Correction: Krayem et al. Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance. Cancers 2020, 12, 512.

In the original article [...].

Trocar Site Recurrence after Laparoscopic Cholecystectomy for Unsuspected Isolated Gallbladder Metastasis of Melanoma: A Case Report and Review of the Literature.

Cutaneous melanoma can metastasize to almost any organ, including in-transit metastases, lymph nodes, liver, lungs, brain, and bones. Spread to the gastrointestinal tract is less common and generally concerns the small bowel, colon, and stomach. Gallbladder involvement is rarer, and only few cases describe it as the sole site of metastasis upon diagnosis. Melanoma metastases to the gallbladder are usually detected on staging or surveillance imaging, as patients usually show few or no symptoms. In resectable stage IV melanoma patients, complete surgical resection appears to improve the prognosis. However, due to the rarity of isolated gallbladder metastasis of melanoma, there are no guidelines regarding the optimal surgical approach (endoscopic or open cholecystectomy). Here, we report the case of isolated gallbladder melanoma metastasis found after laparoscopic cholecystectomy performed in a 46-year-old female patient with no known history of cancer presenting with acute cholecystitis symptoms. Six weeks after surgery, the patient developed trocar site recurrence. This case highlights the importance of a planned and open surgery for resectable melanoma metastases rather than a laparoscopic approach.

A Rare Case of Hepatic Vanishing Bile Duct Syndrome Occurring after Combination Therapy with Nivolumab and Cabozantinib in a Patient with Renal Carcinoma.

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease.

A Late Dermatologic Presentation of Bullous Pemphigoid Induced by Anti-PD-1 Therapy and Associated with Unexplained Neurological Disorder.

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.

Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma.

Tissue-based tests for BRAFV600 mutation-positive melanoma involve invasive biopsy procedures, and can lead to an erroneous diagnosis when the tumor samples degrade. Herein, we explored a minimally invasive, cell-free deoxyribonucleic acid (cfDNA)-based platform, to retest patients for BRAFV600 mutations. This phase 2 study enrolled adult patients with unresectable/metastatic melanoma. A prescreening testing phase evaluated the concordance between a prior tissue-based BRAFV600 mutation test result and a subsequent plasma cfDNA-based test result. A treatment phase evaluated the patients who were confirmed as BRAFV600 mutation-positive, and were treated with cobimetinib plus vemurafenib. It was found that 35/54 patients (64.8%) with a mutant BRAF status by prior tissue test had a positive BRAFV600 mutation with the cfDNA test. Further, 7/118 patients (5.9%) with a wild-type BRAF status had a positive BRAFV600 mutation cfDNA test; tissue retests on archival samples confirmed BRAFV600 mutation positivity in 5/7 patients (71.4%). One of these patients received BRAF pathway-targeted therapy (cobimetinib plus vemurafenib), and had progression-free survival commensurate with previous experience. In the overall cobimetinib plus vemurafenib-treated population, 29/36 patients (80.6%) had an objective response. The median progression-free survival was 13.6 months (95% confidence interval, 9.5-16.5). Cell-free DNA-based tests may be a fast and convenient option to identify BRAF mutation status in melanoma patients, and help inform treatment decisions.

Persistent anti-tumor response in cancer patients experiencing pneumonitis related to immune checkpoint blockade.

Background: Immunotherapy in the form of immune checkpoint inhibition (ICI) is now well established as acornerstone for treating many advanced malignancies. Nevertheless, as the number of indications for checkpoint inhibitors increases, so does the risk of immune-related adverse events (irAEs).Methods: We report two patient cases who, after being treated by an anti-programmed cell death 1 (PD-1), presented with grade III dyspnea due to pneumonitis.Discussion: Immunotherapy was discontinued and the patients required treatment with systemic corticosteroids. At the time of writing, both patients are still in complete response (CR), more than 1year beyond immunotherapy discontinuation. We discuss our cases with regard to recent literature reports on immune-related pneumonitis and persistence of response beyond discontinuation.

Erratum: Krayem, M., et al. Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance Short Title: Sensitivity Prediction to MAPK Inhibitors in Melanoma. Cancers 2020, 12, 512.

The authors would like to make a correction to their published paper [...].

Feasibility and clinical impact of routine molecular testing of gastrointestinal cancers at a tertiary centre with a multi-gene, tumor-agnostic, next generation sequencing panel.

BACKGROUND: High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice. MATERIAL AND METHODS: We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq Amplicon Cancer Panel, Illumina) was requested as part of standard care in one of the largest Belgian cancer networks between 2014 and 2019. Feasibility of NGS was assessed in all study patients, while the impact of NGS on the decision making was analyzed in the group of gastrointestinal cancer patients. RESULTS: Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time (p < .0001). Success rate and median turnaround time were 91.4% and 12.5 days, respectively, both significantly decreasing over time (p ≤ .0002). Non-surgical sampling procedure (OR 7.97, p < .0001), tissue from metastatic site (OR 2.35, p = .0006) and more recent year of testing (OR 1.79, p = .0258) were independently associated with NGS failure. Excluding well-known actionable or clinically relevant mutations which are recommended by international guidelines and commonly tested by targeted sequencing, 57/279 (20.4%) assessable gastrointestinal cancer patients were found to have tumors harboring at least one actionable altered gene according to the OncoKB database. NGS results, however, had a direct impact on management decisions by the treating physician in only 3 cases (1.1%). CONCLUSIONS: Our findings confirm that NGS is feasible in the clinical setting with acceptably low failure rates and rapid turnaround time. In gastrointestinal cancers, however, NGS-based multiple-gene testing adds very little to standard targeted sequencing, and in routine practice the clinical impact of NGS panels including genes which are not routinely recommended by international guidelines remains limited.

Immunotherapy in gynecological cancers: where are we?

PURPOSE OF REVIEW: This manuscript discusses the clinical evidence on immunotherapy for ovarian, endometrial, and cervical cancer. We report here the results of the clinical trials and present the ongoing trial in this area. RECENT FINDINGS: Immunotherapy has become a pillar of cancer treatment improving the prognosis of many patients with a broad variety of solid malignancies. Unfortunately, until recently the progress achieved in some other tumors has not been seen in the majority of patients with gynecological cancer. Except for some subgroups of endometrial cancers the immune checkpoint inhibitors in monotherapy have shown unsatisfactory results. However, several combinations of immunotherapy with other drugs are under investigation and are very promising. It is essential, to develop tools to select the patients who will response best to immunotherapy. SUMMARY: Combined immune checkpoint inhibitors with targeted therapies are awaited in gynecological cancers and could provide additional benefit.

Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover.

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42-0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00-4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61-1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.

Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance.

Mitogen-activated protein kinase (MAPK) inhibition with the combination of BRAF (Rapidly Accelerated Fibrosarcoma) and MEK (Mitogen-activated protein kinase kinase) inhibitors has become the standard of first-line therapy of metastatic melanoma harbouring BRAF V600 mutations. However, about half of the patients present with primary resistance while the remaining develop secondary resistance under prolonged treatment. Thus, there is a need for predictive biomarkers for sensitivity and/or resistance to further refine the patient population likely to benefit from MAPK inhibitors. In this study, we explored a top-down approach using a multiplex kinase assay, first, to discover a kinome signature predicting sensitivity, intrinsic and acquired resistance to MAPK inhibitors in melanoma, and second, to understand the mechanism of resistance using cell lines. Pre-dose tissues from patients (four responders and three non-responders to BRAFi monotherapy) were profiled for phosphotyrosine kinase (PTK) and serine-threonine kinase (STK) activities on a PamChip® peptide microarray in the presence and absence of ex vivo BRAFi. In addition, molecular studies were conducted on four sensitive parental lines, their offspring with acquired resistance to BRAFi and two lines with intrinsic resistance. PTK and STK activities in cell lysates were measured in the presence and absence of ex vivo BRAFi and/or MEKi. In tissue lysates, concentration-dependent ex vivo inhibition of STK and PTK activities with dabrafenib was stronger in responders than in non-responders. This difference was confirmed in cell lines comparing sensitive and resistant ones. Interestingly, common features of resistance were increased activity of receptor tyrosine kinases, Proto-oncogene tyrosine-protein kinase Src (Src) family kinases and protein kinase B (PKB, AKT) signalling. These latter results were confirmed by Western blots. While dabrafenib alone showed an inhibition of STK and PTK activities in both tissues and cell lines, the combination of dabrafenib and trametinib showed an antagonism on the STK activities and a synergism on PTK activities, resulting in stronger inhibitions of overall tyrosine kinase activities. Altogether; these data reveal that resistance of tumours and cell lines to MAPK inhibitors can be predicted using a multiplex kinase assay and is associated with an increase in specific tyrosine kinase activities and globally to AKT signalling in the patient's tissue. Thus, such a predictive kinome signature would help to identify patients with innate resistance to MAPK double inhibition in order to propose other therapies.

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial.

PURPOSE: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.

Recurrence dynamics of breast cancer according to baseline body mass index.

BACKGROUND: In cancer follow-up, in addition to the evaluation of survival probabilities, there is a fundamental need of assessing recurrence dynamics for optimal disease management. Although the time-dependent effect of the oestrogen receptor (ER) status of the tumour has already been described, so far no factor has proven to disentangle the multi-peak behaviour observed for breast cancer recurrences. Here, we aimed at investigating whether adiposity at diagnosis, reflected by increased patient's body mass index (BMI), could be associated with breast cancer recurrence patterns over time after primary cancer therapy. METHODS: We retrieved BMI from 734 of 777 patients with node-positive breast cancer from a phase III randomised clinical trial, which compared different chemotherapy regimens and had a median follow-up of 15.4 years. Cumulative incidence estimation as well as piecewise exponential models were carried out to estimate the distant recurrence dynamics, in all patients, as well as in subgroups based on the ER status, with the ER-positive group being further split according to the menopausal status. RESULTS: In patients with ER-negative breast cancer, time-dependent analyses revealed that the hazard of late relapses could mainly be attributed to the overweight and obese patients. Within the subgroup of premenopausal patients with ER-positive tumours, obesity was associated with an early high narrow peak of distant recurrences followed by another main peak after 5 years of follow-up. The risk for overweight patients was intermediate between obese and normal-weight patients. In the postmenopausal subgroup of patients with ER-positive tumours, the distant recurrence rate was significantly more elevated in the overweight patients compared to the other BMI categories, and a second late peak of recurrences was also observed for the obese patients. CONCLUSION: These results demonstrate that the patient's BMI at diagnosis is associated with cancer recurrence dynamics. Patient adiposity should therefore be central to the exploration of late adjuvant treatment modalities.

New Drug Combination Strategies in Melanoma: Current Status and Future Directions.

Melanoma is the deadliest form of skin cancer and one of the most difficult cancers to treat. Overall, melanomas have more mutations than any other cancer type. Oncogenic mutations in c-KIT, NRAS and BRAF components of the MAPK pathway have been identified in nearly 90% of cutaneous melanoma and this information has been used to develop small molecules that inhibit their activity. Highly selective BRAF and MEK inhibitors have demonstrated impressive clinical results. However, the short duration of response, the acquired resistance in most cases and the toxicity issues support the rationale for drug combination approaches to improve the outcome of MAPK inhibitors, increase their efficacy, prevent and/or overcome resistance. This review discusses several promising rational combinatorial strategies investigated or could be investigated in clinical studies.

Unusual diffuse liver 18F-FDG uptake in melanoma patient treated by ipilimumab.

We present herein a case of unusual 18F-FDG PET-CT diffuse hypermetabolic liver uptake in melanoma patient treated by ipilimumab.

Is there still a role for cytotoxic chemotherapy after targeted therapy and immunotherapy in metastatic melanoma? A case report and literature review.

Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-defined subgroup of patients presenting with specific genetic and molecular features.

Interval Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in First-Line Treatment for Advanced Ovarian Carcinoma: A Feasibility Study.

OBJECTIVES: We conducted a phase 2 trial to assess the feasibility of interval cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin in patients with stage III and IV pleural ovarian carcinoma in first-line treatment with no macroscopic residual disease after surgery. METHODS: Patients could be treated either with primary CS with HIPEC followed by 6 conventional cycles of chemotherapy or with 3 or 4 cycles of neoadjuvant chemotherapy before CS with HIPEC and 3 postoperative chemotherapy cycles. Hyperthermic intraperitoneal chemotherapy was performed with cisplatin (50 mg/m) for 60 minutes, only in case of complete cytoreduction. RESULTS: Nineteen patients were included in the study, and they all underwent neoadjuvant chemotherapy before CS. Sixteen patients underwent complete CS with HIPEC. There was no mortality, and morbidity of CS with HIPEC was acceptable. The HIPEC procedure did not prevent the administration of the standard first-line treatment. In the 16 patients who underwent CS with HIPEC, the outcomes were very good. CONCLUSION: Our study shows an acceptable toxicity of adding HIPEC to the standard first-line treatment in patients with stage III ovarian carcinoma treated with interval CS. Further studies are needed to confirm the role of HIPEC in the treatment of ovarian carcinoma.

Severe bilateral panuveitis during melanoma treatment by Dabrafenib and Trametinib.

BACKGROUND: We report a case of severe bilateral panuveitis during melanoma therapy with a combination of Dabrafenib, a B-raf (BRAF) inhibitor, and Trametinib, a mitogen/extracellular signal-regulated kinase (MEK) inhibitor. Both of these drugs are effectors in the mitogen-activated protein kinase (MAPK) pathway, which plays an important role in the physiopathology of melanoma. Dabrafenib and Trametinib have shown improved survival of patients with metastatic melanoma but they have also been associated with the development of uveitis. FINDINGS: Our patient was a 55-year-old woman with metastatic melanoma who presented with sudden onset of bilateral painless visual loss. She had been treated with Dabrafenib and Trametinib. Trametinib was discontinued at the onset of symptoms but there was no improvement. Ophthalmological examination revealed severe bilateral non-granulomatous panuveitis, with choroidal thickening, chorio-retinal folds, and multiple serous retinal detachments (SRDs). Topical corticosteroid treatment was initiated, and Dabrafenib was discontinued. A good response was obtained with a recovery of visual acuity of 20/25 on both eyes and an almost complete resolution of the SRDs. CONCLUSIONS: This case highly suggests that MAPK pathway inhibition can lead to severe uveitis. Dabrafenib and Trametinib could have both played a role in inducing the disease. Further studies are needed to evaluate the possible role of the combination of these drugs in inducing uveitis and SRD.

Adult onset asynchronous multifocal eosinophilic granuloma of bone: an 11-year follow-up.

Multifocal eosinophilic granuloma (EG) is a rare observation within the spectrum of histiocytosis X, generally described in children. We report the case of a 33-year-old man with multifocal EG showing an asynchronous evolution of bone lesions during a follow-up of 11 years. We also present the therapeutic approach chosen for this patient and the repeated magnetic resonance imaging (MRI) examinations used to monitor the disease with a final favorable outcome.