Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

BACKGROUND

Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

METHODS

Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes.

RESULTS

Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC.

CONCLUSIONS

Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018. © 2018 American Cancer Society.

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Phyllodes tumors of the breast: The British Columbia Cancer Agency experience

Publication date: Available online 7 March 2018
Source:Cancer/Radiothérapie
Author(s): M.F. Rodrigues, P.T. Truong, E.C. McKevitt, L.M. Weir, M.A. Knowling, E.S. Wai
PurposePhyllodes tumors of the breast are uncommon fibroepithelial lesions for which optimal management remains unclear. This retrospective population-based study reports treatment and outcomes for patients with phyllodes tumors and evaluates characteristics that influence outcome.Materials and methodsData were analysed on 183 patients with newly diagnosed phyllodes tumors from 1999 to 2014. Five-year Kaplan-Meier local recurrence and survival were compared between cohorts with benign (n=83), borderline (n=50) and malignant phyllodes tumor (n=49) histology.ResultsMedian (range) follow-up was 65 (0.5–197) months. Local excision was performed in 163 and mastectomy in 19 patients. Eleven patients with malignant phyllodes tumors received radiation therapy. Overall, local recurrence occurred in 8.7%, distant metastases in 4.4%, and cause specific deaths in 3.8%. Five-year Kaplan-Meier outcomes among women with benign, borderline, and malignant phyllodes tumors were: local recurrence 6% vs 9% vs 21%, P=0.131; overall survival 96% vs 100% vs 82%, P=0.002; and disease-free survival 94% vs 91% vs 67%, P<0.001. Five-year Kaplan-Meier local recurrence among women with negative vs close vs positive margins were 8% vs 6% vs 37%, P<0.001. Corresponding rates for intermediate vs pushing vs infiltrative borders were 6% vs 6% vs 33%, P=0.006. Positive margins and infiltrative tumor borders were associated with increased local recurrence (all P≤0.006), and the latter remained significant in exploratory analyses after adjusting for margin status and phyllodes tumor classification.ConclusionsFive-year outcomes among women with phyllodes tumors were comparable to those reported in the literature. Exploratory analysis has suggested that infiltrative tumor borders may be used in conjunction with margin status to assess local recurrence risk.



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Phyllodes tumors of the breast: The British Columbia Cancer Agency experience

Publication date: Available online 7 March 2018
Source:Cancer/Radiothérapie
Author(s): M.F. Rodrigues, P.T. Truong, E.C. McKevitt, L.M. Weir, M.A. Knowling, E.S. Wai
PurposePhyllodes tumors of the breast are uncommon fibroepithelial lesions for which optimal management remains unclear. This retrospective population-based study reports treatment and outcomes for patients with phyllodes tumors and evaluates characteristics that influence outcome.Materials and methodsData were analysed on 183 patients with newly diagnosed phyllodes tumors from 1999 to 2014. Five-year Kaplan-Meier local recurrence and survival were compared between cohorts with benign (n=83), borderline (n=50) and malignant phyllodes tumor (n=49) histology.ResultsMedian (range) follow-up was 65 (0.5–197) months. Local excision was performed in 163 and mastectomy in 19 patients. Eleven patients with malignant phyllodes tumors received radiation therapy. Overall, local recurrence occurred in 8.7%, distant metastases in 4.4%, and cause specific deaths in 3.8%. Five-year Kaplan-Meier outcomes among women with benign, borderline, and malignant phyllodes tumors were: local recurrence 6% vs 9% vs 21%, P=0.131; overall survival 96% vs 100% vs 82%, P=0.002; and disease-free survival 94% vs 91% vs 67%, P<0.001. Five-year Kaplan-Meier local recurrence among women with negative vs close vs positive margins were 8% vs 6% vs 37%, P<0.001. Corresponding rates for intermediate vs pushing vs infiltrative borders were 6% vs 6% vs 33%, P=0.006. Positive margins and infiltrative tumor borders were associated with increased local recurrence (all P≤0.006), and the latter remained significant in exploratory analyses after adjusting for margin status and phyllodes tumor classification.ConclusionsFive-year outcomes among women with phyllodes tumors were comparable to those reported in the literature. Exploratory analysis has suggested that infiltrative tumor borders may be used in conjunction with margin status to assess local recurrence risk.



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The role of sciatic nerve block to complement femoral nerve block in total knee arthroplasty: a meta-analysis of randomized controlled trials

Abstract

Introduction

Femoral nerve block (FNB) appears to have higher postoperative analgesic benefits compared with the patient-controlled analgesia (PCA) in total knee arthroplasty (TKA). However, the role of sciatic nerve block (SNB) as a complement to FNB remains controversial. We performed a meta-analysis assessing the benefits of the SNB as a complement to FNB, as well as comparing the efficacy of single-injection versus continuous SNB in TKA.

Methods

Our group conducted a systematic literature search in PubMed, EMBASE and Google Scholar. We retrieved randomized trials comparing either SNB versus placebo or continuous versus single-injection SNB. The intervention group was the use of SNB as a complement to FNB, while the control group was FNB alone. Pain score at rest and movement (at 4, 12, 24, 48 and 72 h), patient-controlled intravenous opioid consumption, length of hospital stay, and incidence of nausea were extracted from each study. Random-effects model was used for meta-analysis and standardized mean difference (SMD) was used as the effect size.

Results

Ten articles comprising 514 patients were included to compare the effects of SNB combined with FNB versus FNB alone. Interventional group was found to significantly reduce pain score at for 4 h (SMD = − 0.94, 95% CI − 1.42 to − 0.47, P < 0.001, I² = 76.5%) compared with the control group. Pain score at rest was significantly reduced at movement for 12 h (SMD = − 0.29, 95% CI − 0.54 to − 0.04, P = 0.02, I² = 0%). Opioid consumption was significantly reduced at 24 (SMD = − 0.60, 95% CI − 1.01 to − 0.17, P = 0.01, I² = 69.1%) and 48 h (SMD = − 1.04, 95% CI − 1.46 to − 0.61, P < 0.001, I² = 43.4%) after TKA using SNB as a complement to FNB. Three articles were additionally meta-analyzed to compare the efficacy of single-injection (n = 79) versus continuous SNB (n = 79), being the latter one significantly associated with less pain score at 24 (SMD = -0.77, 95% CI − 1.10 to − 0.45, P < 0.001, I² = 0%) and 48 h (SMD = − 0.69, 95% CI − 1.01 to − 0.36, P < 0.001, I² = 0%), but not at 12 h (SMD = − 0.34, 95% CI − 0.73 to − 0.06, P = 0.10, I² = 0%).

Conclusions

This meta-analysis provides evidence-based supports to the benefits of SNB as a complement to FNB in TKA. The combination sciatic–femoral nerve block appears to be the optimal choice for patients in high risk of postoperative opioids consumption or acute pain after TKA.

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PD-1 and PD-L1 inhibitors after platinum-based chemotherapy or in first-line therapy in cisplatin-ineligible patients

Summary

Until recently, there were no true innovations in the management of locally advanced (aUC) and metastatic urothelial cancer (mUC) in the last three decades. Vinflunine has been approved by the EMA (European Medicines Agency) with only limited improvement compared to best supportive care in second line treatment. In addition, gemcitabine/cisplatin has been established as an alternative to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The advent of checkpoint inhibitors (CPI) revolutionized the care of these patients, transforming a unanimously deadly disease into one with hope through sustained disease control. Five immune CPI have recently been approved for aUC/mUC by the US Food and Drug Administration (FDA) including atezolizumab, nivolumab, pembrolizumab, durvalumab and avelumab. All five CPI are FDA-approved as second-line therapy with atezolizumab and pembrolizumab also being approved for first-line therapy in cisplatin-ineligible patients. The rapid acceptance in the treatment algorithm of UC is based on the impressive clinical efficacy of these agents in some patients, combined with their excellent safety profile. These new agents are indeed the most important advancement in UC care. However, the challenge in the age of precision medicine is to identify the patients who are most likely to benefit from CPIs, as the majority of patients do not respond to CPI. Toward this goal, validation of clinical, molecular and imaging biomarkers that serve for prediction and monitoring of treatment response are of central necessity.

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PD-1 and PD-L1 inhibitors after platinum-based chemotherapy or in first-line therapy in cisplatin-ineligible patients

Summary

Until recently, there were no true innovations in the management of locally advanced (aUC) and metastatic urothelial cancer (mUC) in the last three decades. Vinflunine has been approved by the EMA (European Medicines Agency) with only limited improvement compared to best supportive care in second line treatment. In addition, gemcitabine/cisplatin has been established as an alternative to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The advent of checkpoint inhibitors (CPI) revolutionized the care of these patients, transforming a unanimously deadly disease into one with hope through sustained disease control. Five immune CPI have recently been approved for aUC/mUC by the US Food and Drug Administration (FDA) including atezolizumab, nivolumab, pembrolizumab, durvalumab and avelumab. All five CPI are FDA-approved as second-line therapy with atezolizumab and pembrolizumab also being approved for first-line therapy in cisplatin-ineligible patients. The rapid acceptance in the treatment algorithm of UC is based on the impressive clinical efficacy of these agents in some patients, combined with their excellent safety profile. These new agents are indeed the most important advancement in UC care. However, the challenge in the age of precision medicine is to identify the patients who are most likely to benefit from CPIs, as the majority of patients do not respond to CPI. Toward this goal, validation of clinical, molecular and imaging biomarkers that serve for prediction and monitoring of treatment response are of central necessity.

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Development of the functional social network index for adolescent and young adult cancer survivors

BACKGROUND

To the authors' knowledge, social network status in adolescent and young adult (AYA) cancer survivors has not been adequately studied to date. The authors developed and validated a functional social network index (FSNI) for AYA survivors, and compared its performance with that of 2 traditional indices (density and betweenness centrality).

METHODS

A total of 102 AYA survivors and 102 noncancer controls who were matched for age, sex, and race were recruited from an Internet panel. Each participant reported relationships with up to 25 close friends and/or relatives. The authors developed a FSNI with reported marital status, contact frequency with friends/relatives, available resources for emotional and tangible support, and available resources for physical activity and weight management advice. Linear regression was used to analyze associations between the FSNI and cancer diagnoses, treatments, and coping skills.

RESULTS

Based on the FSNI, survivors were found to have more available resources for emotional support (beta [b] = 3.02; P = .003), tangible support (b = 4.17; P<.001), physical activity advice (b = 3.94; P<.001), and weight management advice (b = 4.10; P<.001) compared with noncancer controls. Survivors of lymphoma had the largest FSNI, whereas survivors of central nervous system malignancies had the smallest (b = 2.77; P = .02). A higher FSNI was associated with better coping skills: less denial (b = 0.10; P = .01), using emotional support (b = 0.08; P = .04), using instrumental support (b = 0.12; P<.001), less behavioral disengagement (b = 0.08; P = .04), venting of emotions (b = 0.10; P = .004), positive reframing (b = 0.12; P = .003), planning for the future (b = 0.08; P = .03), and religious engagement (b = 0.16; P<.001). Density and betweenness centrality indices demonstrated neither significant differences in social networks between cancer survivors and controls (all P values >.05) nor significant associations with coping skills (all P values >.05).

CONCLUSIONS

The FSNI appears to provide a better social network assessment for AYA cancer survivors than traditional indices. Cancer 2018. © 2018 American Cancer Society.

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