Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome.

INTRODUCTION: Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. METHODS: In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: We included 191 patients. After NAC, 107 (56%) patients had breast conserving surgery (BCS) and 84 (44%) patients underwent mastectomy. Tumor-positive margins were observed in 67 (35%) patients. Fifty five (51%) had BCS and 12 (14%) underwent mastectomy (p value < 0.001). Re-excision was performed in 35 (33%) patients with BCS and in 4 (5%) patients with mastectomy. Definitive surgery was mastectomy in 107 (56%) patients and BCS in 84 (44%) patients. Tumor-positive margins were associated with cT ≥ 3 status (OR 4.62, 95% CI 1.26-16.98, p value 0.021) in the BCS group. Five-year LRR (4.7%), RFS (81%), and OS (93%) were not affected by type of surgery after NAC. CONCLUSION: Although 33% of ILC breast cancer patients undergoing BCS after NAC required re-excision for positive resection margins, it is considered safe given that five-year RFS remained excellent and LRR and OS did not differ by extent of surgery.

Low-GDP, pH-neutral solutions preserve peritoneal endothelial glycocalyx during long-term peritoneal dialysis.

BACKGROUND: During peritoneal dialysis (PD), solute transport and ultrafiltration are mainly achieved by the peritoneal blood vasculature. Glycocalyx lies on the surface of endothelial cells and plays a role in vascular permeability. Low-glucose degradation product (GDP), pH-neutral PD solutions reportedly offer higher biocompatibility and lead to less peritoneal injury. However, the effects on the vasculature have not been clarified. METHODS: Peritoneal tissues from 11 patients treated with conventional acidic solutions (acidic group) and 11 patients treated with low-GDP, pH-neutral solutions (neutral group) were examined. Control tissues were acquired from 5 healthy donors of kidney transplants (control group). CD31 and ratio of luminal diameter to vessel diameter (L/V ratio) were evaluated to identify endothelial cells and vasculopathy, respectively. Immunostaining for heparan sulfate (HS) domains and Ulex europaeus agglutinin-1 (UEA-1) binding was performed to assess sulfated glycosaminoglycans and the fucose-containing sugar chain of glycocalyx. RESULTS: Compared with the acidic group, the neutral group showed higher CD31 positivity. L/V ratio was significantly higher in the neutral group, suggesting less progression of vasculopathy. Both HS expression and UEA-1 binding were higher in the neutral group, whereas HS expression was markedly more preserved than UEA-1 binding in the acidic group. In vessels with low L/V ratio, which were found only in the acidic group, HS expression and UEA-1 binding were diminished, suggesting a loss of glycocalyx. CONCLUSION: Peritoneal endothelial glycocalyx was more preserved in patients treated with low-GDP, pH-neutral solution. The use of low-GDP, pH-neutral solutions could help to protect peritoneal vascular structures and functions.

No Relation Between Peritoneal Fibrosis and Free Water Transport in a Rat Model.

Free water transport (FWT) during peritoneal dialysis (PD) can easily be measured by Na+ kinetics. In long-term PD, FWT might reflect peritoneal fibrosis, but morphologic or functional relationships have not been investigated. Nonconventional dialysis solutions might be associated with better preservation of peritoneal tissues and function. We developed a long-term peritoneal exposure model in rats with impaired kidney function and investigated peritoneal morphology and function in that model after exposure to conventional and nonconventional solutions.Two studies were reanalyzed. Transport was assessed using a standard peritoneal permeability analysis adapted for the rat. Omental tissue was stained with picro-sirius red (PSR) for uniform quantification of fibrosis. A semiquantitative fibrosis score was also calculated.Rats (n = 9) exposed to a conventional solution for 16 weeks were compared with rats (n = 9) exposed to other solutions. Peritoneal transport parameters were similar, but the degree of fibrosis tended to be more severe in the conventional-solution group. Compared with the situation in humans, the contribution of FWT to ultrafiltration in rats was larger than that of small-pore fluid transport. No correlation between the percentage PSR positivity and FWT was observed. A marked difference in PSR positivity was found between the two studies.The long-term exposure model is not suitable for the study of relationships between FWT and peritoneal fibrosis. Quantitative assessment of the fibrosis is difficult.

New Insights into the Effects of Chronic Kidney Failure and Dialysate Exposure on the Peritoneum.

♦ INTRODUCTION: Chronic uremia and the exposure to dialysis solutions during peritoneal dialysis (PD) induce peritoneal alterations. Using a long-term peritoneal exposure model, we compared the effects of chronic kidney failure (CKD) itself and exposure to either a 'conventional' or a 'biocompatible' dialysis solution on peritoneal morphology and function. ♦ METHODS: Wistar rats (Harlan, Zeist, the Netherlands) were grouped into: normal kidney function (NKF), CKD induced by 70% nephrectomy, CKD receiving daily peritoneal infusions with 3.86% glucose Dianeal (CKDD), or Physioneal (both solutions from Baxter Healthcare, Castlebar, Ireland) (CKDP). At 16 weeks, a peritoneal function test was performed, and histology, ultrastructure, and hydroxyproline content of peritoneal tissue were assessed. ♦ RESULTS: Comparing CKD with NKF, peritoneal transport rates were higher, mesothelial cells (MC) displayed increased number of microvilli, blood and lymph vasculature expanded, vascular basal lamina appeared thicker, with limited areas of duplication, and fibrosis had developed. All alterations, except lymphangiogenesis, were enhanced by exposure to both dialysis fluids. Distinct MC alterations were observed in CKDD and CKDP, the latter displaying prominent basolateral protrusions. In addition, CKDP was associated with a trend towards less fibrosis compared to CKDD. ♦ CONCLUSIONS: Chronic kidney failure itself induced peritoneal alterations, which were in part augmented by exposure to glucose-based dialysis solutions. Overall, the conventional and biocompatible solutions had similar long-term effects on the peritoneum. Importantly, the latter may attenuate the development of fibrosis.

Can Plasma Hyaluronan and Hyaluronidase Be Used As Markers of the Endothelial Glycocalyx State in Patients with Kidney Disease?

Hyaluronan (HA) is widely spread in the body and is an important component of the extracellular matrix, including the endothelial glycocalyx (EG). Essential for its vasculoprotective function, HA is involved in vascular permeability and many other processes. In patients with kidney disease, plasma HA is higher than expected, but the extent to which plasma HA and its degrading enzyme hyaluronidase can be used as markers for the state of the EG has not yet been determined. In the first part of this review, we describe HA synthesis and degradation; we then focus on the involvement of the kidney in the process. In the second part, we summarize the available data on HA and hyaluronidase in patients with kidney failure. Plasma HA is somewhat elevated in kidney failure and predicts for poor survival in dialysis patients. The increased HA levels in kidney failure are probably a result of decreased excretion, but an upregulated turnover cannot be ruled out with certainty in some patients. Hyaluronan might be involved in the regulation of peritoneal transport in PD.

Lymphangiogenesis and Lymphatic Absorption Are Related and Increased in Chronic Kidney Failure, Independent of Exposure to Dialysis Solutions.

Increased lymphatic absorption might contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphangiogenesis develops during PD, but little is known about the relationship between its morphologic and functional parameters. The relationships between lymph vessel density, the effective lymphatic absorption rate (ELAR), and fibrosis were investigated in a rat model of chronic kidney failure (CKD) with exposure to dialysis solutions. Wistar rats (n = 44) were allocated to these groups: NKF (normal kidney function), CKD (70% nephrectomy), CKDD [CKD, with daily intraperitoneal (i.p.) Dianeal 3.86% (Baxter Healthcare BV, Utrecht, Netherlands)], CKDP [CKD, with daily i.p. Physioneal 3.86% (Baxter Healthcare BV)]. After 16 weeks, a peritoneal function test was performed, and the ELAR was calculated from the disappearance rate of i.p. dextran 70. The lymph vessel profile density (LVPD) was assessed using STEPanizer image analysis (Java application from Tschanz SA, Bern, Germany) of omental sections after anti-podoplanin immunostaining. Fibrosis was quantified by picro-sirius red staining. The LVPD was significantly increased in CKD rats compared with NKF rats, and no additional effect of dialysis solutions was present. The ELAR was increased in uremic rats compared with NKF rats. For all rats together, the LVPD correlated positively with the ELAR and with the amount of fibrosis. Chronic kidney disease itself induces lymphangiogenesis and fibrosis and increases the ELAR, independent of exposure to dialysis fluids. The ELAR is related to the LVPD in peritoneal tissue.

Is the systemic microvascular endothelial glycocalyx in peritoneal dialysis patients related to peritoneal transport?

BACKGROUND/AIMS: The capillary wall coated by the endothelial glycocalyx is the main transport barrier during peritoneal dialysis (PD). Here, we investigated the relationships between measurements of the systemic endothelial glycocalyx and peritoneal transport in PD patients. METHODS: We performed sidestream darkfield (SDF) imaging of the sublingual microvasculature in 15 patients, measured the perfused boundary region (PBR), which includes the permeable part of the glycocalyx, and calculated the estimated blood vessel density (EBVD). All patients underwent a peritoneal permeability analysis. RESULTS: No relationships were present between the imaging and peritoneal transport parameters, neither in the group as a whole nor in fast transporters. In patients with nonfast peritoneal transport status, PBR had a negative relationship with EBVD and small solute transport, and a positive one with net ultrafiltration (NUF). The EBVD showed a positive correlation with glucose absorption and a negative one with NUF. We found no relationships with the peritoneal transport of albumin. CONCLUSIONS: No relationships are present between the systemic endothelial glycocalyx, which was assessed by SDF, and peritoneal transport. In nonfast transporters, a reduction in blood vessel density caused by endothelial glycocalyx alterations or a thicker permeable phase of the glycocalyx delaying the access of small solutes to the small pores may be important. .

Damage of the endothelial glycocalyx in dialysis patients.

Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD.