A differential process mining analysis of COVID-19 management for cancer patients.

During the acute phase of the COVID-19 pandemic, hospitals faced a challenge to manage patients, especially those with other comorbidities and medical needs, such as cancer patients. Here, we use Process Mining to analyze real-world therapeutic pathways in a cohort of 1182 cancer patients of the Lausanne University Hospital following COVID-19 infection. The algorithm builds trees representing sequences of coarse-grained events such as Home, Hospitalization, Intensive Care and Death. The same trees can also show probability of death or time-to-event statistics in each node. We introduce a new tool, called Differential Process Mining, which enables comparison of two patient strata in each node of the tree, in terms of hits and death rate, together with a statistical significance test. We thus compare management of COVID-19 patients with an active cancer in the first vs. second COVID-19 waves to quantify hospital adaptation to the pandemic. We also compare patients having undergone systemic therapy within 1 year to the rest of the cohort to understand the impact of an active cancer and/or its treatment on COVID-19 outcome. This study demonstrates the value of Process Mining to analyze complex event-based real-world data and generate hypotheses on hospital resource management or on clinical patient care.

[2020 oncology update]. / Oncologie.

The COVID-19 pandemic that has swept around the world in early 2020 has changed our daily practice and habits. Fortunately, however, 2020 also brings its share of new approaches and therapeutic combinations as well as new therapies. These advances are improving the outcomes and quality of life of our patients across the spectrum of oncological diseases. This article summarises the latest oncological advances and novelties for 2020 in the following tumor entities : lung, breast, digestive, gynecological, urological and ENT.

La pandémie de Covid-19 survenue début 2020 dans le monde entier aura bouleversé notre pratique quotidienne et nos habitudes. Heureusement, sur le plan thérapeutique, l'année 2020 apporte également son lot de nouvelles approches et combinaisons thérapeutiques ainsi que l'introduction de nouvelles molécules, permettant d'améliorer le pronostic vital et la qualité de vie de nos patients, dans de nombreux domaines. Cet article résume les dernières avancées et nouveautés oncologiques de l'année 2020 dans les domaines suivants : poumon, sein, sphère digestive, gynécologique, urologique et ORL.

Sertoli-Leydig Cell Ovarian Tumors: Is Fertility or Endocrine-Sparing Surgery an Option upon Relapse?

Sertoli-Leydig cell ovarian tumors (SLCT) are rare ovarian tumors of the sex cord-stroma subset. Their incidence peaks in the second to third decade of life. Most SCLT are diagnosed at an early stage and have a good prognosis. Fertility-sparing surgery may thus be offered. Adjuvant chemotherapy may be indicated according to prognostic factors. However, outcome in relapsing SLCT is poor. There is no evidence supporting a best treatment option upon relapse, but most publications combine radical surgery, chemotherapy, and rarely radiotherapy. Two years after left adnexectomy for FIGO IA SLCT, a now 22-year-old patient presented with peritoneal recurrence without involvement of the remaining ovary and uterus. Since there is no evidence of a survival benefit in the literature of macroscopically healthy contralateral ovary ablation in relapse and hormonal replacement therapy is contraindicative, we consented to endocrine-sparing surgery with conservation of the contralateral ovary, followed by 3 cycles of BEP chemotherapy regimen. Our patient is disease-free 16 months after relapse diagnosis. Since recurrence of SLCT has a very poor prognosis and hormonal treatment is contraindicated, endocrine-sparing surgery for young patients with a normal contralateral ovary might be a legitimate option. This is one of the first reported cases of conservative surgery in SLCT recurrence, we therefore aimed to illustrate its management in a young patient with considerations of contraception, fertility- and then endocrine-sparing surgery, and quality of life.

[Locally advanced and metastatic melanoma : novelties]. / Mélanome localement avancé et métastatique : nouveautés.

The standard of care of melanoma patients has evolved at a rapid pace with the advent of immune checkpoint inhibitors and BRAF and MEK inhibitors. ESMO guidelines were revised in September 2019 to integrate the results of recent studies that broaden the indication of these treatments to the adjuvant setting and validated new limitations to completion lymph node dissection in the case of a positive sentinel lymph node biopsy in locally advanced melanoma. We hereby detail the main novelties of the revised ESMO 2019 guidelines.

L'évolution de la prise en charge des patients atteints d'un mélanome a été accélérée avec l'avènement des inhibiteurs de points de contrôle immunitaire et des inhibiteurs BRAF et MEK. Les guidelines de la Société européenne d'oncologie médicale (ESMO) ont été révisées en septembre 2019 pour intégrer les résultats des récentes études, élargissant les indications de ces traitements en situation adjuvante. La place du curage ganglionnaire en cas d'atteinte du ganglion sentinelle dans les mélanomes localement avancés est aussi rediscutée. Nous détaillons ici les principales nouveautés des guidelines de l'ESMO 2019.

Clinicopathological Characteristics, Treatment and Outcome of 123 Patients with Synchronous or Metachronous Bilateral Breast Cancer in a Swiss Institutional Retrospective Series.

OBJECTIVE: To evaluate the prognosis, the patient and tumor characteristics, and the treatment of bilateral breast cancer (BBC) and to compare synchronous (sBBC) and metachronous BBC (mBBC). MATERIALS AND METHODS: For this retrospective study, data from 123 consecutive BBC patients (56 sBBC and 67 mBBC) that were presented at the Sion Hospital tumor board between 2007 and 2018 were collected retrospectively. RESULTS: Mean follow-up was 85 months. 2nd tumors in both groups were more often diagnosed radiologically. Mean time interval between mBBC was 115 months. A shorter interval was positively correlated with a negative hormonal receptor (HR) status and higher grade for the 2nd tumor. There was no difference in overall survival (OS) and relapse-free survival (RFS) between sBBC and mBBC. OS was longer if both tumors were hormonal receptor (HR) positive. mBBC exhibited a higher local recurrence rate than sBBC (p=0.03). CONCLUSION: sBBC and mBBC patients did not show any difference in OS or RFS, although mBBC patients were more prone to local relapses.

Rapid and Continued T-Cell Differentiation into Long-term Effector and Memory Stem Cells in Vaccinated Melanoma Patients.

Purpose: Patients with cancer benefit increasingly from T-cell-based therapies, such as adoptive T-cell transfer, checkpoint blockade, or vaccination. We have previously shown that serial vaccinations with Melan-AMART-126-35 peptide, CpG-B, and incomplete Freund adjuvant (IFA) generated robust tumor-specific CD8 T-cell responses in patients with melanoma. Here, we describe the detailed kinetics of early- and long-term establishment of T-cell frequency, differentiation (into memory and effector cells), polyfunctionality, and clonotype repertoire induced by vaccination.Experimental Design: Twenty-nine patients with melanoma were treated with multiple monthly subcutaneous vaccinations consisting of CpG-B, and either the native/EAA (n = 13) or the analogue/ELA (n = 16) Melan-AMART-126-35 peptide emulsified in IFA. Phenotypes and functionality of circulating Melan-A-specific CD8 T cells were assessed directly ex vivo by multiparameter flow cytometry, and TCR clonotypes were determined ex vivo by mRNA transcript analyses of individually sorted cells.Results: Our results highlight the determining impact of the initial vaccine injections on the rapid and strong induction of differentiated effector T cells in both patient cohorts. Moreover, long-term polyfunctional effector T-cell responses were associated with expansion of stem cell-like memory T cells over time along vaccination. Dominant TCR clonotypes emerged early and persisted throughout the entire period of observation. Interestingly, one highly dominant clonotype was found shared between memory and effector subsets.Conclusions: Peptide/CpG-B/IFA vaccination induced powerful long-term T-cell responses with robust effector cells and stem cell-like memory cells. These results support the further development of CpG-B-based cancer vaccines, either alone or as specific component of combination therapies. Clin Cancer Res; 23(13); 3285-96. ©2016 AACR.

Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation.

BACKGROUND: De-regulation of the wingless and integration site growth factor (WNT) signaling pathway via mutations in APC and Axin, proteins that target beta-catenin for destruction, have been linked to various types of human cancer. These genetic alterations rarely, if ever, are observed in breast tumors. However, various lines of evidence suggest that WNT signaling may also be de-regulated in breast cancer. Most breast tumors show hypermethylation of the promoter region of secreted Frizzled-related protein 1 (sFRP1), a negative WNT pathway regulator, leading to downregulation of its expression. As a consequence, WNT signaling is enhanced and may contribute to proliferation of human breast tumor cells. We previously demonstrated that, in addition to the canonical WNT/beta-catenin pathway, WNT signaling activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in mouse mammary epithelial cells via epidermal growth factor receptor (EGFR) transactivation. METHODS: Using the WNT modulator sFRP1 and short interfering RNA-mediated Dishevelled (DVL) knockdown, we interfered with autocrine WNT signaling at the ligand-receptor level. The impact on proliferation was measured by cell counting, YOPRO, and the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay; beta-catenin, EGFR, ERK1/2 activation, and PARP (poly [ADP-ribose]polymerase) cleavages were assessed by Western blotting after treatment of human breast cancer cell lines with conditioned media, purified proteins, small-molecule inhibitors, or blocking antibodies. RESULTS: Phospho-DVL and stabilized beta-catenin are present in many breast tumor cell lines, indicating autocrine WNT signaling activity. Interfering with this loop decreases active beta-catenin levels, lowers ERK1/2 activity, blocks proliferation, and induces apoptosis in MDA-MB-231, BT474, SkBr3, JIMT-1, and MCF-7 cells. The effects of WNT signaling are mediated partly by EGFR transactivation in human breast cancer cells in a metalloprotease- and Src-dependent manner. Furthermore, Wnt1 rescues estrogen receptor-positive (ER+) breast cancer cells from the anti-proliferative effects of 4-hydroxytamoxifen (4-HT) and this activity can be blocked by an EGFR tyrosine kinase inhibitor. CONCLUSION: Our data show that interference with autocrine WNT signaling in human breast cancer reduces proliferation and survival of human breast cancer cells and rescues ER+ tumor cells from 4-HT by activation of the canonical WNT pathway and EGFR transactivation. These findings suggest that interference with WNT signaling at the ligand-receptor level in combination with other targeted therapies may improve the efficiency of breast cancer treatments.