Drug Interactions Causing Warfarin Overdose in a Patient with Pancreatic Cancer: A Case Report.

Mistletoe, Viscum album, is a medicinal plant used in complementary medicine in oncology. Patients do not necessarily mention to their oncologist this phytotherapeutic treatment which may be responsible for unsuspected drug interactions. Some patients are adept at taking medicinal plants, a practice often unknown to health professionals who take care of them. This case reports drug interactions leading to bleeding secondary to warfarin overdose. A patient over 75 years of age was treated with nab-paclitaxel and gemcitabine as a first course for metastatic pancreatic adenocarcinoma (day 0). He was also treated with warfarin for atrial fibrillation. At day 3, he reported faintness and melena. At day 5, the biological assessment revealed anemia with hemoglobinemia of 5.1 g/dL and an international normalized ratio of 7.3, indicating vitamin K antagonist (VKA) overdose. Warfarin was discontinued and the patient received vitamin K supplementation and transfusions. The final diagnosis was an anemic syndrome due to gastrointestinal bleeding secondary to VKA overdose. Based on the chronology, a drug interaction between chemotherapy and warfarin was first suspected. Then, the patient interview found out that he self-medicated with subcutaneous injections of mistletoe extracts: 10 mg on day 0 and on day 2. Nab-paclitaxel can displace warfarin from its albumin binding sites and increase the free and active concentration of warfarin. Mistletoe extracts (V. album) are used as complementary medicine in oncology. Warfarin is predominantly metabolized in the liver by 1A2, 2C9, and 3A4 cytochrome P450 (CYP) isoforms. An inhibitor of these cytochromes prevents the degradation of warfarin into inactive metabolites, leading to accumulation or even overdose of this narrow therapeutic index VKA. Nab-paclitaxel and gemcitabine do not act on these cytochromes. V. album is a cytochrome P450 3A4 inhibitor which therefore probably led to an increase in exposure to warfarin. Thus, there are two pharmacokinetic hypotheses that may explain warfarin overdose: the displacement of warfarin from its albumin binding sites or the inhibition of CYP3A4 by mistletoe. This adverse drug event was reported to the Regional Pharmacovigilance Center of Strasbourg on June 30, 2021, and registered under the number ST20212767.

[Immune checkpoint inhibitors for treatment of advanced stage melanoma]. / Immunothérapie dans le traitement du mélanome au stade avancé.

Immune checkpoint inhibitors for treatment of advanced stage melanoma. Immunotherapy, which stimulates the anti-tumor immune response, has significantly modified the prognosis of advanced stage melanoma. Anti-CTLA4 monoclonal antibody, ipilimumab, showed a benefit on survival compared to chemotherapy in 2011. Anti-PD1, nivolumab and pembrolizumab subsequently showed superior clinical benefit including overall survival and tolerance over anti-CTLA4. Currently, the combination of ipilimumab and nivolumab appears as the most effective immunotherapy but the toxicity of this regimen is a limitation. Anti-PD1 antibodies have also been evaluated in the adjuvant setting for patients with stage III or IV resected melanoma where they have shown a significant benefit in term of relapse-free-survival. Studies are underway to evaluate these drugs in stage II resected melanoma and in neo-adjuvant setting with promising results.

Immunothérapie dans le traitement du mélanome au stade avancé. L'immunothérapie, consistant à stimuler la réponse immunitaire antitumorale, a considérablement modifié la prise en charge du mélanome au stade avancé. En 2011, l'ipilimumab, un anticorps monoclonal anti-CTLA-4, a été le premier à montrer un bénéfice en survie par rapport à la chimiothérapie. Le nivolumab et le pembrolizumab sont des anticorps anti-PD-1 qui ont été développés par la suite. Ils ont montré leur supériorité en termes de taux de réponse et de survie globale et une meilleure tolérance par rapport à l'anti-CTLA-4. Actuellement, l'association ipilimumab-nivolumab semble être l'immunothérapie la plus efficace, mais au prix d'une toxicité importante. Les anti-PD1 ont également démontré un bénéfice en situation adjuvante chez des patients opérés d'un mélanome à haut risque de récidive (stades III et IV). Des études sont en cours pour évaluer ces traitements dans les stades II opérés et en situation néo-adjuvante, avec des résultats prometteurs.

Immunotherapy discontinuation - how, and when? Data from melanoma as a paradigm.

The optimal duration of therapy in patients receiving immune-checkpoint inhibitors (ICIs) is a new but crucial question that has arisen owing to the observation of durable remissions in >85% of patients with metastatic melanoma who stop receiving an anti-PD-1 antibody after a complete response (CR). Long-term treatment-free remissions have also been seen, albeit much less frequently, in patients receiving ICIs for other forms of cancer who have a CR. Despite these promising observations, the optimal duration of treatment with ICIs remains unknown and requires further investigation in randomized controlled trials. In the absence of prospective data, some general criteria to guide the safe cessation of ICIs can be proposed, at least for patients with melanoma, in whom ICI cessation after a confirmed CR and at least 6 months of treatment is generally deemed safe. In this Perspective, we describe the available data on ICI interruption in patients with melanoma and in those with various other cancers. We also address the patient management implications of stopping ICI therapy.

Agranulocytosis Induced by Tamoxifen in a Breast Cancer Patient.

BACKGROUND: The main side effects of tamoxifen are menopausal symptoms. We report a case of agranulocytosis induced by tamoxifen in a 33-year-old woman treated in the adjuvant setting. CASE PRESENTATION: Ten days after the beginning of tamoxifen treatment, the patient complained of asthenia and mucositis. Blood testing showed a grade 4 neutropenia (0.06 G/L) without any other major hematologic disorder. Tamoxifen was discontinued, and the patient received granulocyte colony-stimulating factor. Within 2 days, she recovered to a normal granulocyte count. Tamoxifen was then switched to the combination of ovarian suppression (triptorelin) and aromatase inhibitor (anastrozole). CONCLUSION: Agranulocytosis is a very rare adverse event of tamoxifen.

[MiT family translocation renal cell carcinomas: Natural history, molecular features and multidisciplinary management]. / Les carcinomes du rein à translocation de la famille MiT : histoire naturelle, caractéristiques moléculaire et prise en charge multidisciplinaire.

MiT family translocation renal cell carcinomas (tRCC) represent a rare subtype of renal cell carcinomas. These tumors have been introduced for the first time in the World Health Classification (WHO) classification of kidney cancers in 2004. tRCC are characterized by reccurent translocations involving members of the MiT family transcription factors, mainly TFE3 and TFEB. The estimated incidence of these tumors is ∼1-5 % among all renal cell carcinomas, with female prodominance. tRCC were initially described in children, and the spectrum has been expanded over time to encompass adolescents and adults. TFE3- and TFEB-rearranged RCC harbor characteristic clinicopathological and immunohistochemical features and fluorescent hybridization in situ is considered the gold standard for their diagnosis, although it has some limitations especially when the partners are located in the vicinity of TFE3. Nephron-sparing surgery is an efficient treatment of localized cases when achievable. In metastatic setting, targeted agents and immunotherapy showed modest efficacy, with response rates and median overall survival inferior to those observed in clear-cell renal cell carcinomas. Management of tRCC necessite a multidisciplinary team and accrual in clinical trials have to be encouraged when possible. Novel biological insights are urgently awaited to better understand the mechanisms associated with kidney oncogenesis in this setting, and ultimately help to identify therapeutic targets.

Fulvestrant and palbociclib combination in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer patients.

PURPOSE: We report the results of a retrospective analysis of the fulvestrant and palbociclib combination within a temporary authorization of use (TAU) program in 77 heavily pretreated patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. METHODS: All patients who received the fulvestrant and palbociclib combination within this TAU program were included. Toxicities were graded using the CTCAE v5 scale. RESULTS: The majority of patients (62.3%) were previously treated with the mTOR inhibitor everolimus. The median number of previous treatments for their metastatic disease was 4. With a median follow-up of 14 months, the median progression-free survival (PFS) was 7.6 months. The median PFS significantly (p < 0.0001) decreased with the number of previous treatment lines in the metastatic setting. The median PFS was 5.5 months in patients who had previously progressed on everolimus compared to 9.3 months in the everolimus non-pretreated subgroup. No significant difference in median PFS was detected in patients according to age. The median overall survival rate was not reached. The clinical benefit rate was 64%, including 4% of complete responses, 26% partial responses, and 34% stable diseases for the entire cohort. CONCLUSIONS: The fulvestrant and palbociclib combination exerts an appreciable effect on metastatic heavily pretreated patients with a tolerable toxicity profile.

Immune checkpoint inhibitors in melanoma in the metastatic, neoadjuvant, and adjuvant setting.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) are now standards of care in metastatic melanoma. We highlight here the dramatic improvement that these drugs brought in the history of melanoma care. RECENT FINDINGS: The monoclonal antibody directed against cytotoxic T-lymphocyte-associated protein 4, ipilimumab, was approved in 2011. Antiprogramed death cell protein 1 antibodies, nivolumab and pembrolizumab, were developed afterward and approved in 2014, demonstrating an improved efficacy/safety ratio as compared with ipilimumab. The association of ipilimumab and nivolumab now appears as the most efficient immunotherapy but the toxicity of this regimen is a limitation. These drugs have also been evaluated in the adjuvant setting for patients with stage III or IV resected melanoma where they have shown a significant benefit in terms of relapse-free survival. SUMMARY: ICI-based immunotherapy radically modified melanoma management and now appear as the most efficient treatment for patients with metastatic melanoma with characterized by long-lasting cancer remissions, and a distinct spectrum of immune-related adverse events. Their efficacy is now also established in the adjuvant setting and they are now actively evaluated as neoadjuvant treatment with promising early results.Intensive translational work is ongoing to identify predictive biomarkers of efficacy and toxicity to improve ICI benefit/risk ratio.

Intensive care for patients with gastric cancers: outcome and survival prognostic factors.

BACKGROUND: Admission and management of patients with solid malignancies in intensive care unit (ICU) is a controversial topic. To this day, there is no data published concerning patients with gastric cancers hospitalized in ICU. This single center retrospective study reports the characteristics, outcome and prognostic factors of patients hospitalized in ICU for medical reasons over a period of 10 years. METHODS: We performed a single center retrospective study which reports the characteristics, outcome and prognostic factors of patients hospitalized in ICU for medical reasons over a period of 10 years. RESULTS: Thirty-seven patients were included, among whom 24 (64.9%) had metastatic cancer. The most frequent diagnosis on admission was septic shock (48.6%) and 24 patients (64.9%) required intubation. Ten patients (27.0%) were alive 3 months after their admission in ICU. Metastatic cancer and intubation were independently associated with a higher risk of dying within 3 months of admission in multivariate analysis: odds ratio (OR) =13.7; 95% confidence interval (CI), 1.7-108 (P<0.01). Seventeen patients (45.9%) died during their ICU stay. Metastatic cancer: OR =89; 95% CI, 2.7-6,588, therapeutic intensification: OR =1,471; 95% CI, 9.8-811,973 and the logistic organ dysfunction score (LODS) on admission: OR =1.4; 95% CI, 1.1-2.3 were independently associated with mortality within the ICU in multivariate analysis (P<0.01). CONCLUSIONS: This is the first study that examines the outcome and prognostic factors of patients with gastric cancers who require life-sustaining therapy in ICU. The identification of 3 months and ICU mortality prognostic factors could contribute to guiding clinicians in the management of these patients and assist health professionals in their discussions with these patients and their families.