Minimally Invasive Radical Hysterectomy for Cervical Cancer Is Associated With Reduced Morbidity and Similar Survival Outcomes Compared With Laparotomy.

STUDY OBJECTIVE: To assess outcomes of women with cervical cancer undergoing upfront radical hysterectomy (RH) via a minimally invasive surgery (MIS) or a traditional laparotomy (XL) approach at 2 large US academic institutions to determine whether the mode of surgery affects patient outcomes. DESIGN: Retrospective cohort study (Canadian Task Force classification II-1). SETTING: Two academic medical institutions in the United States. PATIENTS: Women undergoing upfront RH for cervical cancer between 2000 and 2013. INTERVENTION: Minimally invasive techniques (laparoscopic and robotic) for RH compared with XL. MEASUREMENTS AND MAIN RESULTS: A total of 383 women met the eligibility requirements. Of these, 101 underwent an MIS (i.e., traditional laparoscopy, laparoendoscopic single site, or robotic) approach, and 282 underwent an XL approach. Overall survival (median not reached; p = .29) was not different between the 2 groups. Recurrence was rare and equivalent in the 2 groups, affecting 5.0% of patients in the MIS group and 6.4% of those in the XL group (p = .86). Pelvic lymph nodes were dissected in 98% of patients in the MIS group and 97% of those in the XL group (p > .99) and were found to be positive in 10.9% and 8.5% of those patients, respectively (p = .55). The mean number of pelvic lymph nodes retrieved was higher in the MIS group (19.4 vs 16.0; p < .001). There was no between-group difference in the rate of postoperative chemotherapy (p = .32) or radiation therapy (p = .28). Surgical margins were positive in 5.0% of specimens in the MIS group and in 4.6% of specimens in the XL group (p = .54). Although there was no difference in the overall rate of complications (15.1% and 17.2%, respectively; p = .87), laparotomy was associated with a higher median estimated blood loss (EBL) (50 cm3 vs 500 cm3) and a higher rate of perioperative blood transfusion (3.0% vs 26.2%; p < .001). Length of perioperative hospital stay was significantly shorter in the MIS group (1.9 days vs 4.9 days; p < .001). CONCLUSION: MIS RH does not compromise patient outcomes, including overall survival, rate of recurrence, and the frequency of pelvic lymph node dissection or positivity. Morbidity was decreased in the MIS group, including decreased EBL, fewer blood transfusions, and shorter hospital stay.

Renal injury is a third hit promoting rapid development of adult polycystic kidney disease.

The 'two-hit' model is a widely accepted genetic mechanism for progressive cyst formation in autosomal dominant polycystic kidney disease. We have previously shown that adult inactivation of Pkd1 using the Mx1Cre(+) allele causes a late onset of focal cystic disease. An explanation for the delayed appearance of cysts is the requirement for an additional independent factor, or 'third hit'. Here we show that renal injury leads to massive cystic disease in the same mouse line. Cysts are labeled with a collecting duct/tubule marker, Lectin Dolichos biflorus Agglutinin, which correlates with the site of Cre-mediated recombination in the collecting system. 5-Bromo-2'-deoxyuridine labeling reveals that cyst-lining epithelial cells are comprised of regenerated cells in response to renal injury. These data demonstrate, for the first time, a role for polycystin-1 in kidney injury and repair and indicate that renal injury constitutes a 'third hit' resulting in rapid cyst formation in adulthood.

Pkd1 inactivation induced in adulthood produces focal cystic disease.

Autosomal dominant polycystic kidney disease, the most common monogenetic disorder, is characterized by gradual replacement of normal renal parenchyma by fluid-filled cysts. Mutations in either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease. Pkd1(-/-) or Pkd2(-/-) mice develop rapid renal cystic disease and exhibit embryonic lethality; this supports the "two-hit" hypothesis, which proposes that a germline mutation in PKD1 (or PKD2) followed by a second somatic mutation later in life is responsible for the phenotype. Here, for investigation of the loss of Pkd1 at specific times of development, an inducible Pkd1-knockout mouse model was generated. Inactivation of Pkd1 in 5-wk-old mice resulted in formation of only focal renal cysts 6 to 9 wk later but in a severe polycystic phenotype nearly 1 yr later. Cysts derived from either collecting tubules or distal tubules but not from proximal tubules, which correlated with sites of Cre-mediated recombination. Inactivation of Pkd1 in 1-wk-old mice, however, resulted in massive cyst disease 6 wk later, despite a similar pattern of Cre-mediated recombination between 1- and 5-wk-old kidneys. Moreover, a germline heterozygous Pkd1 mutation facilitated cyst formation when a somatic Pkd1 mutation was induced. A marked increase in proliferating cell nuclear antigen expression was observed in cyst-lining epithelia and in normal-looking tubules adjacent to but not in those distant from cysts. These data suggest that Pkd1 inactivation is not sufficient to initiate the cell proliferation necessary for cyst formation; a paracrine mechanism may account for focal cell proliferation and regional disease progression. We propose that an additional genetic or nongenetic "third hit" may be required for rapid development of cysts in polycystic kidney disease.

Assessment of treatment factors and clinical outcomes in cervical cancer in older women compared to women under 65 years old.

OBJECTIVE: This study aims to understand the treatment patterns and clinical outcomes of older women with cervical cancer compared to younger women. METHODS: Women undergoing care for cervical cancer between 2000 and 2013 at two academic institutions were identified. The cohort of older patients was defined as >65 years old at diagnosis. Patient charts were retrospectively reviewed, and clinical variables were extracted. Fisher's exact tests, logistic regression, and Kaplan-Meier analyses were performed. RESULTS: From 2000 to 2013 1119 women with cervical cancer were identified. Of these, 191 (17.0%) were >65 years old at the time of diagnosis. Older women were more likely to present with higher stage disease (p < 0.001). Controlling for stage, older women were less likely to undergo surgery during their treatment course (38% versus 70%, p < 0.001) and more likely to undergo radiation (77% versus 52%, p < 0.001), but no more likely to receive chemotherapy (p = 0.34). If they did undergo surgery, older women were less likely to have a pelvic lymph node dissection performed (41% versus 61%, p = 0.04), though the rate of positive pelvic lymph nodes was not different (p = 0.80). Overall survival was decreased in the older cohort (p < 0.001). A multivariate model identified age > 65 (HR 1.76, 95%CI 1.30-2.40), stage (HR 2.77, 95%CI 2.40-3.21), and ever undergoing surgery (HR 0.60, 95%CI 0.44-0.82) as independently associated with overall survival. CONCLUSIONS: Women over age 65 with cervical cancer are less likely to undergo surgical management and were observed to have a decreased overall survival, even when controlling for use of surgery and stage of disease.

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B-lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with α3ß1 integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD.