Subclassification of pT3 urothelial carcinoma of the renal pelvicalyceal system is associated with recurrence-free and cancer-specific survival: proposal for a revision of the current TNM classification

Background

The clinical course of pT3 upper tract urothelial carcinoma (UTUC) is highly variable.

Objectives

The aim of the current study was to validate the clinical and prognostic importance of pT3 subclassification in the renal pelvicalyceal system in a large international cohort of patients.

Design, setting, and participants

From a multi-institutional international database, 858 renal pelvicalyceal tumors treated with radical nephroureterectomy (RNU) were systematically reevaluated by genitourinary pathologists. Category pT3 pelvic tumors were categorized as pT3a (infiltration of the renal parenchyma on a microscopic level only) versus pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

Intervention

RNU.

Measurements

Associations of pT3 subclassifications with clinicopathologic features were assessed with the chi-square test. Prognostic impact was assessed with the log-rank test and multivariable Cox regression analyses.

Results and limitations

Of 858 patients with renal pelvicalyceal tumors, 266 (31%) had pT3 disease. Of these, 146 (54.9%) were classified as pT3a and 120 (45.1%) as pT3b. Compared with pT3a, pT3b cancers were associated with higher tumor grade, nodal disease, and tumor necrosis. Ten-year recurrence-free (pT3a 58% vs pT3b 38%; p < 0.001) and cancer-specific (pT3a 60% vs pT3b 39%; p = 0.002) survival rates were lower for patients with pT3b disease. In multivariable analyses, classification pT3b was an independent predictor of both disease recurrence (hazard ratio [HR]: 1.8, p = 0.003) and cancer-specific mortality (HR: 1.7; p = 0.02). The major limitation is the retrospective character of the study.

Conclusions

Subclassification of pT3 renal pelvicalyceal UTUC helps identify patients who are at increased risk of disease progression and cancer-related death. Further research may help assess the value of subclassification and its inclusion in future editions of the American Joint Committee on Cancer–International Union Against Cancer TNM classification system.     

Cerebral air embolization in the Electrophysiology Laboratory during Transseptal Catheterization: Curative treatment of acute left hemiparesis with prompt hyperbaric oxygen therapy

We present a case of a 44 year-old man with medically refractory symptomatic paroxysmal atrial fibrillation in whom the initial attempt at left atrial catheter ablation was complicated by coronary and cerebral arterial air embolization during transseptal catheter exchange. The manifestations, management, and long term outcomes are detailed. Following the case report is a review of published reports and contemporary management strategies for treatment of acute air embolization. Dramatic clinical consequences can be aborted by prompt intervention including volume loading, oxygenation, lidocaine, and hyperbaric oxygen therapy.     

Exposure of Children to Environmental Tobacco Smoke (ETS) and Its Association with Respiratory Ailments

Objectives. To assess the impact of domestic passive smoking (cigarettes or narghile) on the development of respiratory ailments among children ages 10-15 years. Methods. Students were recruited from five private schools in Beirut, and information on demographic, in-home smoking, and students' respiratory tract illnesses (cough, wheezing, runny nose, or nasal congestion) were collected from each participant. Results. Of 625 students surveyed, 438 (70.1%) had at least one individual smoking at home. Compared with the nonexposed group, the odds ratio of having respiratory illness for children exposed to narghile or cigarette smoke were 2.3 (95% Confidence Iinterval [CI] 1.1-5.1) and 3.2 (95% CI 1.9-5.4), respectively. Conclusions. In addition to the well-established effect of smoking, domestic passive smoking of the misconceived “innocuous” habitual smoking device, narghile, is associated with significant respiratory health ailments.     

Predictive value of early EEG after epilepsy surgery.

To determine whether EEG performed within few months after epilepsy surgery is predictive of seizure outcome, 58 consecutive patients undergoing surgery for presumptive temporal lobe epilepsy (TLE) who had clinical follow-up of at least 2 years and EEG data available both pre- and postoperatively were analyzed. Patients were classified by preoperative brain magnetic resonance imaging into lesional, cryptogenic, and hippocampal sclerosis groups. Seizure outcome was classified according to Engel's outcome scale. Comparison was made between the presence of interictal epileptiform discharges (IEDs) in the postoperative EEG and seizure outcome. Patients who experienced seizures within 2 months after surgery were considered to have early recurrence. The mean follow-up period was 3 years. Sixty percent of patients achieved a class I seizure outcome. Almost all (95%) postoperative EEGs were obtained within 4 months after surgery. IEDs were present in 26% of postoperative EEGs, but were significantly less frequent in EEGs recorded after the first two postoperative months (P = 0.011). The presence of IEDs on postoperative EEGs was not predictive of seizure outcome either in the whole cohort or in any of the subgroups, regardless of whether it was performed within or after the first two postoperative months. It was also not predictive of outcome in the 44 patients (76%) who did not suffer early recurrence. The authors conclude that EEG performed a few months after epilepsy surgery is not useful as a predictor of long-term seizure outcome.     

Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways, such as phosphatidylinositol-3 kinase/Akt and Ras/mitogen-activated protein kinase (MAPK), have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the urogenital tumors. To investigate the mechanism of resistance to EGFR inhibition in bladder cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-3beta (GSK-3beta). We found that the resistance to the antiproliferative effects of gefitinib, in vitro as well as in vivo in nude mice models, was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-3beta activation and degradation of its target cyclin D1 were indicators of a high cell sensitivity to gefitinib. Further analysis of one phenotypic sensitive (253J B-V) and resistant (UM-UC13) cell lines revealed that platelet-derived growth factor receptor-beta (PDGFRbeta) activation was responsible for short circuiting the EGFR/MAPK pathway for mitogenic stimuli. However, invasion as well as actin dynamics were efficiently reduced by EGFR inhibition in UM-UC13. Chemical disruption of signaling pathways or of PDGFR kinase activity significantly reduced the inactive pool of cellular GSK-3beta in UM-UC13 cells. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in bladder cancer. Although this uncoupling may arise through different mechanisms, we suggest that the resistance of bladder cancer cells to EGFR blockade can be predicted early in the course of treatment by measuring the activation of GSK-3beta and of nuclear cyclin D1.     

Chronological age is not an independent predictor of clinical outcomes after radical nephroureterectomy

Purpose

Higher chronological age has been suggested to confer worse prognosis in patients with upper tract urothelial carcinoma (UTUC). The aim of the current study was to test this hypothesis in a large multicenter external validation cohort of patients treated with radical nephroureterectomy (RNU) while controlling for patient performance status.

Materials and methods

We retrospectively reviewed the data from 1,169 patients treated with RNU for UTUC. Age at RNU was analyzed both as a continuous and categorical variable (<50?years, n?=?66; 50?C59.9?years, n?=?185; 60?C69.9?years, n?=?367; 70?C79.9?years, n?=?419; ??80?years, n?=?132). Median follow-up was 37?months.

Results

Actuarial recurrence-free, cancer-specific, and all-cause survival estimates at 5?years after RNU were 69, 73, and 61%, respectively. Advanced age was associated with female gender, higher ECOG status, higher ASA score, and a lower probability of receiving adjuvant chemotherapy (all P values????0.02). In multivariable analyses, advanced age was associated with decreased recurrence-free (P?=?0.021), cancer-specific (P?=?0.002), and all-cause survival (P?P?>?0.001).

Conclusions

We confirmed that advanced patient age at the time of RNU is associated with worse clinical outcomes after surgery. However, ECOG performance status abrogated the association. Furthermore, a large proportion of elderly patients were cured with RNU. This suggests that chronological age alone is an inadequate indicator criterion to predict response of older UTUC patients to RNU.     

No overt influence of lymphadenectomy on cancer-specific survival in organ-confined versus locally advanced upper urinary tract urothelial carcinoma undergoing radical nephroureterectomy: a retrospective international, multi-institutional study

Purpose

Lymph node dissection (LND) is not routinely performed during radical nephroureterectomy (RNU) in upper tract urothelial carcinomas (UTUC), and its clinical relevance is unclear. The purpose of the present study was to evaluate the impact of LND on clinical outcomes in a large multicenter series of RNU for UTUC.

Methods

Detailed data on 785 patients subject to RNU were provided by nine international academic centers. The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were evaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models evaluated the association of nodal status with recurrence-free (RFS) and cancer-specific (CSS) survival.

Results

One hundred and ninety patients had LND. Pathological N stage was pN0 in 17%, pNx in 76%, and pN+ in 7%. The median follow-up period of the entire cohort was 34?months (interquartile range [IQR]: 15?C65?months). Overall, five-year RFS and CSS estimates were 72.2 and 76%, respectively. In multivariable Cox regression analyses, pN0/pNx substaging was not an independent predictor of either RFS (hazard ratio [HR]: 1.1; P?=?0.631) or CSS (HR: 1.3; P?=?0.223). Similar results were obtained in a subgroup analysis limited to patients with organ-confined disease (HR: 0.9; P?=?0.907 for RFS; HR: 0.4; P?=?0.419 for CSS). Conversely, in patients with locally advanced disease, patients with pN0 disease have significantly better cancer-related outcomes (HR: 0.3; P?P?Conclusion The present series suggests pNx is more significantly associated with a worse prognosis than pN0, but only in patients with locally advanced UTUC.