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.

Dynamic profiling of immune microenvironment during anti-PD-1 immunotherapy for head and neck squamous cell carcinoma: the IPRICE study.

BACKGROUND: Immune checkpoint inhibitors of programmed cell death protein 1 (PD-1) represent a significant breakthrough in treating head and neck squamous cell carcinoma (HNSCC), with long-lasting responses and prolonged survival observed in first- and second-line therapy. However, this is observed in < 20% of patients and high primary/secondary resistance may occur. The primary objective of the identification of predictive factors for the response to anti-PD-1 immunotherapy in head and neck squamous cell carcinoma (IPRICE) study is to identify predictive factors of response to anti-PD-1 immunotherapy. METHODS: The IPRICE study is a single-center, prospective, non-randomized, open-label, and interventional clinical trial. Liquid and tumor biopsies will be performed in 54 patients with recurrent/metastatic (R/M) HNSCC undergoing anti-PD-1 immunotherapy alone to compare the evolution of gene expression and immunological profile between responders and non-responders. We will use a multidisciplinary approach including spatial transcriptomics, single seq-RNA analysis, clinical data, and medical images. Genes, pathways, and transcription factors potentially involved in the immune response will also be analyzed, including genes involved in the interferon-gamma (IFN-γ) pathway, immunogenic cell death and mitophagy, hypoxia, circulating miRNA-mediated immunomodulation, cytokines, and immune repertoire within the tumor microenvironment (TME). With a follow-up period of 3-years, these data will help generate effective biomarkers to define optimal therapeutic strategy and new immunomodulatory agents based on a better understanding of primary/secondary resistance mechanisms. Tumor biopsy will be performed initially before the start of immunotherapy at the first tumor assessment and is only proposed at tumor progression. Clinical data will be collected using a dedicated Case Report Form (CRF). DISCUSSION: Identifying predictive factors of the response to anti-PD-1 immunotherapy and optimizing long-term immune response require a thorough understanding of the intrinsic and acquired resistance to immunotherapy. To achieve this, dynamic profiling of TME during anti-PD-1 immunotherapy based on analysis of tumor biopsy samples is critical. This will be accomplished through the anatomical localization of HNSCC, which will allow for the analysis of multiple biopsies during treatment and the emergence of breakthrough technologies including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. TRIAL REGISTRATION: Clinicaltrial.gov. Registered April 14, 2022, https://www. CLINICALTRIALS: gov/study/NCT05328024 .

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.

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.

Incidental axillary dose delivery to axillary lymph node levels I-III by different techniques of whole-breast irradiation: a systematic literature review.

BACKGROUND AND OBJECTIVE: In breast cancer treatment, radiotherapy is an essential component for locoregional management. Axillary recurrence in patients with invasive breast carcinoma remains an issue. The question of whether breast irradiation may unintentionally include levels I, II, and III, and may decrease the risk of axillary recurrence, remains a topic of discussion. PATIENTS AND METHODS: A literature search was performed in PubMed and the Cochrane Library to identify articles that have published data regarding dose-volume analysis of axillary levels in breast irradiation. The following MESH terms were used: "breast cancer/lymph nodes" AND "radiotherapy dosage." RESULTS: Thirteen articles were identified. The irradiation technique, initial dose prescribed to the breast, delineated volumes, and dose received at axillary levels were heterogeneous. The average dose delivered to axilla levels I, II, and III with three-dimensional conformal radiotherapy using standard fields (ST) ranged between 22 and 43.5 Gy, 3 and 35.6 Gy, and 1.0 and 20.5 Gy, respectively. The average doses delivered to axilla levels I, II, and III with three-dimensional conformal radiotherapy using "high tangential" fields (HT) ranged between 38 and 49.7 Gy, 11 and 47.1 Gy, and 5 and 44.7 Gy, respectively. Finally, the average doses delivered to axilla levels I, II, and III using intensity-modulated radiation therapy (IMRT) were between 14.5 and 42.6 Gy, 3.4 and 35 Gy, and 1.2 and 25.5 Gy, respectively. CONCLUSION: Our literature review suggests that the incidental dose delivered to the axilla during whole-breast irradiation is heterogenous and dependent on the irradiation technique used. However, whether this observation can be translated into a therapeutic effect is still a matter of debate.

Persistent taxane-induced neuropathy in elderly patients treated for localized breast cancer.

Breast cancer is the most common cancer among women. Localized breast cancer treatments involve taxanes which are often responsible for acute peripheral neuropathy. The persistence of taxane-induced peripheral neuropathy (TIPN) is scarcely described among elderly women. A monocenter historical cohort study including all women over 65 years of age treated between 2001 and 2016 with a taxane-based chemotherapy for localized breast cancer was carried out at the Paul Strauss Regional Comprehensive Cancer Center. All cases included were followed up for at least 2 years, deaths from causes unrelated to TIPN were excluded. We report on the frequency and risk factors and establish a prognostic score of persistent Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and 3 TIPN. Among the 302 included patients, 21% and 9% developed persistent TIPN of grade 2 and 3, respectively. Two patients died from complications of grade 3 TIPN. Risk factors of persistent grade 2 and higher neuropathy included age (P < .0001), body mass index (P < .0001), and diabetes (P = .0093). Persistent TIPN was more frequent with paclitaxel than docetaxel (OR = 5.43; P < .0001). Patients presenting all four major risk factors had a 97.2% probability of developing long-term symptoms against 1.2% for patients showing no risk factor. We therefore identified 3 prognostic groups. TIPN is a frequent and sometimes severe persistent side effect of breast cancer treatment among elderly women with a major impact on health-related quality of life. Chemotherapy regimens without taxane could therefore be a valid option in elderly patients with neurotoxicity risk factors.

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 with 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 with concentric cycling sessions matched for power output (CON power ; 80% of concentric peak power output, 95 ± 23 W) or oxygen uptake ( ; 10 ± 2 mL·min·kg -1 ). Preexercise to postexercise changes (30-s 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 and lactate dehydrogenase activities were measured in the plasma before and 24 h after exercise as markers of muscle damage. RESULTS: Compared with CON power (-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 CON power (-39% ± 21% and -40% ± 16%, P > 0.99) but lower in ( P < 0.001). The CON power session resulted in twofold greater compared with the ECC and sessions ( P < 0.001). No change in creatine kinase or lactate dehydrogenase activity was reported from preexercise to 24 h postexercise. CONCLUSIONS: The ECC session induced greater neuromuscular fatigue compared with the concentric cycling sessions without generating severe muscle damage. ECC is a promising exercise modality for counteracting neuromuscular maladaptation in patients with breast cancer.

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.

Consequences of Discontinuing a 4/6 Cyclin D-Dependent Kinase Inhibitor During Endocrine Treatment in Hormone-Sensitive Metastatic Breast Cancer Patients in the Context of the COVID-19 Outbreak.

BACKGROUND: The impact of some hasty medical decision made during the first wave of the Coronavirus Disease 2019 (COVID-19) remains unknown. We have evaluated the consequences of one of these precautionary measures: the withdrawal of the cyclin D-dependent kinases 4/6 inhibitor (CDK4/6i) in patients whose metastatic disease was controlled by a combination of endocrine treatment and CDK 4/6i. METHOD: This study was noninterventional, retrospective, multicentric, and included 60 patients with HR+ HER2- metastatic disease. Their disease was controlled with the combination of endocrine treatment and CDK 4/6i. The CDK 4/6i was stopped for two months during the first COVID-19 outbreak. A univariate analysis was performed to assess the risk factors associated with disease progression. RESULTS: During this therapeutic break, 22 (37 %) patients had a radiological and/or clinical disease progression. Among them, the CDK 4/6i was re-introduced to 16 patients (n = 16/22; 73 %). A new line of treatment (chemotherapy or targeted therapy) was initiated due to the rapid symptomatic tumor progression in four patients (n = 4/22; 18 %). Two patients (n = 2/22) died in visceral crisis before another anti-tumoral treatment was introduced. In univariate analysis, the presence of liver metastases increased the risk of metastatic disease progression during the withdrawal of the CDK 4/6 (OR = 6.6; 95 % CI 1.87-23.22; P= .0033). CONCLUSION: Progression was observed in 37% of patients during the two-month treatment interruption of the CDK 4/6i. A prolonged CDK 4/6i treatment interruption in patients with clinical benefit on endocrine treatment does not seem to be a reasonable option in light of these results.

The Impact of an Incidental Dose on Axillary Tumor Control and Toxicity in Localized Breast Cancer: A Retrospective Analysis.

PURPOSE: The dosimetric analysis of the incidental axillary dose delivered to axillary lymph node levels I-III by different techniques of whole breast irradiation and the analysis of prognostic factors of axillary recurrence of breast cancer. METHODS: We perform a retrospective analysis that includes 171 patients with localized breast carcinoma irradiated at Centre Paul Strauss. To be included in the study, patients had to have a histological confirmation of breast cancer diagnosis, surgical treatment without axillary lymph node dissection (ALND), whole breast irradiation without axillary irradiation by a specific field, and a treatment plan available. RESULTS: Three patients had lymph node recurrence. There was no significant correlation between the maximal or mean dose delivered at the three axillary levels and the risk of axillary lymph node recurrence. There was no significant correlation between the irradiation technique and the risk of axillary lymph node recurrence. Two patients, both in the HT group, had lymphoedema. There was significantly more lymphoedema in the HT group than in the ST and IMRT groups (p < 0.048). The mean dose in level II was significantly higher in the group of patients with lymphoedema (3.45 Gy (1.08; 9.62) vs. 23.4 Gy (23.1; 23.6)) (p < 0.02). CONCLUSION: The irradiation technique has an influence on the incidental dose delivered to the axillary area, but has no influence on the risk of axillary recurrence. The risk of lymphoedema could be related to the use of HT and the mean dose delivered at level II.

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.

Efficacy of trastuzumab emtansine (T-DM1) and lapatinib after dual HER2 inhibition with trastuzumab and pertuzumab in patient with metastatic breast cancer: Retrospective data from a French multicenter real-life cohort.

PURPOSE: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies. METHODS: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine. RESULTS: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS. CONCLUSION: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine.

New-onset systemic sclerosis and scleroderma renal crisis under docetaxel.

Systemic sclerosis is a rare systemic autoimmune disease characterized by microvascular impairment and fibrosis of the skin and other organs with poor outcomes. Toxic causes may be involved. We reported the case of a 59-year-old woman who developed an acute systemic sclerosis after two doses of adjuvant chemotherapy by docetaxel and cyclophosphamide for a localized hormone receptor + human epithelial receptor 2-breast cancer. Docetaxel is a major chemotherapy drug used in the treatment of breast, lung, and prostate cancers, among others. Scleroderma-like skin-induced changes (morphea) have been already described for taxanes. Here, we report for the first time a case of severe lung and kidney flare with thrombotic microangiopathy after steroids for acute interstitial lung disease probably induced by anti-RNA polymerase III + systemic sclerosis after docetaxel.

Expression of immune response biomarkers (PD­L1, p16, CD3+ and CD8+ TILs) in recurrent head and neck squamous cell carcinoma within previously irradiated areas.

The immune landscape of head and neck squamous cell carcinoma in pretreated areas remains poorly documented. We aimed to assess the tumor microenvironment for biomarkers of antitumor immune responses in tumors in previously irradiated areas compared with de novo tumors. This retrospective monocentric study analyzed 100 paraffin­embedded surgical samples of invasive head and neck squamous cell carcinoma (oral cavity, oropharynx, larynx, hypopharynx) from patients who underwent surgery between January 2010 and November 2017. We compared the immune microenvironment in 50 de novo tumors and 50 tumors recurring within irradiated areas. We used immunohistochemistry to assess p16 status, CD3+/CD8+ tumor­infiltrating lymphocytes (TILs), and programmed death­ligand 1 (PD­L1) expression on tumor and immune cells in stromal and intratumoral components. CD3+ TIL counts were significantly lower in intratumoral and stromal components (P=0.003 and P=0.020, respectively) in the irradiated area cohort; there was no significant difference between CD8+ TIL counts in the two cohorts. The percentage of tumors with PD­L1+ tumor cells (tumor proportion score ≥1%) was significantly lower within the irradiated area cohort than the de novo cohort (56.0% vs. 86.0%, P<0.001). There were also significantly fewer tumors with PD­L1+ immune cells in the irradiated area cohort. Predominantly, tumors from the irradiated area cohort had microenvironments classified as 'adaptive immune resistance'. There was persistence of cytotoxic cells in tumors in the irradiated areas but lower PD­L1 expression and CD3+ TIL counts than in the de novo tumors. This offers an initial hypothesis to explain why these lesions are less responsive to immunotherapy, even though they may still have antitumor capacities. Assessment of immune response biomarkers in patients treated with immunotherapy in randomized trials is required.

Impact of Neck Dissection in Head and Neck Squamous Cell Carcinomas of Unknown Primary.

PURPOSE: Management of head and neck cancers of unknown primary (HNCUP) combines neck dissection (ND) and radiotherapy, with or without chemotherapy. The prognostic value of ND has hardly been studied in HNCUP. METHODS: A retrospective multicentric study assessed the impact of ND extent (adenectomy, selective ND, radical/radical-modified ND) on nodal relapse, progression-free survival (PFS) or survival, taking into account nodal stage. RESULTS: 53 patients (16.5%) had no ND, 33 (10.2%) had lymphadenectomy, 116 (36.0%) underwent selective ND and 120 underwent radical/radical-modified ND (37.3%), 15 of which received radical ND (4.7%). With a 34-month median follow-up, the 3-year incidence of nodal relapse was 12.5% and progression-free survival (PFS) 69.1%. In multivariate analysis after adjusting for nodal stage, the risk of nodal relapse or progression was reduced with lymphadenectomy, selective or radical/modified ND, but survival rates were similar. Patients undergoing lymphadenectomy or ND had a better PFS and lowered nodal relapse incidence in the N1 + N2a group, but the improvement was not significant for the N2b or N2 + N3c patients. Severe toxicity rates exceeded 40% with radical ND. CONCLUSION: In HNCUP, ND improves PFS, regardless of nodal stage. The magnitude of the benefit of ND does not appear to depend on ND extent and decreases with a more advanced nodal stage.

Unilateral or bilateral irradiation in cervical lymph node metastases of unknown primary? A retrospective cohort study.

INTRODUCTION: Patients with cervical lymphadenopathy of unknown primary carcinoma (CUP) usually undergo neck dissection and irradiation. There is an ongoing controversy regarding the extent of nodal and mucosal volumes to be irradiated. We assessed outcomes after bilateral or unilateral nodal irradiation. METHODS: This retrospective multicentre study included patients with CUP and squamous cellular carcinoma who underwent radiotherapy (RT) between 2000 and 2015. RESULTS: Of 350 patients, 74.5% had unilateral disease and 25.5% had bilateral disease. Of 297 patients with available data on disease and irradiation sides, 61 (20.5%) patients had unilateral disease and unilateral irradiation, 155 (52.2%), unilateral disease and bilateral irradiation and 81 (27.3%), bilateral disease and bilateral irradiation. Thirty-four (9.7%) and 217 (62.0%) patients received neoadjuvant and/or concomitant chemotherapy, respectively. Median follow-up was 37 months. Three-year local, regional, locoregional failure rates and CUP-specific survival were 5.6%, 11.7%, 15.0% and 84.7%, respectively. In patients with unilateral disease, the 3-year cumulative incidence of regional/local relapse was 7.7%/4.3% after bilateral irradiation versus 16.9%/11.1% after unilateral irradiation (hazard ratio = 0.56/0.61, p = 0.17/0.32). The cumulative incidence of CUP-specific deaths was 9.2% after bilateral irradiation and 15.5% after unilateral irradiation (p = 0.92). In multivariate analysis, mucosal irradiation was associated with better local control, whereas no neck dissection, ≥N2b and interruption of RT for more than 4 days were associated with poorer regional control. Toxicity was higher after bilateral irradiation (p < 0.05). No positron-emission tomography-computed tomography, largest node diameter, ≥N2b, neoadjuvant chemotherapy and interruption of RT were associated with poorer cause-specific survival. CONCLUSION: Bilateral nodal irradiation yielded non-significant better nodal and mucosal control rates but was associated with higher rates of severe toxicity.

[Advances in the management of cervical lymphadenopathies of unknown primary: advances in diagnostic imaging and surgical modalities and new international staging system]. / Évolutions dans la prise en charge des métastases ganglionnaires cervicales sans cancer primitif retrouvé : avancées diagnostiques et nouvelle classification TNM.

INTRODUCTION: Cervical lymphadenopathies of unknown primary represent 3 % of head and neck cancers. Their diagnostic work up has largely changed in recent years. This review provides an update on diagnostic developments and their potential therapeutic impact. MATERIALS AND METHODS: This is a systematic review of the literature. RESULTS: In recent years, changes in epidemiology-based prognostic factors such as human papilloma virus (HPV) cancers, advances in imaging and minimally invasive surgery have been integrated in the management of cervical lymphadenopathies of unknown primary. In particular, systematic use of PET scanner and increasing practice of robotic or laser surgery have contributed to increasing detection rate of primary cancers. These allow more adapted and personalized treatments. The impact of changes in the eighth TNM staging system is discussed. CONCLUSION: The management of cervical lymphadenopathies of unknown primary cancer has changed significantly in the last 10 years. On the other hand, practice changes will have to be assessed.