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.

Think of the Conus Medullaris at the Time of Diagnosis of Fetal Sacral Agenesis.

BACKGROUND: There is no precise prenatal indicator to refine an accurate prognosis in case of sacral agenesis and to define the diagnostic approach and outcome criteria in case of fetal sacral agenesis using 3 characteristics of the conus medullaris (CM): its position, its appearance, and associated spinal abnormalities. METHODS: Ten cases of prenatally diagnosed sacral agenesis were included between 1995 and 2014 after collating ultrasound findings and prenatal computed tomography data. RESULTS: Two cases of total sacral agenesis and 8 of partial agenesis were included. There were 1 or more spinal abnormalities in 8/10 cases: 6 lipomas, 4 low-lying tethered cords, 2 diastematomyelias, and 1 syringomyelia. Three situations were distinguished: sacral agenesis with low-lying tethered cord, sacral agenesis with a truncated CM, and sacral agenesis with CM in place. If the sacral agenesis is isolated, a lipoma should be sought. Lipomas of the filum have a good prognosis, whereas lipomas of the CM cause neurological deficits in 1/3 of cases. When there is a low-lying tethered cord, a diastematomyelia or a syringomyelia may be associated. In truncated CM, there may be a severe form suggestive of caudal regression syndrome. Serious ultrasound signs are immobility of the lower limbs, talipes equinovarus, impaired bladder emptying, and dilatation of the upper urinary tract. CONCLUSION: A precise description of the morphology of the CM, its position, and associated spinal malformations are important in defining the neurological, urinary, gastrointestinal, and motor functions prognosis in cases of fetal sacral agenesis.

Brain and lung metastasis of Bartholin's gland adenoid cystic carcinoma: a case report.

INTRODUCTION: Adenoid cystic carcinoma of Bartholin's gland is a very rare disease. CASE PRESENTATION: A 48-year-old premenopausal woman of Caucasian origin was delivered adjuvant pelvic and inguinal radiotherapy after prior complete left Bartholin's gland tumor excision and inguinal lymph node dissection for adenoid cystic carcinoma of Bartholin's gland with one metastatic inguinal lymph node.Two years after primary treatment, she presented to the Emergency Room with acute headache, hypoacousia, decrease in visual acuity, and a decrease in right leg muscle strength. A cranial magnetic resonance imaging scan demonstrated three cystic brain lesions with associated perifocal edema. Chest and abdomen computed tomography scans and a magnetic resonance imaging scan of the pelvis did not find any metastatic or residual disease elsewhere. A physical examination found no local recurrence.Stereotactic brain biopsies with pathology examination revealed the presence of adenoid cystic carcinoma metastasis. She thus received 30Gy of brain radiotherapy but, three months later, the brain lesions did not decrease in size and left mid lobular lung lesions appeared on her chest computed tomography scan. A mid left lobe lung excision was undertaken followed by chemotherapy consisting of six cycles of cyclophosphamide, adriamycin and cisplatin. Five months after beginning chemotherapy, the brain disease progressed and our patient died. CONCLUSION: Our case report shows the difficulty in managing brain and lung metastasis of Bartholin's gland adenoid cystic carcinoma as no consensus on the optimal treatment exists.