Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification.

Chemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). However, predictive markers for patient selection are still missing. The aim of this study was a retrospective evaluation of the clinicopathological characteristics of pNEN patients receiving STZ-based chemotherapies and to identify predictive and prognostic markers.We retrospectively analyzed 77 patients treated at our center between 1995 and 2013. The median overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. Uni- and multivariate analyses were performed.The median PFS (mPFS) in patients receiving STZ/5-FU/Dox was 16 months with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as independent risk factors for shorter PFS. Additionally, performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities.STZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response

Immunohistochemiocal subtyping using CK20 and CK5 can identify urothelial carcinomas of the upper urinary tract with a poor prognosis

PURPOSE:Genome-wide analyses revealed basal and luminal subtypes of urothelial carcinomas of the bladder. It is unknown if this subtyping can also be applied to upper tract urothelial carcinomas. MATERIALS AND METHODS:Tumor samples from 222 patients with upper tract urothelial carcinomas who were treated with radical nephroureterectomy were analyzed for the expression of seven basal/luminal immunohistochemical markers (CK5, EGFR, CD44, CK20, p63, GATA3, FOXA1). RESULTS:Hierarchical clustering revealed a basal-like subtype (enrichment of CK5, EGFR and CD44) in 23.9% and a luminal-like subtype (enrichment of CK20, GATA3, p63 and FOXA1) in 13.1% of the patients. In 60.8%, little to no markers were expressed, whereas markers of both subtypes were expressed in 2.2%. By using CK5 and CK20 as surrogate markers for the basal and luminal subtypes, we defined four subtypes of upper tract urothelial carcinomas: (i) exclusively CK20 positive and CK5 negative (CK20+/CK5-), (ii) exclusively CK5 positive and CK20 negative (CK20-/ CK5+), (iii) both markers positive (CK20+/CK5+) and (iv) both markers negative (CK20-/CK5-). A receiver-operator analysis provided the optimal cut-off values for this discrimination. An immunoreactive score >1 for CK5 and >6 for CK20 were defined as positive. In multivariate Cox's regression analysis, the CK20+/CK5- subtype was an independent negative prognostic marker with a 3.83-fold increased risk of cancer-specific death (p = 0.02) compared to the other three subtypes. CONCLUSIONS:Immunohistochemical subgrouping of upper tract urothelial carcinomas by analyzing CK5 and CK20 expression can be performed in a routine setting and can identify tumors with a significantly worse cancer-specific survival prognosis

Response and predictive markers (in 64 evaluable patients).

<p>Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ORR = objective response rate, DCR = disease control rate, LN = lymph node, others = bone, lung, cerebral, peritoneal, lienal and adrenal gland, CTx = chemotherapy, PS = performance status.</p><p>Response and predictive markers (in 64 evaluable patients).</p

Multivariate analysis for prognostic indicators.

<p>Abbreviations: PS = performance status, OR = objective response, DC = disease control, HR = Hazard ratio, PFS = progression-free survival, OS = overall survival, CI = confidence interval.</p><p>Multivariate analysis for prognostic indicators.</p

Kaplan Meier survival analyses in patients treated with streptozocin.

<p>(A) Progression-free survival (mPFS = 16 months) for the entire group of patients (n = 64). (B) Overall survival (mOS = 28 months) for the entire group of patients (N = 64). (C) Association between Ki-67 and mPFS (cut-off 10%; 20 vs. 8 months, P = 0.015; N = 60) (D) Association between objective response (OR) and mPFS (20 vs 4 months, P < 0.001; N = 62).</p

Clinicopathological features of patients (N = 77).

<p>Abbreviations: CTx = chemotherapy, Dox = doxorubicin, STZ = streptozocin.</p><p>Clinicopathological features of patients (N = 77).</p

Heatmap and cluster dendrogram demonstrating the expression patterns of CK5 and CK20 in UTUC.

<p>Using CK5 and CK20 as surrogate markers for the subtypes, hierarchical clustering again found four subtypes: a basal-like subtype with high CK5 expression (green cluster), a luminal-like subtype with high CK20 expression (red cluster); a subtype with expression of CK5 and CK20 (blue cluster); a cluster without a predominant expression of CK5 nor CK20 (black cluster).</p

Cancer-specific survival depending on subtype of UTUC defined by CK5 and CK20 expression using IRS cut-off values determined by ROC analysis.

<p>Using ROC analysis the optimal IRS cut-off values for CK5 and CK20 were defined. IRS scores >1 for CK5 and >6 for CK20 were defined as high expression. Using these cut-off values to define the four subgroups, the CK20+/CK5- subtype showed a significantly worse cancer-specific survival when compared to the other subtypes.</p