The Impact of Histological Subtype on the Incidence, Timing, and Patterns of Recurrence in Patients with Renal Cell Carcinoma After Surgery-Results from RECUR Consortium

Background: Current follow-up strategies for patients with renal cell carcinoma (RCC) after curative surgery rely mainly on risk models and the treatment delivered, regardless of the histological subtype. Objective: To determine the impact of RCC histological subtype on recurrence and to examine the incidence, pattern, and timing of recurrences to improve follow-up recommendations. Design, setting, and participants: This study included consecutive patients treated surgically with curative intention (ie, radical and partial nephrectomy) for non-metastatic RCC (cT1-4, M0) between January 2006 and December 2011 across 15 centres from 10 countries, as part of the euRopEan association of urology renal cell carcinoma guidelines panel Collaborative multicenter consortium for the studies of follow-Up and recurrence patterns in Radically treated renal cell carcinoma patients (RECUR) database project. Outcome measurements and statistical analysis: The impact of histological subtype (ie, clear cell RCC [ccRCC], papillary RCC [pRCC], and chromophobe RCC [chRCC]) on recurrence-free survival (RFS) was assessed via univariate and multivariate analyses, adjusting for potential interactions with important variables (stage, grade, risk score, etc.) Patterns of recurrence for all histological subtypes were compared according to recurrence site and risk criteria. Results and limitations: Of the 3331 patients, 62.2% underwent radical nephrectomy and 37.8% partial nephrectomy. A total of 2565 patients (77.0%) had ccRCC, 535 (16.1%) had pRCC, and 231 (6.9%) had chRCC. The median postoperative follow-up period was 61.7 (interquartile range: 47-83) mo. Patients with ccRCC had significantly poorer 5-yr RFS than patients with pRCC and chRCC (78% vs 86% vs 91%, p = 0.001). The most common sites of recurrence for ccRCC were the lung and bone. Intermediate-/high-risk pRCC patients had an increased rate of lymphatic recurrence, both mediastinal and retroperitoneal, while recurrence in chRCC was rare (8.2%), associated with higher stage and positive margins, and predominantly in the liver and bone. Limitations include the retrospective nature of the study. Conclusions: The main histological subtypes of RCC exhibit a distinct pattern and dynamics of recurrence. Results suggest that intermediate- to high-risk pRCC may benefit from cross-sectional abdominal imaging every 6 mo until 2 yr after surgery, while routine imaging might be abandoned for chRCC except for abdominal computed tomography in patients with advanced tumour stage or positive margins. Patient summary: In this analysis of a large database from 15 countries around Europe, we found that the main histological subtypes of renal cell carcinoma have a distinct pattern and dynamics of recurrence. Patients should be followed differently according to subtype and risk score. (C) 2020 Published by Elsevier B.V. on behalf of European Association of Urology.Peer reviewe

Management of Sporadic Renal Angiomyolipomas: A Systematic Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma Guidelines Panel

CONTEXT: Little is known about the natural history of sporadic angiomyolipomas (AMLs); there is uncertainty regarding the indications of treatment and treatment options. OBJECTIVE: To evaluate the indications, effectiveness, harms, and follow-up of different management modalities for sporadic AML to provide guidance for clinical practice. EVIDENCE ACQUISITION: A systematic review of the literature was undertaken, incorporating Medline, Embase, and the Cochrane Library (from 1 January 1990 to 30 June 2017), in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. No restriction on study design was imposed. Patients with sporadic AML were included. The main interventions included active surveillance, surgery (nephron-sparing surgery and radical nephrectomy), selective arterial embolisation, and percutaneous or laparoscopic thermal ablations (radiofrequency, microwaves, or cryoablation). The outcomes included indications for active treatment, AML growth rate, AML recurrence rate, risk of bleeding, post-treatment renal function, adverse events of treatments, and modalities of follow-up. Risk of bias assessment was performed using standard Cochrane methods. EVIDENCE SYNTHESIS: Among 2704 articles identified, 43 were eligible for inclusion (zero randomised controlled trials, nine nonrandomised comparative retrospective studies, and 34 single-arm case series). Most studies were retrospective and uncontrolled, and had a moderate to high risk of bias. CONCLUSIONS: In active surveillance series, spontaneous bleeding was reported in 2% of patients and active treatment was undertaken in 5%. Active surveillance is the most chosen option in 48% of the cases, followed by surgery in 31% and selective arterial embolisation in 17% of the cases. Selective arterial embolisation appeared to reduce AML volume but required secondary treatment in 30% of the cases. Surgery (particularly nephron-sparing surgery) was the most effective treatment in terms of recurrence and need for secondary procedures. Thermal ablation was an infrequent option. The association between AML size and the risk of bleeding remained unclear; as such the traditional 4-cm cut-off should not per se trigger active treatment. In spite of the limitations and uncertainties relating to the evidence base, the findings may be used to guide and inform clinical practice, until more robust data emerge. PATIENT SUMMARY: Sporadic angiomyolipoma (AML) is a benign tumour of the kidney consisting of a mixture of blood vessels, fat, and muscle. Large tumours may have a risk of spontaneous bleeding. However, the size beyond which these tumours need to be treated remains unclear. Most small AMLs can be monitored without any active treatment. For those who need treatment, options include surgical removal of the tumour or stopping its blood supply (selective embolisation). Surgery has a lower recurrence rate and lower need for a repeat surgical procedure

Mortality and incidence of second cancers following treatment for testicular cancer

We studied 5555 seminoma patients and 3733 patients with nonseminomatous testicular cancers diagnosed in Southeast England between 1960 and 2004. For both groups survival improved over time: 10-year relative survival increased from 78% in 1960–1969 to 99% in 1990–2004 for seminomas, and from 55 to 95% for nonseminomas. In the early period mortality was still significantly increased more than 15 years after diagnosis in both groups, whereas in more recent periods the excess deaths mainly occurred in the first 5 years after diagnosis. For seminomas, there was a significant excess of cancers of the colon (standardised incidence ratio (SIR) 2.36; 95% confidence interval (CI) 1.13–4.35), soft tissue (SIR 13.64; CI 1.65–49.28) and bladder (SIR 4.28; CI 2.28–7.31) in the long term (20+ years after diagnosis), of pancreatic cancer in both the medium (10–19 years) (SIR 2.91; CI 1.26–5.73) and long term (SIR 5.48; CI 2.37–10.80), of leukaemia in both the short (0–9 years) (SIR 3.01; CI 1.44–5.54) and long term (SIR 4.48; CI 1.64–9.75), and of testis cancer in both the short (SIR 6.69; CI 4.28–9.95) and medium term (SIR 3.96; CI 1.08–10.14). For nonseminomas, significant excesses were found in the long term for cancers of the stomach (SIR 5.13; CI 1.40–13.13), rectum (SIR 4.49; CI 1.22–11.51) and pancreas (SIR 10.17: CI 3.73–22.13), and for testis cancer in the medium term (SIR 5.94; CI 2.18–12.93). Leukaemia was significantly increased in the short term (SIR 6.78; CI 2.93–13.36). The better survival observed is largely attributable to improved treatment, and the trend in reducing the toxicity of therapy should continue to reduce future health risks in testicular cancer survivors

Economic evaluation of chemoprevention of breast cancer with tamoxifen and raloxifene among high-risk women in Japan

Raloxifene was approved for chemoprevention against breast cancer among high-risk women in addition to tamoxifen by the US Food and Drug Administration. This study aims to evaluate cost-effectiveness of these agents under Japan's health system. A cost-effectiveness analysis with Markov model consisting of eight health states such as healthy, invasive breast cancer, and endometrial cancer is carried out. The model incorporated the findings of National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 trial, and key costs obtained from health insurance claim reviews. Favourable results, that is cost saving or cost-effective, are found by both tamoxifen and raloxifene for the introduction of chemoprevention among extremely high-risk women such as having a history of atypical hyperplasia, a history of lobular carcinoma in situ or a 5-year predicted breast cancer risk of ⩾5.01% starting at younger age, whereas unfavourable results, that is ‘cost more and gain less' or cost-ineffective, are found for women with a 5-year predicted breast cancer risk of ⩽5.00%. Therapeutic policy switch from tamoxifen to raloxifene among postmenopausal women are implied cost-effective. Findings suggest that introduction of chemoprevention targeting extremely high-risk women in Japan can be justifiable as an efficient use of finite health-care resources, possibly contributing to cost containment

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, &gt;35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement