Impact of Eccentric versus Concentric Cycling Exercise on Neuromuscular Fatigue and Muscle Damage in Breast Cancer Patients.

INTRODUCTION: This study investigated the magnitude and etiology of neuromuscular fatigue and muscle damage induced by eccentric cycling compared to conventional concentric cycling in patients with breast cancer. METHODS: After a gradual familiarization protocol for eccentric cycling, nine patients with early-stage breast cancer performed three cycling sessions in eccentric or concentric mode. The eccentric cycling session (ECC) was compared to concentric cycling sessions matched for power output (CONpower, 80% of concentric peak power output, 95 ± 23 W) or oxygen uptake (10 ± 2 mL.min.kg-1). Pre- to postexercise changes (30s through 10 min recovery) in knee extensor maximal voluntary contraction force (MVC), voluntary activation, and quadriceps potentiated twitch force (Qtw) were quantified to determine global, central, and peripheral fatigue, respectively. Creatine kinase (CK) and lactate dehydrogenase (LDH) activities were measured in the plasma before and 24 h postexercise as markers of muscle damage. RESULTS: Compared to CONpower (-11 ± 9%) and (-5 ± 5%), the ECC session resulted in a greater decrease in MVC (-25 ± 12%) postexercise (P < 0.001). Voluntary activation decreased only in ECC (-9 ± 6% postexercise, P < 0.001). The decrease in Qtw was similar postexercise between ECC and CONpower (-39 ± 21% and -40 ± 16%, P > 0.99) but lower in (P < 0.001). The CONpower session resulted in twofold greater compared to the ECC and sessions (P < 0.001). No change in CK or LDH activity was reported from preexercise to 24 h postexercise. CONCLUSIONS: The ECC session induced greater neuromuscular fatigue compared to the concentric cycling sessions without generating severe muscle damage. ECC is a promising exercise modality for counteracting neuromuscular maladaptation in patients with breast cancer.

Antibody-Drug Conjugates as Novel Therapeutic Agents for Non-Small Cell Lung Carcinoma with or without Alterations in Oncogenic Drivers.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics for lung cancer, and several are currently in development for this malignancy. The structure of these molecules is based on an antibody that targets a protein on the lung cancer cell surface and a cytotoxic payload attached by a linker. Many protein targets, including TROP2, c-MET, CEACAM5, HER2, and HER3 have been identified. In metastatic non-small cell lung carcinoma (NSCLC) without alterations in oncogenic drivers, platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death-ligand 1 (PD1/PDL1) interaction are the standard first-line treatments. In patients with EGFR-mutated or ALK-rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are recommended. However, although the prognosis of patients with metastatic NSCLC differs between such with and without alterations in oncogenic drivers, most patients eventually experience disease progression. A novel therapeutic class is needed in routine practice to overcome the mechanisms of resistance to ICIs and EGFR/ALK TKIs. Several ADCs have already been approved for other cancers, such as breast cancer and urothelial carcinoma. This review summarizes the knowledge about the efficacy and tolerance profiles of ADCs targeting TROP2, HER2, HER3, CEACAM5 and c-MET in metastatic NSCLC with and without alterations in oncogenic drivers.

Outcomes of non-small cell lung cancer patients with non-V600E BRAF mutations: a series of case reports and literature review.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of cases of lung cancer. The standard first-line therapy for patients without oncogenic driver metastatic NSCLC is anti PD-L1 immune checkpoint inhibition (ICI) with platinum-based chemotherapy. Approximately 4% of NSCLC patients harbor BRAF mutations; the V600E mutation is the most common. Non-V600 mutations is an heterogeneous population and account for approximately 50% of BRAF-mutated NSCLC. BRAF mutations are classified into 3 functional classes based on their kinase activity and their signaling mechanism. The European Medicines Agency and the United States Food and Drug Administration have approved dabrafenib, an anti-BRAF tyrosine kinase inhibitor (TKI), in combination with trametinib, an anti-MEK TKI, for the treatment of patients with BRAF V600E-mutated metastatic NSCLC. The use of targeted therapies in NSCLC with BRAF non-V600E mutations remains controversial. There is a lack of guidelines regarding therapeutic options in non-V600E BRAF-mutated NSCLC. Herein, we presented 3 cases of NSCLC with BRAF non-V600E mutations and reviewed the current state of therapies for this particular population of lung cancer.

Outcomes of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with the Upfront Single Agent Pembrolizumab: A Retrospective and Multicentric Study of the ESCKEYP GFPC Cohort.

Non-small cell lung cancer (NSCLC) is the most common cause of brain metastasis (BM). Little is known about immune checkpoint inhibitor activity in the central nervous system, especially in patients receiving monotherapy for tumors with a tumor proportion score (TPS) ≥ 50%. This noninterventional, retrospective, multicenter study, conducted with the GFPC, included treatment-naïve patients strongly positive for PD-L1 (TPS ≥ 50%) with BM receiving first-line single-agent pembrolizumab treatment between May 2017 and November 2019. The primary endpoints were centrally reviewed intracranial overall response rates (ORRs), centrally reviewed intracranial progression-free survival (cPFS), extracranial PFS, and overall survival were secondary endpoints. Forty-three patients from five centers were included. Surgical or local radiation therapy was administered to 31 (72%) patients, mostly before initiating ICI therapy (25/31). Among 38/43 (88.4%) evaluable patients, the intracranial ORR was 73%. The median PFS was 8.3 months. The cerebral and extracerebral median PFS times were 9.2 and 5.3 months, respectively. The median OS was 25.5 months. According to multivariate analysis, BM surgery before ICI therapy was the only factor significantly associated with both improved PFS (HR = 0.44) and OS (HR = 0.45). This study revealed the feasibility and outcome of front-line pembrolizumab treatment in this population with BM.

A single chemotherapy administration induces muscle atrophy, mitochondrial alterations and apoptosis in breast cancer patients.

BACKGROUND: Breast cancer patients are commonly treated with sequential administrations of epirubicin-cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients. METHODS: Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed. RESULTS: Decrease in muscle fibres cross-sectional area was only observed post-EC (-25%; P < 0.001), associated with a reduction in mitochondrial respiratory capacity for the complex I (CI)-linked substrate state (-32%; P = 0.001), oxidative phosphorylation (OXPHOS) by CI (-35%; P = 0.002), CI&CII (-26%; P = 0.022) and CII (-24%; P = 0.027). If H2 O2 production was unchanged post-EC, an increase was observed post-TAX for OXPHOS by CII (+25%; P = 0.022). We found a decrease in makers of mitochondrial content, as shown post-EC by a decrease in the protein levels of citrate synthase (-53%; P < 0.001) and VDAC (-39%; P < 0.001). Despite no changes in markers of mitochondrial fission, a decrease in the expression of a marker of mitochondrial inner-membrane fusion was found post-EC (OPA1; -60%; P < 0.001). We explored markers of mitophagy and found reductions post-EC in the protein levels of PINK1 (-63%; P < 0.001) and Parkin (-56%; P = 0.005), without changes post-TAX. An increasing trend in Bax protein level was found post-EC (+96%; P = 0.068) and post-TAX (+77%; P = 0.073), while the Bcl-2 level was decreased only post-EC (-52%; P = 0.007). If an increasing trend in TUNEL-positive signal was observed post-EC (+68%; P = 0.082), upregulation was highlighted post-TAX (+86%; P < 0.001), suggesting activation of the apoptosis process. CONCLUSIONS: We demonstrated that a single administration of EC induced, in only 4 days, skeletal muscle atrophy and mitochondrial alterations in breast cancer patients. These alterations were characterized by reductions in mitochondrial function and content as well as impairment of mitochondrial dynamics and an increase in apoptosis. TAX administration did not worsen these alterations as this group had already received EC during the preceding weeks. However, it resulted in an increased apoptosis, likely in response to the increased H2 O2 production.

Primary resistance to ALK inhibitors in KLC1/ALK-rearranged pleural metastatic lung adenocarcinoma: a case report.

Background: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to second- and third-generation ALK inhibitors, which have become the standard of care for ALK-positive non-small cell lung carcinoma (NSCLC). However, primary resistance to these inhibitors remains a rare and poorly understood phenomenon, especially in cases involving kinesin light chain 1 (KLC1)/ALK-rearranged metastatic NSCLC. Case Description: In this report, we present a unique and challenging case of primary resistance to second- and third-generation ALK tyrosine kinase inhibitors (TKIs) attributed to KLC1/ALK gene fusion partners in a patient with ALK-positive pleural metastatic NSCLC. The patient's disease progression was rapid and unresponsive to multiple lines of ALK-targeted therapies, including alectinib, brigatinib, and lorlatinib, underscoring the need for a deeper understanding of primary resistance mechanisms in such cases. Conclusions: The occurrence of primary resistance to ALK inhibitors in metastatic NSCLC with ALK rearrangement is an infrequent occurrence, and its underlying mechanisms remain elusive. This case emphasizes the importance of further research to elucidate the specific mechanisms of primary resistance to ALK TKIs in non-canonical ALK fusion partners like KLC1. Developing targeted therapies for such rare cases is a clinical challenge that warrants continued investigation and innovation in the field of precision oncology.

Anaplastic Lymphoma Kinase Inhibitor-Induced Neutropenia: A Systematic Review.

Lung cancers with ALK rearrangement represent less than 5% of all lung cancers. ALK inhibitors are currently used to treat first-line metastatic non-small cell lung cancer with ALK rearrangement. Compared to chemotherapy, ALK inhibitors have improved progression-free survival, overall survival, and quality of life for patients. The results of several phase 3 studies with a follow-up of over 6 years suggest that the life expectancy of these patients treated with targeted therapies is significantly higher than 5 years and could approach 10 years. Nevertheless, these treatments induce haematological toxicities, including neutropenia. Few data are available on neutropenia induced by ALK inhibitors and on the pathophysiological mechanism and therapeutic adaptations necessary to continue the treatment. Given the high efficacy of these treatments, managing side effects to avoid treatment interruptions is essential. Here, we have reviewed the data from published clinical studies and case reports to provide an overview of neutropenia induced by ALK inhibitors.

Solitary acrometastasis of the phalanx as initial presentation of an oligometastatic Kirsten rat sarcoma viral oncogene homolog-mutated lung adenocarcinoma: a case report.

BACKGROUND: Acrometastasis is an uncommon finding in non-small cell lung cancer and is usually a sign of multimetastatic disease. Few case reports have suggested solitary digital metastasis as the single secondary lesion of oligometastatic non-small cell lung cancer. CASE PRESENTATION: This case report describes an unusual presentation of a Kirsten rat sarcoma viral oncogene homolog-mutated lung adenocarcinoma with a solitary bone metastasis in the fourth finger medial phalanx, which was also the first sign of the disease, in a 63-year-old Caucasian female patient. Digital surgical amputation was performed. After histopathological confirmation and radiological exclusion of other secondary lesions, chemoimmunotherapy in a first-line setting was initiated. A partial metabolic response in the primary lung lesion was observed after four cycles. Maintenance therapy is currently being continued. CONCLUSION: Solitary digital metastasis is a rare finding in non-small cell lung cancer. Further studies are needed to investigate the mechanisms behind this particular dissemination process.

Second Cancer Affecting the Central Nervous System: Systematic Literature Review Exploring the Link Between Malignant Melanoma and Glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a malignant primary brain cancer, among the most devastating and lethal diseases of the central nervous system. Similarly, malignant melanoma (MM) is responsible for most skin cancer-related deaths. A link between those 2 aggressive cancers has not yet been established. We present here a systematic review of the literature and an exemplificative case. METHODS: A systematic review of the literature was conducted to assess possible commonalities between MM and GBM. An exemplificative surgical vignette of a 73-year-old patient with the occurrence of a frontobasal GBM after surgical removal of a metastasis of MM in the same location was then detailed. RESULTS: Fifteen studies published in the English international literature support a link between MM and GBM, both based on epidemiologic and pathophysiologic/genetic aspects. This theory is reinforced by our surgical vignette of a collision tumor with the occurrence of both tumors in the same location several years apart. CONCLUSIONS: The evidence reported in the literature, as well as our surgical vignette, support a likely link between the pathogenesis of GBM and MM.

Survival outcomes of patients with metastatic non-small cell lung cancer receiving chemotherapy or immunotherapy as first-line in a real-life setting.

Treatment of metastatic non-small cell lung cancer (mNSCLC) has been modified due to the development of immunotherapy. We assessed survival outcomes (overall [OS] and progression-free [rwPFS] survivals, time-to-next-treatment [TNT]) in mNSCLC patients after first-line immunotherapy and chemotherapy in real-life settings. Association between rwPFS and TNT, two candidate surrogate endpoints (SE), with OS was assessed. This retrospective multi-center study uses data from patients included in the Epidemio-Strategy Medico-Economic program with mNSCLC over 2015-2019. The impact of treatment on rwPFS/OS was evaluated with Cox models. Individual-level associations between SE and OS were estimated with an iterative multiple imputation approach and joint survival models. The population included 5294 patients (63 years median age). Median OS in immunotherapy group was 16.4 months (95%CI [14.1-NR]) and was higher than in chemotherapy group (11.6 months; 95%CI [11.0-12.2]). Improved OS was observed for the immunotherapy group after 3 months for subjects with performance status 0-1 (HR = 0.59; 95%CI [0.42-0.83], p < 0.01). The associations between rwPFS and TNT with OS were close ([Formula: see text]=0.57). Results emphasized a survival improvement with immunotherapy for patients in good health condition. There was moderate evidence of individual-level association between candidate SE and OS.

p16 Immunohistochemical Expression as a Surrogate Assessment of CDKN2A Alteration in Gliomas Leading to Prognostic Significances.

CDKN2A is a tumor suppressor gene encoding the p16 protein, a key regulator of the cell cycle. CDKN2A homozygous deletion is a central prognostic factor for numerous tumors and can be detected by several techniques. This study aims to evaluate the extent to which immunohistochemical levels of p16 expression may provide information about CDKN2A deletion. A retrospective study was conducted in 173 gliomas of all types, using p16 IHC and CDKN2A fluorescent in situ hybridization. Survival analyses were performed to assess the prognostic impact of p16 expression and CDKN2A deletion on patient outcomes. Three patterns of p16 expression were observed: absence of expression, focal expression, and overexpression. Absence of p16 expression was correlated with worse outcomes. p16 overexpression was associated with better prognoses in MAPK-induced tumors, but with worse survival in IDH-wt glioblastomas. CDKN2A homozygous deletion predicted worse outcomes in the overall patient population, particularly in IDH-mutant 1p/19q oligodendrogliomas (grade 3). Finally, we observed a significant correlation between p16 immunohistochemical loss of expression and CDKN2A homozygosity. IHC has strong sensitivity and high negative predictive value, suggesting that p16 IHC might be a pertinent test to detect cases most likely harboring CDKN2A homozygous deletion.

Exacerbated central fatigue and reduced exercise capacity in early-stage breast cancer patients treated with chemotherapy.

PURPOSE: The present study aimed to characterize the etiology of exercise-induced neuromuscular fatigue and its consequences on the force-duration relationship to provide mechanistic insights into the reduced exercise capacity characterizing early-stage breast cancer patients. METHODS: Fifteen early-stage breast cancer patients and fifteen healthy women performed 60 maximal voluntary isometric quadriceps contractions (MVCs, 3 s of contraction, 2 s of relaxation). The critical force was determined as the mean force of the last six contractions, while W' was calculated as the force impulse generated above the critical force. Quadriceps muscle activation during exercise was estimated from vastus lateralis, vastus medialis and rectus femoris EMG. Central and peripheral fatigue were quantified via changes in pre- to postexercise quadriceps voluntary activation (ΔVA) and quadriceps twitch force (ΔQTw) evoked by supramaximal electrical stimulation, respectively. RESULTS: Early-stage breast cancer patients demonstrated lower MVC than controls preexercise (- 15%, P = 0.022), and this reduction persisted throughout the 60-MVC exercise (- 21%, P = 0.002). The absolute critical force was lower in patients than in controls (144 ± 29N vs. 201 ± 47N, respectively, P < 0.001), while W' was similar (P = 0.546), resulting in lower total work done (- 23%, P = 0.001). This was associated with lower muscle activation in the vastus lateralis (P < 0.001), vastus medialis (P = 0.003) and rectus femoris (P = 0.003) in patients. Immediately following exercise, ΔVA showed a greater reduction in patients compared to controls (- 21.6 ± 13.3% vs. - 12.6 ± 7.7%, P = 0.040), while ΔQTw was similar (- 60.2 ± 13.2% vs. - 52.8 ± 19.4%, P = 0.196). CONCLUSION: These findings support central fatigue as a primary cause of the reduction in exercise capacity characterizing early-stage breast cancer patients treated with chemotherapy. CLINICAL TRIALS REGISTRATION: No. NCT04639609-November 20, 2020.

Molecular Heterogeneity in BRAF-Mutant Gliomas: Diagnostic, Prognostic, and Therapeutic Implications.

Over the last few decades, deciphering the alteration of molecular pathways in brain tumors has led to impressive changes in diagnostic refinement. Among the molecular abnormalities triggering and/or driving gliomas, alterations in the MAPK pathway reign supreme in the pediatric population, as it is encountered in almost all low-grade pediatric gliomas. Activating abnormalities in the MAPK pathway are also present in both pediatric and adult high-grade gliomas. Across those alterations, BRAF p.V600E mutations seem to define homogeneous groups of tumors in terms of prognosis. The recent development of small molecules inhibiting this pathway retains the attention of neurooncologists on BRAF-altered tumors, as conventional therapies showed no significant effect, nor prolonged efficiency on the high-grade or low-grade unresectable forms. Nevertheless, tumoral heterogeneity and especially molecular alteration(s) associated with MAPK-pathway abnormalities are not fully understood with respect to how they might lead to the specific dismal prognosis of those gliomas and/or affect their response to targeted therapies. This review is an attempt to provide comprehensive information regarding molecular alterations related to the aggressiveness modulation in BRAF-mutated gliomas and the current knowledge on how to use those targeted therapies in such situations.

Early skeletal muscle deconditioning and reduced exercise capacity during (neo)adjuvant chemotherapy in patients with breast cancer.

BACKGROUND: Fatigue is a hallmark of breast cancer and is associated with skeletal muscle deconditioning. If cancer-related fatigue occurs early during chemotherapy (CT), the development of skeletal muscle deconditioning and its effect on exercise capacity remain unclear. The aim of this study was to investigate the evolution of skeletal muscle deconditioning and exercise capacity in patients with early-stage breast cancer during CT. METHODS: Patients with breast cancer had a visit before undergoing CT, at 8 weeks, and at the end of chemotherapy (post-CT). Body composition was determined through bioelectrical impedance analysis. Knee extensor, handgrip muscle force and fatigue was quantified by performing maximal voluntary isometric contractions and exercise capacity using the 6-min walking test. Questionnaires were also administered to evaluate quality of life, cancer-related fatigue, and physical activity level. RESULTS: Among the 100 patients, reductions were found in muscle mass (-2.3%, p = .002), exercise capacity (-6.7%, p < .001), and knee extensor force (-4.9%, p < .001) post-CT, which occurred within the first 8 weeks of treatment with no further decrease thereafter. If muscle fatigue did not change, handgrip muscle force decreased post-CT only (-2.5%, p = .001), and exercise capacity continued to decrease between 8 weeks and post-CT (-4.6%, p < .001). Quality of life and cancer-related fatigue were impaired after 8 weeks (p < .001) and remained stable thereafter, whereas the physical activity level remained stable during chemotherapy. CONCLUSIONS: Similar to cancer-related fatigue, skeletal muscle deconditioning and reduced exercise capacity occurred early during breast cancer CT. Thus, it appears essential to prevent these alterations through exercise training implemented during CT.

Impact of KRAS G12C mutation in patients with advanced non-squamous non-small cell lung cancer treated with first-line pembrolizumab monotherapy.

OBJECTIVES: Few data are available on the impact of KRAS mutation in patients with advanced non-squamous non-small cell lung cancer (aNSCLC) treated with immunotherapy. This analysis assessed the impact of KRAS mutation on the efficiency of first-line pembrolizumab immunotherapy in aNSCLC patients with PD-L1 ≥ 50 %. METHODS: This was a secondary analysis of the ESCKEYP study, a retrospective, national, multicenter study which included consecutively all metastatic NSCLC patients who initiated first-line treatment with pembrolizumab monotherapy from May 2017 (date of pembrolizumab availability in this indication in France) to November 22, 2019 (pembrolizumab-chemotherapy combination approval). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of pembrolizumab treatment by the Kaplan-Meier method. Tumor response and PFS were assessed locally. RESULTS: Among the 681 non-squamous aNSCLC PD-L1 ≥ 50 % patients treated with pembrolizumab in the first line, 227 (33.0 %) had a KRAS mutation (KRAS G12C, 12.5 %; KRAS non-G12C, 20.5 %). Except among non-smokers (KRAS G12C, 0 %; KRAS non-G12C, 2.9 %; no KRAS mutation, 9.2 %), patients presented no differences in terms of sex, age, number and sites of metastatic disease at diagnosis, use of corticosteroids, use of antibiotics, and for biological factors between wild-type KRAS, KRAS G12C and non-KRAS G12C groups. Median (95 % CI) PFS in months were 7.0 (3.7-14) for KRAS G12C, 4.8 (3.4-6.7) for KRAS non-G12C and 8.5 (7.3-10.6) for wild-type KRAS genotypes (p = 0.23). Median OS were 18.4 (12.6-NR), 20.6 (11.4-NR) and 27.1 (18.7-34.2) months, respectively (p = 0.57). CONCLUSION: No difference in efficacy was observed in non-squamous aNSCLC patients treated with first-line pembrolizumab immunotherapy whether they presented a KRAS G12C, non KRAS G12C or wild-type KRAS genotype.

Development of skeletal muscle atrophy and intermuscular adipose tissue in patients with early breast cancer treated with chemotherapy.

Chemotherapy is a common therapy to treat patients with breast cancer but also leads to skeletal muscle deconditioning. Skeletal muscle deconditioning is multifactorial and intermuscular adipose tissue (IMAT) accumulation is closely linked to muscle dysfunction. To date, there is no clinical study available investigating IMAT development through a longitudinal protocol and the underlying mechanisms remain unknown. Our study was dedicated to investigating IMAT content in patients with early breast cancer who were treated with chemotherapy and exploring the subsequent cellular mechanisms involved in its development. We included 13 women undergoing chemotherapy. Muscle biopsies and ultrasonography assessment were performed before and after chemotherapy completion. Histological and Western blotting analyses were conducted. We found a substantial increase in protein levels of three mature adipocyte markers (perilipin, +901%; adiponectin, +135%; FABP4, +321%; P < 0.05). These results were supported by an increase in oil red O-positive staining (+358%; P < 0.05). A substantial increase in PDGFRα protein levels was observed (+476%; P < 0.05) highlighting an increase in fibro-adipogenic progenitors (FAPs) content. The cross-sectional area of the vastus lateralis muscle fibers substantially decreased (-21%; P < 0.01), and muscle architecture was altered, as shown by a decrease in fascicle length (-15%; P < 0.05) and a decreasing trend in muscle thickness (-8%; P = 0.08). We demonstrated both IMAT development and muscle atrophy in patients with breast cancer who were treated with chemotherapy. FAPs, critical stem cells inducing both IMAT development and skeletal muscle atrophy, also increased, suggesting that FAPs likely play a critical role in the skeletal muscle deconditioning observed in patients with breast cancer who were treated with chemotherapy.

Outcome of lung oligometastatic patients treated with stereotactic body irradiation.

Purpose: The oligometastatic stage is an intermediate stage of cancer between the localized stage and polymetastatic stage. The prognosis of patients in this stage also appears to be intermediate. Lung stereotactic body radiotherapy is a possible tool for treating oligometastatic lung sites. The objective of our study was to evaluate the clinical outcomes in terms of local control, progression-free survival, overall survival, and toxicity of SBRT in oligometastatic patients with lung metastases from any solid primary tumor. Materials and methods: Clinical records of consecutive lung oligometastatic patients treated between January 2010 and December 2020 for lung SBRT at 60 Gy in 3- or 8-fraction schedules and a controlled primary tumor were retrospectively analyzed. Results: After a median follow-up of 20.3 months, local failure occurred for 14 lesions, 57 patients experienced lung progression, and 64 patients experienced disease progression. Overall survival rates at 1 and 2 years were 85.6 and 69.7%, respectively. Fifty-two patients experienced radiation pneumonitis, but only 2 patients were symptomatic and presented grade 2 late pneumonitis. No grade 3-4 toxicity was observed. ECOG 0 was the only prognostic factor for overall survival (HR = 3.5; 95% CI 3.2-3.8; p < 0.01). Conclusion: SBRT with a 60-Gy schedule in 8 fractions is an effective and well-tolerated treatment for patients with lung oligometastases from any solid primary tumor.

Ellipsoid calculations versus manual tumor delineations for glioblastoma tumor volume evaluation.

In glioblastoma, the response to treatment assessment is essentially based on the 2D tumor size evolution but remains disputable. Volumetric approaches were evaluated for a more accurate estimation of tumor size. This study included 57 patients and compared two volume measurement methods to determine the size of different glioblastoma regions of interest: the contrast-enhancing area, the necrotic area, the gross target volume and the volume of the edema area. The two methods, the ellipsoid formula (the calculated method) and the manual delineation (the measured method) showed a high correlation to determine glioblastoma volume and a high agreement to classify patients assessment response to treatment according to RANO criteria. This study revealed that calculated and measured methods could be used in clinical practice to estimate glioblastoma volume size and to evaluate tumor size evolution.

[Semantic analysis of online conversations on lung cancer: The WE-Lung research]. / Analyse sémantique de conversations sur le web portant sur le cancer du poumon : étude Web Ethnography-Lung.

INTRODUCTION: Today, patients with lung cancer and their relatives can easily search information on the Internet and express themselves online. METHODS: Within this web-ethnographic research, we found, based on 246 search terms related to lung cancer, and collected, a sample of 136 online conversations that were published between January 2004 and September 2018, including 1220 messages by 762 authors. RESULTS: The authors of messages, many of them close relatives of patients (35%), share their experience (34%). Seven areas of worrying concern, each of them prominent in 10 to 24% of the corpus, can be grouped under three headings: accepting the disease in order for the patient or their caregiver to fight it ("decide on the prognosis", "managing the treatments", "stopping the progression"), conjuring fate ("naming the guilty ones", "conjuring powerlessness"), asserting resilience ("adopt the right attitude" and "telling one's story in order to survive"). The question of time - disrupted, lost, to be caught up with or controlled - runs through all the issues. DISCUSSION: The patients' and caregivers' concerns go beyond the pace of medical treatment and beyond death. Their mental representations of the disease influence their adherence to the care pathway. Welcoming them in our care and dialogue goes hand in hand with personalized treatment.

Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients.

BACKGROUND: Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. METHODS: Women undergoing (neo)adjuvant anthracycline-cyclophosphamide and taxane-based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. RESULTS: Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching -52.0% for citrate synthase protein levels (P = 0.02) and -38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC-1α1 protein levels (-29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (-33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P < 0.02). Despite no change in mitochondrial respiratory capacity and COX IV protein levels, we found an elevation in H2 O2 production (P < 0.05 for all substrate additions) without change in antioxidant enzymes. We investigated the apoptosis pathway and found an increase in the protein expression of the apoptosis initiation marker Bax (+72.0%; P = 0.04), without variation in the anti-apoptotic protein Bcl-2. CONCLUSIONS: This study demonstrated major mitochondrial alterations subsequent to chemotherapy in early breast cancer patients: (i) a striking reduction in mitochondrial biogenesis, (ii) altered mitochondrial dynamics and potential mitophagy defects, (iii) exacerbated H2 O2 production, and (iv) increased initiation of apoptosis. All of these alterations likely explain, at least in part, the high prevalence of skeletal muscle and cardiorespiratory deconditioning classically observed in breast cancer patients.