This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) ...regimens.
Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose HD) or 72,000 U/kg (low-dose LD), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned.
A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04).
Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated.
We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary ...(GU) malignances.
Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).
Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.
CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
It has long been recognized that spinal meningiomas show particular clinical and histological features. Here, we compare the clinico-biological characteristics as well as the genetic abnormalities ...and patterns of gene expression of spinal and intracranial meningiomas. Fourteen spinal and 141 intracranial meningioma patients were analyzed at diagnosis. In all tumors, interphase fluorescence in situ hybridization (iFISH) studies were performed for the detection of quantitative abnormalities for 11 different chromosomes. Additionally, microarray analyses were performed on a subgroup of 18 histologically benign meningiomas (7 spinal and 11 intracranial). Upon comparison with intracranial tumors, spinal meningiomas showed a marked predominance of psammomatous and transitional tumors (p = 0.001), together with a higher proportion of cases displaying a single tumor cell clone by iFISH (p = 0.004). In 86% of the spinal versus 56% of the intracranial tumors (p = 0.01), the ancestral tumor cell clone detected showed either absence of any chromosomal abnormality or monosomy 22/22qalone. Analysis of gene expression profiles showed differential expression between spinal and intracranial meningiomas for a total of 1555 genes, 35 of which allowed a clear distinction between both tumor types. Most of these 35 genes (n = 30) showed significantly higher expression among spinal tumors and corresponded to genes involved in signal transduction pathways, which did not show a significantly different expression according to tumor histopathology. In summary, we show the occurrence of unique patterns of genetic abnormalities and gene expression profiles in spinal as compared to intracranial meningiomas that provide new insights into the molecular pathways involved in the tumorigenesis and progression of spinal meningiomas, and could help explain their particular clinical and histological features.
Eleven patients treated at the University of Texas M. D. Anderson Cancer Center for recurrent disease after resection of a stage I ovarian serous neoplasm of low malignant potential (SNLMP) are ...reported. At the time of diagnosis, the age of the patients ranged from 26 to 43 years (mean 33). Seven patients had stage IB tumors and 4 had stage IA tumors. All patients were treated with a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The size of the ovarian tumors ranged from 4 to 15 cm in maximum dimension. Stromal microinvasion was seen in 2 cases, and foci of endosalpingiosis were seen in the peritoneum in 8 cases. Nine patients were treated with radiotherapy and 2 with chemotherapy. The time to recurrent disease ranged from 7 to 39 years (mean 16). Eight tumors recurred in the pelvis or abdomen, 2 in the neck with subsequent abdominal involvement, and 1 in the pleura without abdominal or pelvic involvement. In 10 cases, the recurrent tumors were serous carcinoma, and in 1 case it was a SNLMP. Recurrences were treated with chemotherapy in 10 cases and with hormones in 1 case. Seven patients died of progressive serous carcinoma 2 to 5 years after the recurrence. One patient died of leukemia with recurrent ovarian tumor 10 years after the recurrence was detected. Two patients are alive with progressive disease 1 and 7 years after the recurrence, and 1 patient whose disease recurred as a SNLMP is alive with no evidence of disease 9 years after the recurrence. These 11 patients were compared with 16 patients who had stage I ovarian SNLMPs that did not recur after a minimum follow-up of 15 years. There was no difference in the age of the patients, gravidity, size of the tumors, or several microscopic parameters, including degree of epithelial proliferation, number of mitoses, and nuclear atypia. Microinvasion was found in one case. The only significant difference between the two groups was the low frequency of endosalpingiosis in the cases that had no disease recurrences (12.5% versus 72.7%). In summary, we found no clinical or pathologic features that can unequivocally predict the recurrence of stage I ovarian SNLMPs. Because of the long interval to recurrence, the fact that the recurrent tumors in 10 of 11 patients were serous carcinomas, and the result of the X-chromosome inactivation in one case, the recurrent tumors could represent independent primaries or a slow progression of one clone present in the SNLMPs.
The purpose of this study was to evaluate agreement among radiologists in detecting and assessing prostate cancer at multiparametric MRI using Prostate Imaging Reporting and Data System version 2 ...(PI-RADSv2).
Treatment-naïve patients underwent 3-T multipara-metric MRI between April 2012 and June 2015. Among the 163 patients evaluated, 110 underwent prostatectomy after MRI and 53 had normal MRI findings and transrectal ultrasound-guided biopsy results. Nine radiologists participated (three each with high, intermediate, and low levels of experience). Readers interpreted images of 58 patients on average (range, 56-60) using PI-RADSv2. Prostatectomy specimens registered to MRI were ground truth. Interob-server agreement was evaluated with the index of specific agreement for lesion detection and kappa and proportion of agreement for PI-RADS category assignment.
The radiologists detected 336 lesions. Sensitivity for index lesions was 80.9% (95% CI, 75.1-85.9%), comparable across reader experience (
= 0.392). Patient-level specificity was experience dependent; highly experienced readers had 84.0% specificity versus 55.2% for all others (
< 0.001). Interobserver agreement was excellent for detecting index lesions (index of specific agreement, 0.871; 95% CI, 0.798-0.923). Agreement on PI-RADSv2 category assignment of index lesions was moderate (κ = 0.419; 95% CI, 0.238-0.595). For individual category assignments, proportion of agreement was slight for PI-RADS category 3 (0.208; 95% CI, 0.086-0.284) but substantial for PI-RADS category 4 (0.674; 95% CI, 0.540-0.776). However, proportion of agreement for T2-weighted PI-RADS 4 in the transition zone was 0.250 (95% CI, 0.108-0.372). Proportion of agreement for category assignment of index lesions on dynamic contrast-enhanced MR images was 0.822 (95% CI, 0.728-0.903), on T2-weighted MR images was 0.515 (95% CI, 0.430-0623), and on DW images was 0.586 (95% CI, 0.495-0.682). Proportion of agreement for dominant lesion was excellent (0.828; 95% CI, 0.742-0.913).
Radiologists across experience levels had excellent agreement for detecting index lesions and moderate agreement for category assignment of lesions using PI-RADS. Future iterations of PI-RADS should clarify PI-RADS 3 and PI-RADS 4 in the transition zone.
Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor ...cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma.
This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999.
Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8–70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9–34). The most common grade 3–4 adverse events were fatigue (six 9% patients), hypertension (five 7%), proteinuria (four 6%), and hypophosphataemia (four 6%). There were no treatment-related deaths.
Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies.
National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.
Purpose: Recurrence is the major factor influencing the clinical outcome of meningioma patients although the exact relationship between
primary and recurrent tumors still needs to be clarified. The ...aim of the present study is to analyze the cytogenetic relationship
between primary and subsequent recurrent meningiomas developed within the same individual.
Experimental Design: Multicolor interphase fluorescence in situ hybridization was done for the identification of numerical abnormalities of 12 chromosomes in single-cell suspensions from
59 tumor samples corresponding to 25 recurrent meningioma patients. In 47 of these tumors, the distribution of different tumor
cell clones was also analyzed in paraffin-embedded tissue sections. In parallel, 132 nonrecurrent cases were also studied.
Results: Most recurrent meningiomas showed complex cytogenetic aberrations associated with two or more tumor cell clones in the first
tumor analyzed. Interestingly, in most individuals (74%), exactly the same tumor cell clones identified in the initial lesion
were also detected in the subsequent recurrent tumor samples. In the recurrent tumor samples of the remaining cases (26%),
we observed tumor cell clones related to those detected in the initial lesion but which had acquired one or more additional
chromosome aberrations associated with either the emergence of new clones with more complex karyotypes or the disappearance
of the most representative clones from the primary lesions. Multivariate analysis of prognostic factors showed that the Maillo
et al. prognostic score, based on age of patient, tumor grade, and monosomy 14, together with tumor size was the best combination
of independent variables for predicting tumor recurrence at diagnosis.
Conclusion: Overall, our results indicate that the development of recurrent meningiomas after complete tumor resection is usually due
to regrowth of the primary tumor and rarely to the emergence of an unrelated meningioma, underlining the need for alternative
treatment strategies in cases at high risk of relapse, particularly those with a high Maillo et al. prognostic score and larger
tumors.
Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic ...RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene.
BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.
Objective To determine the effectiveness of early physiotherapy in reducing the risk of secondary lymphoedema after surgery for breast cancer.Design Randomised, single blinded, clinical trial.Setting ...University hospital in Alcalá de Henares, Madrid, Spain.Participants 120 women who had breast surgery involving dissection of axillary lymph nodes between May 2005 and June 2007.Intervention The early physiotherapy group was treated by a physiotherapist with a physiotherapy programme including manual lymph drainage, massage of scar tissue, and progressive active and action assisted shoulder exercises. This group also received an educational strategy. The control group received the educational strategy only.Main outcome measure Incidence of clinically significant secondary lymphoedema (>2 cm increase in arm circumference measured at two adjacent points compared with the non-affected arm).Results 116 women completed the one year follow-up. Of these, 18 developed secondary lymphoedema (16%): 14 in the control group (25%) and four in the intervention group (7%). The difference was significant (P=0.01); risk ratio 0.28 (95% confidence interval 0.10 to 0.79). A survival analysis showed a significant difference, with secondary lymphoedema being diagnosed four times earlier in the control group than in the intervention group (intervention/control, hazard ratio 0.26, 95% confidence interval 0.09 to 0.79).Conclusion Early physiotherapy could be an effective intervention in the prevention of secondary lymphoedema in women for at least one year after surgery for breast cancer involving dissection of axillary lymph nodes.Trial registration Current controlled trials ISRCTN95870846.
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