[Cardio-oncology and cardio-obstetrics : crucial role of a multidisciplinary approach]. / Cardio-oncologie et cardio-obstétrique : importance d'une approche multidisciplinaire.

In this clinical case, we describe the cardio-oncological history and the complexity of the management of a patient presenting a breast cancer diasgnosed during pregnancy followed by a postpartum cardiomyopathy. A multidisciplinary approach is mandatory.

Dans ce cas clinique, nous décrivons l'histoire cardio-oncologique et la complexité de prise en charge d'une patiente présentant un cancer mammaire découvert lors d'une grossesse, puis, une cardiomyopathie du post-partum. Une approche multidisciplinaire s'avère indispensable.

Real-World Effectiveness, Safety, and Health-Related Quality of Life in Patients Receiving Adjuvant Nivolumab for Melanoma in Belgium and Luxembourg: Results of PRESERV MEL.

BACKGROUND: Nivolumab, an anti-programmed cell death 1 immuno-oncology therapy, is approved as an adjuvant treatment for patients with completely resected stage III or stage IV melanoma. PRESERV MEL (Prospective and REtrospective Study of nivolumab thERapy in adjuVant MELanoma) is a real-world observational study evaluating the effectiveness and safety of adjuvant nivolumab in patients with completely resected stage III or stage IV melanoma in clinical practice in Belgium and Luxembourg. METHODS: Patients were enrolled prospectively and retrospectively during a 2-year period (January 2019-January 2021), and will be followed for 5 years. The results reported here are for the second interim analysis (cutoff date 31 December 2021). The index date was the date of first administration of adjuvant nivolumab. Patients received nivolumab for up to 12 months per label. Outcomes included relapse-free survival (RFS), adverse events (AEs)/treatment-related AEs (TRAEs), and health-related quality of life (HRQoL; assessed in prospectively enrolled patients using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Melanoma (FACT-M), and EQ-5D-3L instruments). HRQoL was evaluated at group level (mean change in scores from baseline based on minimally important differences) and individual patient level (percentage of patients with clinically important scores based on threshold of clinical importance). Outcomes were analyzed descriptively. RESULTS: The study enrolled 152 patients (125 prospective, 27 retrospective) at 15 hospitals in Belgium and Luxembourg. Minimum potential follow-up at time of analysis was 11.4 months. Median age was 60 years (range 29-85), and 53% of patients were male. At 12 and 18 months, the RFS rates were 74.7% (95% confidence interval (CI): 66.9-80.9) and 68.4% (95% CI: 60.0-75.5), respectively. Median RFS was not reached. Grade 3 or 4 TRAEs were reported in 14% of patients. AEs led to treatment discontinuation in 23% of patients. Deaths occurred in 3% of patients and were not related to treatment. Questionnaire completion rates for HRQoL were high at baseline (90-94%) and at 24 months (78-81%). In the group-level analysis for HRQoL, mean changes in scores from baseline remained stable and did not exceed prespecified thresholds for minimally important differences during and after treatment, except for a clinically meaningful improvement in FACT-M surgery subscale scores. In the individual patient-level analysis for EORTC QLQ-C30 subscales, the percentages of patients who reported clinically relevant scores for fatigue and cognitive impairment increased during treatment (at 9 months) compared with baseline. After treatment cessation (at 18 months), the percentage of patients who reported clinically relevant scores for fatigue decreased. However, the percentages of patients who reported clinically relevant scores for emotional, cognitive, and social impairment increased at 18 months compared with during treatment. Most patients with emotional impairment at 9 and 18 months did not experience disease recurrence (91% and 89%, respectively). CONCLUSIONS: These results confirm the real-world effectiveness and safety of nivolumab as an adjuvant treatment for patients with completely resected stage III or stage IV melanoma. Cancer-specific, disease-specific, and generic HRQoL were maintained during and after treatment. The percentage of patients reporting emotional and cognitive impairment increased after treatment cessation, emphasizing the need for further investigation and tailored supportive care in these patients.

Cemiplimab for locally advanced and metastatic basal cell carcinoma.

INTRODUCTION: Locally advanced basal cell carcinoma (laBCC) represents approximatively 1% of all BCCs. Metastatic BCC (mBCC) is even more rare. Most cases are observed in immunocompromised patients, particularly solid organ transplant recipients (OTRs). When surgery and/or radiation therapy for laBCC or mBCC is not reasonable, oral hedgehog inhibitor (HHI) therapy may be initiated. LaBCC or mBCC patients with primary or secondary resistance, progression or intolerance to HHIs could benefit from programmed cell death protein-1 (PD-1) inhibitors as this has recently been published for cemiplimab, a recombinant IgG4 human monoclonal antibody anti-PD-1 for the intravenous treatment of laBCC and mBCC. AREAS COVERED: Principal studies evaluating the efficacy and safety of cemiplimab for laBCC and mBCC are presented and discussed. EXPERT OPINION: Cemiplimab is the first FDA (2021) approved anti-PD-1 antagonist for the systemic treatment of laBCC and mBCC which had previously shown disease progression on or intolerance to HHIs. Experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is associated with a risk of organ graft rejection, advantages and disadvantages should be evaluated for every individual OTR patient with laBCC or mBCC, eligible for cemiplimab therapy.

Oncological patients' reactions to COVID-19 pandemic: A single institution prospective study.

BACKGROUND: The spread of the COVID-19 pandemic has led to a rapid reorganization in all human and hospital activities, with impact on cancer patients. AIM: An analysis of cancer patients fears, and awareness of COVID-19 has been done in this study. METHODS AND RESULTS: We analyzed cancer patients' reactions to the pandemic and their perception of oncological care reorganization, through a 12-item survey, proposed at the peak of pandemic and 3 months later. Overall, 237 patients were included in the study. During the peak of pandemic 34.6% of patients were more worried about COVID-19 than cancer versus 26.4% in the post-acute phase (p = .013). Although 49.8% of patients in the acute phase and 42.3% in the post-acute phase considered their risk of death if infected ≥50%, and more than 70% of patients thought to be at higher risk of complications, the majority of them did not consider the possibility to stop or delay their treatment. Patients were more interested in following news about COVID-19 than cancer and they complied with all preventive measures in more than 90% of the cases. CONCLUSIONS: Although cancer patients worried about COVID-19 and evaluated the risk of complication or death due to COVID-19 as extremely high, they were still asking for the best oncological treatment.

Cemiplimab for locally advanced cutaneous squamous cell carcinoma: safety, efficacy, and position in therapy panel.

INTRODUCTION: Locally advanced cutaneous squamous cell carcinoma (lacSCC) is rare. Approximately one-fourth of the cases are observed among immunocompromised patients, in particular in solid organ transplant recipients (OTRs). LacSCC has a very poor prognosis. Surgery with or without radiotherapy remains the golden standard of treatment for cSCC. However, in advanced cases, there is a medical need for alternative treatment options. Classic systemic treatments include chemotherapy and/or EGFR inhibitors. Recently the effectiveness of programmed cell death protein-1 (PD-1) inhibitors has been demonstrated for lacSCC. Cemiplimab is a recombinant IgG4 human monoclonal antibody against the PD-1 protein for the intravenous treatment of lacSCC. AREAS COVERED: The principal studies evaluating the efficacy and safety of cemiplimab for lacSCC are presented. EXPERT OPINION: Cemiplimab is the first anti-PD-1 antibody that was FDA (2018) and EMA (2019) approved as a systemic treatment for lacSCC and/or metastatic cSCC when curative surgery or radiotherapy is no longer amenable. For this situation, experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is potentially associated with a risk of organ graft rejection, pros and cons should be evaluated for every individual OTR patient with lacSCC.

Granulomatous Reactions from Tattoos Following BRAF Inhibitor Therapy.

BRAF inhibitors may present several cutaneous adverse effects, including actinic keratosis, squamous cell carcinoma, keratoacanthoma, rashes, increased photosensitivity, panniculitis, palmoplantar and capillary involvement, pruritus and xerosis as well as granulomatous reactions. A 30-year-old patient with multiple tattoos received dabrafenib and trametinib for metastatic melanoma. After 4 months, he developed an induration and thickening strictly limited to several tattoos. Histopathology revealed nonnecrotizing granulomas in the dermis. Topical steroids relieved pruritus but not the granulomatous aspect of the tattoos. As far as we know, this is the first description of granulomatous reactions restricted to preexisting tattoos following BRAF inhibitor therapy.

Codon-specific translation reprogramming promotes resistance to targeted therapy.

Reprogramming of mRNA translation has a key role in cancer development and drug resistance 1 . However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation2,3. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAF V600E -expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.

Melanoma masquerading as nonmelanocytic lesions.

Increased awareness among dermatologists as well as the development of dermoscopy and sequential dermoscopy have contributed significantly toward an increase in the diagnostic accuracy of pigmented melanoma and even of amelanotic melanoma. However, the dermatologist's nightmare is the small group of melanomas that present as common skin diseases, often associated with a significant delay in diagnosis and hence a poor prognosis. The study was carried out to prospectively assess the number of melanomas lacking any clinical suspicion of melanoma and to describe their clinical and histological features over a 6-year observation period in an University Tertiary Skin Cancer Center. Out of 502 cases of newly diagnosed cases of melanoma, seven (1.4%) nonpigmented and nonamelanotic cases of melanoma were identified. The mean age of the patients was 69 years (two females/five males). All cases were discovered by chance on a punch biopsy. The clinical diagnostic suspicions were basal cell carcinoma, fungal intertrigo, keratoacanthoma, lichenoid keratoma, diabetic foot ulcer, eczema, and necrotic pressure ulcer. Dermoscopy, performed after the punch biopsies, was only partially contributive. The mean histological thickness was 2.7 mm, the mean number of mitoses was 7/mm, local micrometastases were present in 5/7 (71%), the mean Ki67 count was 18.9%, and a positive sentinel lymph node was observed in 4/6 (66%) cases. Nonpigmented and nonamelanotic melanomas are rare, are at high risk, and have a poor prognosis because of a delayed diagnosis. Dermoscopy is only of partial diagnostic aid. Treatment resistance or atypical behavior of the above-mentioned lesions should lead to biopsy.

Biomarker Analysis in a Phase II Study of Sunitinib in Patients with Advanced Melanoma.

AIM: To investigate the efficacy of sunitinib in patients with advanced melanoma and to correlate angiogenic biomarkers with response and survival. PATIENTS AND METHODS: We performed a phase II study in patients with advanced pre-treated melanoma. The primary endpoint was tumor response. Blood samples for biomarker analysis including vascular endothelial growth factor (VEGF), and its receptors VEGFR1 and -2, placental growth factor (PlGF) and circulating endothelial cells (CEC) were collected at baseline and during the first cycle. RESULTS: Four out of 39 patients (13%) achieved a partial response and eight (26%) stable disease. Time to progression was at least six months in seven patients. High baseline VEGFR1 levels and high baseline PlGF levels were both associated with a non-significant worse survival (p=0.08 for both). CONCLUSION: Sunitinib demonstrates limited activity in unselected patients with refractory advanced melanoma, but a minority of patients experienced long-term disease control. Identification of these patients remains a challenge.

Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer.

The identification of additional chemotherapy agents for anthracycline- and taxane-pretreated advanced breast cancer (ABC) is an urgent medical need. Single agent chemotherapy is most times administered because combined therapy is only associated with modest, if any, improvement in median progression-free survival. Randomized trials failed to show overall survival benefit compared with single agent chemotherapy. We hope to modify the natural history of ABC by the consecutive use of treatments with documented activity in heavily pretreated patients. Quality of life remains an important end point as cure is in general not possible. We first review the activity of the approved and the most frequently used agents in heavily pretreated ABC. Thereafter, the potential role and safety profile of etirinotecan pegol is discussed given the results recently released of a Phase III trial comparing this agent to Treatment of Physician's Choice.

Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes.

Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR) inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus). This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus) are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease). Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is impossible to select patients not benefiting from addition of everolimus to exemestane. Side effects and impact on quality of life are other important issues discussed in this review. Second-generation mTOR inhibitors and dual mTOR-phosphatidylinositol-3-kinase inhibitors are currently being evaluated in clinical trials.

Recurrent in situ melanoma successfully treated with ingenol mebutate.

BACKGROUND: Treatment options for melanoma in situ (MIS) include imiquimod, radiation therapy, cryotherapy, excisional and Mohs surgery. Ingenol mebutate is a new topical treatment option recognized for actinic keratosis. Although in vitro effectiveness has been demonstrated on melanoma cell lines, its therapeutic potential for in vivo melanomas is unknown. CASE REPORT: In 2011, a 91-year-old woman presented a thick melanoma of her cheek. The lateral sections revealed persisting in situ melanoma, which were again excised. She presented for follow-up and a recurrent MIS was evidenced centered on the previous scar. She refused further surgery and ingenol mebutate (0.015% gel) was administered on three consecutive days. One month later, a complete clinical resolution was observed. Histology and immunohistology revealed no residual MIS. CONCLUSION: In this patient, ingenol mebutate was successful and well-tolerated as a topical, alternative therapy for MIS after failure of other treatment options.

Pre-study and in-study validation of a SPE-LC-MS-MS method for the determination of 5-S-cysteinyldopa, a melanoma biomarker, in human plasma.

The incidence of malignant melanoma has increased over the past decades, particularly in Caucasian population. This disease presents defavourable prognosis in terms of survey, especially when detection occurs at the metastatic phase. Reliable analytical methods for biomarker determination are thus an interesting tool in pathology detection and follow-up. In this context, a method using SPE-LC-ESI-MS-MS for the determination of 5-S-cysteinyldopa (5-SCD) in human plasma was optimized. The presence of matrix effect was investigated in details while 5-SCD stability was studied according to FDA requirements for the validation of bioanalytical methods. Pre-study and in-study validations of the entire method were then successfully performed by applying the approach based on total measurement error and accuracy profiles over a concentration ranges from 1.6 to 200 ng/ml. Good results with respect to accuracy, trueness and precision were obtained. The maximum risk of observing future measurements falling outside the acceptance limits during routine analysis was also estimated.

¹8F-fluoride PET/CT for assessing bone involvement in prostate and breast cancers.

OBJECTIVE: To evaluate the accuracy of ¹8F-fluoride PET/computed tomography (CT) to detect bone metastases (BMs) in a breast and prostate cancer population, using magnetic resonance imaging (MRI) or thin-slice CT as a gold standard. METHODS: We have prospectively included 34 patients with breast (N=24) or prostate cancer (N=10) at high risk of BMs. Whole-body PET/CT (low-dose CT) and bone scintigraphy (BS) with single photon emission CT were obtained for all 34 patients and the results compared with a radiological gold standard. RESULTS: Out of the 386 foci detected by PET/CT, 219 (56.7%) could be verified by CT or MRI. Eighty-six additional foci were detected by BS (n=46) or seen only by CT (n=9), MRI (n=23), or both CT and MRI (n=8). The total number of verified lesions was therefore 274 (58.1%), including 119 (43.4%) benign and 155 (56.6%) BM. The sensitivity, specificity, and accuracy of ¹8F-fluoride PET/CT were 76, 84.2, and 80%, respectively. For BS, they were 44.8, 79.2, and 60%, respectively. Sensitivity significantly decreased for the lytic lesions. The accuracy of PET/CT was significantly superior to BS for pelvic and lumbar lesions. PET/CT provided a correct diagnosis (M+/M0) in 32 of 33 patients (one false positive) compared with 28 of 33 with BS (four false positive, one false positive). CONCLUSION: ¹8F-fluoride PET/CT is significantly more accurate than BS for detecting BMs from breast and prostate cancers.

[Positron emission tomography in oncology: an update]. / Tomographie à émission de positons: un premier bilan.

Positron emission tomography (PET) has been widely used for several years for staging and response evaluation in oncology. It is time to critically review its role in routine patient care. [18F]-labelled fluorodeoxyglucose ([18F]-FDG) remains the radiotracer of choice in most indications. Its high sensitivity, the half-life of 110 minutes and the easy production of this radiotracer explain its routine use although the specificity is not very good. Infectious or inflammatory processes can mimic tumours. Appropriate selection of patients studied in the recommended indications and interpretation of images by an experienced team having access to both clinical information and other diagnostic studies allows reducing the risk of false positives. Although PET is highly accurate, not all patients suffering from cancer need a PET study. Major improvements were also observed with conventional imaging techniques over the past 10 years. It is important to avoid long waiting lists because otherwise treatment delay may counterbalance the benefit of PET studies.