Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving ...force behind metastatic breast cancer, with promising therapeutic implications.
Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort.
Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
AIM： To report the experience of the CHU Sart Tilman, University of Liege, Belgium, in the management of appendiceal carinoid tumor. METHODS： A retrospective review of 1237 appendectomies performed ...in one single centre from January 2000 to May 2004, was undertaken. Analysis of demographic data, clinical presentation, histopathology, operative reports and outcome was presented. RESULTS： Among the 1237 appendectomies, 5 appendiceal carcinoid tumors were identified （0.4%） in 4 male and 1 female patients, with a mean age of 29.2 years （range： 6-82 years）. Acute appendicitis was the clinical presentation for all patients. Four patients underwent open appendectomy and one a laparoscopic procedure. One patient was reoperated to complete the excision of mesoappendix. All tumors were located at the tip of the appendix with a mean diameter of 0.6 cm （range： 0.3-1.0 cm）. No adjuvant therapy was performed. All patients were alive and disease-free during a mean follow-up of 33 mo. CONCLUSION： Appendiceal carcinoid tumor most of-ten presents as appendicitis. In most cases, it is found incidentally during appendectomies and its diagnosis is rarely suspected before histological examination. Appendiceal carcinoid tumor can be managed by simple appendectomy and resection of the mesoappendix, if its size is ≤ 1cm.
The development of localization studies and quick parathyroid hormone assay (QPTH) has allowed the development of focused surgery in sporadic primary hyperparathyroidism. The aim of this ...investigation was to determine whether localization studies select a specific population of patients.
From 1999 to 2001, 213 patients underwent surgery for sporadic primary hyperparathyroidism. All were investigated with sestamibi scanning and ultrasonography. When at least 1 study showed a positive result (n
=
175), the patient underwent a video-assisted approach with QPTH. When results were negative (n
=
38), the patient underwent cervicotomy and exploratory procedures of all 4 parathyroid glands.
All patients are cured (mean follow-up, 17.8±10.3 months SD). Patients with negative preoperative study results had a high risk of multiglandular disease (12/38 patients; 31,6%), compared with patients with 1 positive study result (3/83 patients; 3.6%;
P<.0001) and those with 2 concordant positive study results (0/92 patients;
P<.0001).
When preoperative localization study results are negative, the patient has a high risk of multiglandular disease, and a conventional cervicotomy with identification of the 4 glands is recommended strongly. When only 1 localization study is positive, the risk of multiglandular disease justifies the use of QPTH during a focused approach. When positive localization study results are concordant, the use of QPTH is questionable during a focused approach.
We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes ...randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8–12·7).
In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293.
Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5–81·0) in the no axillary dissection group, compared with 74·9% (70·5–79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65–1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 3% in the no axillary dissection group vs 40 9% in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae.
The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8–12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer.
International Breast Cancer Study Group.
Adrenal ganglioneuroma Maweja, Sylvie, M.D; Materne, Roland, M.D., Ph.D; Detrembleur, Nancy, M.D ...
The American journal of surgery,
11/2007, Letnik:
194, Številka:
5
Journal Article, Web Resource
Recenzirano
Abstract Background A 20-year-old man was referred after having been discovered a left adrenal incidentaloma. Characteristics on magnetic resonance imaging (MRI) suggested the diagnosis of adrenal ...ganglioneuroma or carcinoma. Pathological examination after adrenalectomy concluded it was an adrenal ganglioneuroma. We studied the characteristics of adrenal ganglioneuroma. Methods We retrospectively reviewed hormonal status, computed tomography and MRI features, and histological findings of our series of 8 adrenal ganglioneuromas. Results Specific features were: (1) no hormonal hypersecretion; (2) presence of calcifications, no vessel involvement; and a non-enhanced attenuation of less than 40 Hounsfield units on computed tomography; and (3) low non-enhanced T1-weighted signal, a slightly high and heterogeneous T2-weighted signal, and a late and gradual enhancement on dynamic MRI, especially if associated with a whorled pattern. Conclusions Even if many aggressive tumors share some of those radiological features, the presence of all or most of them must lead the clinician to consider the diagnosis of adrenal ganglioneuroma.
Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CASR) plays a key role in maintaining calcium homeostasis and study of the CASR gene can ...be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novel CASR gene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CASR function.
A 16-year-old patient had mild hypercalcemia associated with low-normal urinary calcium excretion and normal-to-high parathyroid hormone (PTH) levels. Because of negative family history, familial hypocalciuric hypercalcemia was originally excluded. The second patient was a 54-year-old man with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild hypercalciuria. Familial investigation revealed the same phenotype in the patient's sister. The coding region of the CASR gene was sequenced in both probands and their available first-degree relatives.
The first patient had a novel heterozygous inactivating CASR mutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activating CASR mutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive.
We reported two novel heterozygous mutations of the CASR gene, an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6. These cases illustrate the importance of genetic testing of CASR gene to aid correct diagnosis and to assist in clinical management.
The creation of arteriovenous fistula (AVF) may retard chronic kidney disease progression in the general population. Conversely, the impact of AVF closure on renal function in kidney transplant ...recipients (KTRs) remains unknown.
From 2007 to 2013, we retrospectively categorized 285 KTRs into three groups: no AVF (Group 0, n = 90), closed AVF (Group 1, n = 114) and left-open AVF (Group 2, n = 81). AVF closure occurred at 653 ± 441 days after kidney transplantation (KTx), with a thrombosis:ligation ratio of 19:95. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease equation. Linear mixed models calculated the slope and intercept of eGFR decline versus time, starting at 3 months post-KTx, with a median follow-up of 1807 days (95% confidence interval 1665-2028).
The eGFR slope was less in Group 1 (-0.081 mL/min/month) compared with Group 0 (-0.183 mL/min/month; P = 0.03) or Group 2 (-0.164 mL/min/month; P = 0.09). Still, the eGFR slope significantly deteriorated after (-0.159 mL/min/month) versus before (0.038 mL/min/month) AVF closure (P = 0.03). Study periods before versus after AVF closure were balanced to a mean of 13.5 and 12.5 months, respectively, with at least 10 observations per patient ( n = 99).
In conclusion, a significant acceleration of eGFR decline is observed over the 12 months following the closure of a functioning AVF in KTRs.
Breast desmoid-type fibromatosis (BDF) is a rare mesenchymal tumor accounting for only 0.2% of solid breast tumors. It is classified as an intermediate tumor because it is locally aggressive but has ...no metastatic potential. Its diagnosis is often difficult because it shares many clinical and radiologic aspects with breast carcinomas and therefore relies on anatomopathological analysis which may be supplemented by genetic analysis. The treatment of BDF has considerably evolved in the past years. While surgery was the cornerstone of the management prior to the 2000s, recent data have shown the value of active surveillance (AS) from the time of diagnosis. Indeed, after 2 years of AS, the progression-free survival (PFS) of the disease is identical or superior to surgery. Moreover, spontaneous regression has been observed in 30% of patients undergoing AS. In case of disease progression, surgery can be considered on a case-by-case basis, as well as systemic treatments.
We present a case of bilateral BDF affecting a 20-year-old woman for whom the first suggested treatment was bilateral mastectomy with reconstruction. After a second opinion, the decision was revised and AS was initiated. Almost 3 years after the onset of AS, tumors have shown a continuous regression.
This case demonstrates the need for experience in the management of mesenchymal tumors to avoid overtreatment by mutilating surgeries which promote recurrence. Moreover, to our knowledge, very few cases of bilateral BDF have been published to date. It thus seemed relevant for us to report this rare case which supports the interest of AS for DF, as recently advised by the Desmoid Tumor Working Group guidelines.
Key Points
Surgical AVF ligation in KTRs is associated with a significant increase in diastolic BP while systolic BP remains stable.
AVF closure in KTRs leads to an improvement of LV and LA ...morphology and a decrease in serum NT-proBNP levels.
There is no significant effect of AVF ligation on kidney allograft function: The eGFR remains stable over time.
Background
Kidney transplantation is considered as the best kidney replacement therapy, and arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The systematic ligation of a functioning AVF in stable kidney transplant recipients (KTRs) remains debatable.
Methods
In this prospective study, we investigated the hemodynamic effect of the surgical closure of AVF in KTRs. Forty-three KTRs underwent an ambulatory BP monitoring before surgical closure of AVF (T0) and 12 months later (M12), as well as measurement of serum cardiac biomarkers (
i.e.
, soluble suppression of tumorigenicity 2, N-terminal pro b-type natriuretic peptide NT-proBNP, and galectin-3). Serum tests were also performed 6 months after AVF closure (M6). An echocardiographic examination was performed at each time point. All serum creatinine values were collected to compare the individual eGFR slopes before versus after AVF closure. The latest measure of the AVF flow before kidney transplantation was recorded.
Results
Diastolic BP significantly rose from T0 to M12: +4.4±7.3 mm Hg (
P
= 0.0003) for 24h, +3.8±7.4 mm Hg (
P
= 0.0018) during the day, and +6.3±9.9 mm Hg (
P
= 0.0002) during the night, leading to an increased proportion of KTRs with European Society of Hypertension (ESH)-defined arterial hypertension after AVF ligation. No change was observed for systolic BP. NT-proBNP significantly dropped between T0 and M6 (345 190; 553 to 230 118; 458 pg/ml,
P
= 0.0001) and then remained stable from M6 to M12 while suppression of tumorigenicity 2 and galectin-3 levels did not change from T0 to M12. We observed a significant decrease in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV mass, interventricular septum diameter, left atrial volume, and tricuspid annular plane systolic excursion from T0 to M6 and then a stability from M6 to M12. LV ejection fraction and eGFR slope remained stable during the whole study. These observations remained unchanged after adjustment for AVF flow.
Conclusion
The closure of a patent AVF in KTRs is associated with elevation of diastolic BP, drop in serum NT-proBNP levels, reduction of left ventricular and atrial dimensions, and stability of eGFR slope.
Podcast
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Kidney transplantation (KTx) is considered as the best kidney replacement therapy and arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The systematic ligation of a ...functioning AVF in stable kidney transplant recipients remains debatable.
In this prospective study, we investigated the hemodynamic impact of the surgical closure of AVF in KTRs. Forty-three KTRs underwent an ambulatory blood pressure monitoring (24h-ABPM) before surgical closure of AVF (T0) and 12 months later (M12), as well as measurement of serum cardiac biomarkers (i.e., soluble suppression of tumorigenicity 2 (ST2), N-terminal pro b-type natriuretic peptide (NT-proBNP) and Galectin-3). Serum tests were also performed 6 months after AVF closure (M6). An echocardiographic exam was done at each time-point. All serum creatinine values were collected to compare the individual eGFR slopes before versus after AVF closure. The latest measure of the AVF flow (QAVF) prior to KTx was recorded.
Diastolic blood pressure (DBP) significantly raised from T0 to M12: + 4.4±7.3 mmHg (p=0.0003) for 24h, + 3.8±7.4 mmHg (p=0.0018) during the day, and + 6.3±9.9 mmHg (p=0.0002) during the night, leading to an increased proportion of KTRs with ESH-defined arterial hypertension after AVF ligation. No change was observed for systolic BP. NT-proBNP significantly dropped between T0 and M6 (345 190; 553 to 230 118; 458 pg/mL, p=0.0001) and then remained stable from M6 to M12, while ST2 and Galectin-3 levels did not change from T0 to M12. We observed a significant decrease of left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV mass, interventricular septum diameter, left atrial (LA) volume, and tricuspid annular plane systolic excursion from T0 to M6, and then a stability from M6 to M12. LV ejection fraction and eGFR slope remained stable during the whole study. These observations remained unchanged after adjustment for QAVF.
The closure of a patent AVF in KTRs is associated with elevation of DBP, drop of serum NT-proBNP levels, reduction of LV/LA dimensions, and stable eGFR slope.
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