137) between June-Oct 2019 in 21 Belgian hospitals. Data collected: treatment site (high vs low volume (HV vs LV)); patients’ characteristics (demographics, medical history, comorbidities, autoimmune disease, medications, prior treatment for earlier stage NSCLC); tumor characteristics; patients’ preference; treatment type (chemotherapy (C), immunotherapy (I), immuno-chemotherapy (I+C), best supportive care (BSC)). The primary objective was to identify factors influencing the treatment choice using first a simple logistic regression model, and then entering factors with p < 0.25 in a multiple logistic regression model. Results: HV and LV centers showed similar patients’ characteristics. Median age 68.2 years, 65.1% male, 77% performance status (PS) ≤1, 95.7% (former)smokers, 65.6% non-squamous, 42.1% Programmed Death-Ligand1 (PD-L1) high (≥50%). In the PD-L1 high group, simple logistic regression pointed at age (p = .0167), prior treatment (p = .0544), tumor size (p = .0643), number of comorbidities (p = 0.1679) and weight loss (p = .2146) as factors in the choice of I alone vs I+C; in the multiple regression model, this was age (p = .0642), weight loss (p = .0458) and prior treatment (p = .0582). In the PD-L1 low group, simple logistic regression pointed at PS (p < 0.0001), weight loss (p = .0440), patients’ preference (p = .0636), age (p = .1149), antibiotics (p = .1366) and smoking status (p = 0.1566) for the choice of I+C vs C alone or BSC; in multivariate analysis, this was PS (p = .0005), age (p = .0308), and patients’ preference (p = .0585). Conclusions: In PD-L1 high tumors, the choice of I alone (vs I+C) was more likely with higher age, more weight loss, and no prior treatment. In PD-L1 low tumors, the choice of I+C (vs C alone/BSC) was more likely in case of good PS, younger age or patients’ preference. Clinical trial identification: NCT03959137 Study Start date: June 1, 2019 Study Completion date: October 31, 2019.

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Background Intratumoral (IT) myDC play a pivotal role in initiating antitumor immune responses within the tumor microenvironment. IT injection of the oncolytic virus T-VEC may lead to the release of tumor antigens and maturation signals that can be captured and processed by CD1c (BDCA-1)+/CD141 (BDCA-3)+ myDC, thereby reinvigorating the cancer immunity cycle. Methods Patients (pts) with ICI-refractory melanoma received IT injections of ≥1 non-visceral metastases with T-VEC (106 PFU/mL; max 4 mL) on day 1 followed by IT injection of CD1c (BDCA-1)+ (cohort C1) or CD1c (BDCA-1)+/CD141 (BDCA-3)+ myDC (cohort C2) on day 2. Injection of T-VEC (108PFU/mL; max 4 mL) was repeated on day 21, and Q2w thereafter. In C1, the number of CD1c (BDCA-1)+myDCs was escalated from 0.5x106, to 1x106, and 10x106 cells. In C2, pts received all isolated CD1c (BDCA-1)+/CD141 (BDCA-3)+ myDCs. Primary objectives were safety and feasibility. Immunohistochemistry (IHC), gene expression profiling (GEP), and multiplexed immunofluorescence (mIF) of baseline and on-treatment biopsies was performed. Results 13 pts were enrolled (C1: n=7 [respectively 2, 2, and 3 pts per dose-level of myDC]; C2: n=6). Pts received the predefined dose of myDCs and a median of 6 (range 3-8) T-VEC injections. Most frequent AEs were fatigue in 11 pts (85%), injection-site pain in 9 pts (69%), fever in 8 pts (62%), and chills and flu-like symptoms in 6 pts (46%). There were no G4 or G5 AEs. AEs of special interest were a G3 eosinophilia and a G2 purpuric rash at the injection-site; 2 pts (C1, dose level 3) developed a pathological complete remission that is ongoing at 24 months following treatment initiation. One pt in C2 had an unconfirmed partial response (iRECIST); a mixed response was observed in 2 pts. Responses were observed in both injected and non-injected lesions. In responder pts, infiltration of lymphocytes was observed on IHC. GEP and mIF on biopsies are ongoing. Conclusions IT co-injection of CD1c (BDCA-1)+ +/- CD141 (BDCA-3)+ myDC plus T-VEC is feasible, tolerable, and resulted in encouraging early signs of durable antitumor activity in pts with ICI-refractory melanoma. Clinical trial identification NCT03747744

58 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up, 29.0 months [range, 24.2–33.7]) (Lenz et al. J Clin Oncol 2020;38:Abstract 4040; NCT02060188). Objective response rate (ORR) per investigator (INV) was achieved in 69% of pts (95% CI, 53–82); progressive disease rate was 13%. Median progression-free survival (PFS) and overall survival (OS) were not reached. Median duration of treatment was 19.1 months (95% CI, 11.1–29.0). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 22% of pts. We present the post hoc subgroup analyses of efficacy and safety outcomes in pts from the same follow-up based on demographics and baseline disease characteristics. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. ORR (primary endpoint, RECIST v1.1) and PFS were assessed per INV. Post hoc subgroup analyses of efficacy (by ECOG performance status [PS], stage at initial diagnosis, primary tumor location, and BRAF/KRAS mutation status) and safety (by age and ECOG PS) are presented. Results: Among 45 treated pts, efficacy (Table) and safety were generally consistent across evaluated subgroups. ORR was similar in pt subgroups by BRAF/ KRAS mutation status, stage at initial diagnosis, primary tumor location, and ECOG PS (Table). Median PFS and OS were not reached (NR) in evaluated subgroups after a minimum follow-up of 24.2 months (Table). Incidence of grade 3–4 TRAEs for subgroups by age and ECOG PS were consistent with the overall population. Conclusions: NIVO + low-dose IPI demonstrated robust, durable clinical benefit; was well tolerated with 2-year follow-up; and was consistent in evaluated subgroups in 1L MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]