Expression of cell surface zinc transporter LIV1 in triple negative breast cancer is an indicator of poor prognosis and therapy failure.

Triple negative breast cancers (TNBC) are an aggressive molecular subtype of breast carcinoma (BC) identified by the lack of receptor expression for estrogen, progesterone, & human epidermal growth factor receptor-2. Lack of tangible drug targets warrants further research in TNBC. LIV1, is a zinc (Zn) transporter known to be overexpressed in few cancer types including BCs. Recently, in the United States of America, FDA approved the use of a new drug targeting LIV1, antibody drug conjugate SGN-LIV1A for treatment of TNBC patients. Though LIV1 also has a role in modulating immune cells by its differential transport of Zn, a correlation between the tumor cell expression of LIV1 and immune cell infiltrations were scantily reported. Further adequate baseline data on LIV1 expression in other populations have not been documented. Our objective was to screen a large Indian cohort of TNBC patient samples for LIV1, categorize the immune cell infiltration using CD4/CD8 expression and correlate the findings with therapy outcomes. Further, we also investigated for LIV1 expression in matched samples of primary & secondary tumors; pre & postchemotherapy in TNBC patients. Results showed an elevated expression of LIV1 in TNBC samples as compared to adjacent normal, the mean Q scores being 183.06 ± 6.39 and 120.78 ± 7.37 (p < 0.0001), respectively. Similarly, LIV1 levels were elevated in secondary tumors than primary & in patient samples postchemotherapy as compared to naïve. In the TNBC cohort, using automated method, cell morphology parameters were computed and analysis showed LIV1 levels were elevated in grade 3 TNBC samples presenting with altered cell morphology parameters namely cell size, cell perimeter, & nucleus size. Thus indicating LIV1 expressing TNBC samples portrayed an aggressive phenotype. Finally, TNBC patients with 3+ staining intensity showed poor survival (4.44 year) as compared to patients with 2+ LIV1 expression (5.47 year), emphasizing that LIV1 expression is a poor prognostic factor in TNBC. In conclusion, the study reports elevated expression of LIV1 in a large Indian TNBC cohort; high expression is a poor prognostic factor and correlated with aggressive disease and indicating the need for LIV1 targeted therapies.

Results of Temporary Drainage of Poorly Functioning Kidneys With Ureteropelvic Junction Obstruction: Does the Histology of Persistent Poor Functioning Kidneys Indicate an Increased Risk of Hypertension?

OBJECTIVE: To review our experience with managing poorly functioning kidneys with ureteropelvic junction obstruction (PFK-UPJO) with differential renal function (DRF) <10% by a trial of temporary drainage, as the management of such kidneys is controversial. We also studied the histopathologic changes in the nephrectomy specimens of persistent PFK-UPJO, as tubulointerstitial damage may predispose to hypertension. METHODS: A retrospective review of cases undergoing treatment for unilateral UPJO over 5-year period in 2 centers was conducted. In PFK-UPJO, 4-6 weeks trial of drainage with double J stent or percutaneous nephrostomy was employed. Those kidneys that improved DRF to >10% underwent pyeloplasty, while persistent PFK underwent nephrectomy; the specimens were studied for interstitial fibrosis/tubular atrophy (IF/TA), arterial lesions, and arteriole lesions. RESULTS: Of 402 patients with unilateral UPJO that underwent surgical management, 17 (4.1%) had PFK-UPJO. After 4-6 weeks trial of drainage, 6 kidneys (35.2%) with improved DRF underwent pyeloplasty, while 11 kidneys with persistent PFK underwent nephrectomy; significant IF/TA, arterial, and arteriolar changes were noted in 9 (82%), 9 (82%), and 4 (36%) kidneys, respectively, including 7 kidneys in normotensive children. Two (11.7%) children had hypertension at presentation; 1 child remains hypertensive even after nephrectomy. CONCLUSION: In PFK-UPJO, trial of temporary drainage seems appropriate to decide plan of management; 35% of such kidneys improved function after drainage. Most persistent PFK demonstrated severe and irreversible histologic changes that may predispose to hypertension if they are preserved, and we suggest that such kidneys may be removed. Long-term follow-up of all preserved PFK-UPJO is strongly recommended.

Comparison of different pathological markers in predicting pyeloplasty outcomes in children.

PURPOSE: To compare the efficacy of pathological markers like Interstitial cells of Cajal (ICC), neurons and Collagen to Muscle ratio (CM ratio), in predicting pyeloplasty outcomes. METHODS: Histological sections from 31 patients with UPJO were analyzed for ICC & neurons on immuno-histochemistry and CM ratio on Masson's trichrome staining. Post-operative outcomes were analyzed at 1-year follow up; expressed as excellent, moderate or mild improvement, static and deterioration based on the three factors: ultrasound grade, differential renal function and renogram drainage pattern. The pathological findings were correlated with clinical outcomes. RESULTS: The study group (n = 31) had a mean age 2.9 (0.6) years (M: F = 22:9). UPJ segment had significantly less ICC/neurons and more collagen compared to normal ureter (p = 0.001). Pathological parameters at the anastomosed end of ureter had a better correlation than those at UPJ with clinical outcome. CM ratio with a stronger correlation (r = - 0.94; p = 0.001) was a better predictor of prognosis than ICC (r = 0.76; p = 0.01) or neuron (r = 0.83; p = 0.01) density. ICC >10/HPF, neurons >6/HPF and CM ratio <1.2 at ureteric end anastomosed were predictors of success. CONCLUSIONS: CM ratio analysis at anastomosed ureter is a superior marker for predicting pyeloplasty outcomes. LEVEL OF EVIDENCE: Type 2: Development of diagnostic criteria in a consecutive series of patients.

A Rapid Special Staining Technique for Identification of Normal Ureter by Frozen Section in Children With Ureteropelvic Junction Obstruction.

BACKGROUND: The exact etiology of ureteropelvic junction obstruction (UPJO) is unknown, and inadequate excision of the narrow segment has been proposed as a cause of failure in 5% to 7% of cases of pyeloplasty. AIMS: To study whether frozen section can be useful to detect normal ureter distal to UPJO during pyeloplasty. METHODS: Histological sections from 31 patients with UPJO were analyzed for collagen to muscle ratio (CMR) on conventional (formalin) and rapid (frozen section) Masson's trichrome staining. Pathological findings were correlated with postoperative outcomes analyzed at 1-year follow-up and expressed as excellent, moderate, or mild improvement, static and deterioration based on ultrasound grade, differential renal function, and renogram drainage pattern. RESULTS: There was a very strong positive correlation (r = .94; P = .001) between CMR by conventional and rapid frozen Masson's trichrome staining. There was a very strong negative correlation between pyeloplasty outcomes and CMR on conventional staining (r = -.94; P = .001) or rapid frozen Masson's trichrome staining (r = -.91; P = .001). Regression analysis revealed that a CMR of 1.2 or less (95% confidence interval: 1.9-0.7) was associated with a successful outcome. CONCLUSIONS: It is feasible to intraoperatively identify normal ureter distal to UPJO using CMR analysis on the novel rapid frozen section technique reported.