Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17.

PURPOSE: The integration of immunotherapy in the perioperative setting of muscle-invasive urothelial carcinoma (MIUC) appears promising. SAKK 06/17 investigated the addition of neoadjuvant durvalumab to gemcitabine/cisplatin (GC) chemotherapy followed by radical surgery and adjuvant checkpoint inhibition with durvalumab. PATIENTS AND METHODS: SAKK 06/17 was an investigator-initiated, open-label, single-arm phase II study including cisplatin-fit patients with stage cT2-T4a cN0-1 operable MIUC. Four cycles of neoadjuvant GC in combination with four cycles of durvalumab (start with GC cycle 2) were administered, followed by radical surgery. Adjuvant durvalumab was given for 10 cycles. The primary end point was event-free survival (EFS) at 2 years. RESULTS: Sixty one patients were accrued at 12 sites. The full analysis set consisted of 57 patients, 54 (95%) had bladder cancer. Median follow-up was 40 months. The primary end point was met, with EFS at 2 years of 76% (one-sided 90% CI [lower bound], 67%; two-sided 95% CI, 62 to 85). EFS at 3 years was 73% (95% CI, 59 to 83). Complete pathologic response in resected patients (N = 52) was achieved in 17 patients (33%), and 31 (60%) had pathologic response

Pseudo liposarcomatous plasma cells in a patient with liposarcoma and lymphoplasmacytic lymphoma.

First, patients may always develop a second severe illness, even a second cancer. Second, things are not always as they are expected to be. So, careful diagnosis is mandatory. Third, morphology is very important, but sometimes misleading. Always be aware of morphological variants!

Bariatric Surgery as an Efficient Treatment for Non-Alcoholic Fatty Liver Disease in a Prospective Study with 1-Year Follow-up : BariScan Study.

BACKGROUND: Bariatric surgery gains attention as a potential treatment for non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate improvement of NAFLD after the two most common bariatric procedures with validated non-invasive instruments. MATERIAL AND METHODS: N = 100 patients scheduled for laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB) were included. NAFLD was evaluated preoperatively and postoperatively with liver stiffness measurement by transient elastography and laboratory-based fibrosis scores. Clinical data included body mass index (BMI), total weight loss (%TWL), excess weight loss (%EWL), age, gender, comorbidities, and the Edmonton obesity staging system (EOSS). RESULTS: There were significant improvements of BMI, %TWL, %EWL, and EOSS after bariatric surgery. Liver stiffness was significantly improved from pre- to postoperative (12.9 ± 10.4 vs. 7.1 ± 3.7 kPa, p < 0.001) at median follow-up of 12.5 months. Additionally, there were significant improvements of liver fibrosis scores (aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio 0.8 ± 0.3 vs. 1.1 ± 0.4, p < 0.001; NAFLD fibrosis score - 1.0 ± 1.8 vs. - 1.7 ± 1.3, p < 0.001; APRI score 0.3 ± 0.2 vs. 0.3 ± 0.1, p = 0.009; BARD score 2.3 ± 1.2 vs. 2.8 ± 1.1, p = 0.008) and laboratory parameters (ALT, AST, and GGT). After adjustment for baseline liver stiffness, RYGB showed higher improvements than LSG, and there was no gender difference. Improvement of liver stiffness was not correlated to improvement of BMI, %TWL, %EWL, or EOSS. CONCLUSIONS: NAFLD seems to be improved by bariatric surgery as measured by validated non-invasive instruments. Furthermore, it appears that RYGB is more effective than LSG. No correlation could be detected between NAFLD and weight loss. The present study highlights the potential of bariatric surgery for successful treatment of NAFLD. Further research is required to understand the exact mechanisms.

Role of liver magnetic resonance imaging in hyperferritinaemia and the diagnosis of iron overload.

Hyperferritinaemia is a frequent clinical problem. Elevated serum ferritin levels can be detected in different genetic and acquired diseases and can occur with or without anaemia. It is therefore important to determine whether hyperferritinaemia is due to iron overload or due to a secondary cause. The main causes of iron overload are intestinal iron hyperabsorption disorders and transfusion-dependent disorders. Iron homeostasis and iron overload are quantified by different diagnostic approaches. The evaluation of serum ferritin and transferrin saturation is the first diagnostic step to identify the cause of hyperferritinaemia. The assessment of liver iron concentration by liver biopsy or magnetic resonance imaging (MRI) may guide the further diagnostic and therapeutic workup. Liver biopsy is invasive and poorly accepted by patients and should only be carried out in selected patients with hereditary haemochromatosis. As a non-invasive approach, MRI is considered the standard method to diagnose and to monitor both hepatic iron overload and the effectiveness of iron chelation therapy in many clinical conditions such as thalassaemia and myelodysplastic syndromes. Accurate evaluation and monitoring of iron overload has major implications regarding adherence, quality of life and prognosis. There are different technical MRI approaches to measuring the liver iron content. Of these, T2 and T2* relaxometry are considered the standard of care. MRI with cardiac T2* mapping is also suitable for the assessment of cardiac iron. Currently there is no consensus which technique should be preferred. The choice depends on local availability and patient population. However, it is important to use the same MRI technique in subsequent visits in the same patient to get comparable results. Signal intensity ratio may be a good adjunct to R2 and R2* methods as it allows easy visual estimation of the liver iron concentration. In this review a group of Swiss haematologists and radiologists give an overview of different conditions leading to primary or secondary iron overload and on diagnostic methods to assess hyperferritinaemia with a focus on the role of liver MRI. They summarise the standard practice in Switzerland on the use of liver iron concentration MRI as well as disease-specific guideline recommendations.

When cancer patients suddenly have a positive pregnancy test.

We present the case of non-small cell lung cancer (NSCLC) in a 48-year-old woman with an active history of smoking. The patient initially presented to her general practitioner with a progressive swelling on the neck. Further investigations diagnosed a metastatic lung tumour, and palliative chemotherapy was started. After 5 months of treatment, by newly reported amenorrhoea, cautiously before a restaging CT scan of the abdomen, a pregnancy test was performed and was positive. Both the gynaecological examination and the hormonal panel yielded no signs of pregnancy. Immunohistochemically, staining of the tumour was strongly positive for ß-subunit of human chorionic gonadotropin (ß-hCG) suggesting that the tumour was responsible for high ß-hCG levels.Paraneoplastic ß-hCG secretion from adenocarcinomas is rare. In the literature, only a few such cases have been reported. Previous studies suggested that the ability to secrete ß-hCG in tumours may correlate to some extent to chemoresistance and thus, to a worse prognosis.

Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial.

The combination of lenalidomide (Revlimid® , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46-83]) and were treated with B 75 mg/m2  days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.

Enzalutamide in Patients With Castration-Resistant Prostate Cancer Progressing After Docetaxel: Retrospective Analysis of the Swiss Enzalutamide Named Patient Program.

BACKGROUND: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy-naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial. PATIENTS AND METHODS: The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide. RESULTS: The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). Median progression-free survival was 3.0 months (95% CI, 2.4-3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6-8.1 months). Sixteen patients (36.4%) had a prostate-specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate-specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment. CONCLUSIONS: Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone.

How to facilitate early diagnosis of CNS involvement in malignant lymphoma.

INTRODUCTION: Making the diagnosis of secondary CNS involvement in lymphoma can be difficult due to unspecific signs and symptoms, limited accessibility of brain/myelon parenchyma and low sensitivity and/or specifity of imaging and cerebrospinal fluid (CSF) examination currently available. Areas covered: MRI of the total neuroaxis followed by CSF cytomorphology and flow cytometry are methods of choice when CNS lymphoma (CNSL) is suspected. To reduce the numerous pitfalls of these examinations several aspects should be considered. New CSF biomarkers might be of potential diagnostic value. Attempts to standardize response criteria are presented. Expert commentary: Diagnosing CNSL remains challenging. Until diagnostic methods combining high sensitivity with high specifity are routinely introduced, high level of awareness and optimal utilization of examinations currently available are needed to early diagnose this potentially devastating disease.

Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks.

Histone deacetylase inhibitors (HDACIs) like valproic acid (VPA) display activity in leukemia models and induce tumor-selective cytotoxicity against acute myeloid leukemia (AML) blasts. As there are limited data on HDACIs effects, we aimed to dissect VPA effects in vitro using myeloid cell lines with the idea to integrate findings with in vivo data from AML patients treated with VPA additionally to intensive chemotherapy (n = 12). By gene expression profiling we identified an in vitro VPA response signature enriched for genes/pathways known to be implicated in cell cycle arrest, apoptosis, and DNA repair. Following VPA treatment in vivo, gene expression changes in AML patients showed concordant results with the in vitro VPA response despite concomitant intensive chemotherapy. Comparative miRNA profiling revealed VPA-associated miRNA expression changes likely contributing to a VPA-induced reversion of deregulated gene expression. In addition, we were able to define markers predicting VPA response in vivo such as CXCR4 and LBH. These could be validated in an independent cohort of VPA and intensive chemotherapy treated AML patients (n = 114) in which they were inversely correlated with relapse-free survival. In summary, our data provide new insights into the molecular mechanisms of VPA in myeloid blasts, which might be useful in further advancing HDAC inhibition based treatment approaches in AML.

Accuracy of multidetector-row CT for restaging after neoadjuvant treatment in patients with oesophageal cancer.

OBJECTIVES: To assess the diagnostic accuracy of 64-multidetector CT (MDCT) for restaging of patients with oesophageal cancer undergoing neoadjuvant therapy. METHODS: Results of pathological staging were correlated with those from 64-MDCT before and after neoadjuvant treatment in 35 patients using the American Joint Committee on Cancer/TNM classification (7th edition). CT response was determined using the Response Evaluation Criteria in Solid Tumours (RECIST) method, modified for one-dimensional tumour diameter measurement. RESULTS: 64-MDCT predicted T stage correctly in 34 % (12/35), overstaged in 49 % (17/35) and understaged in 17 % (6/35). Sensitivity/specificity values were as follows: T0, 20 %/92 %; T1-T2, 31 %/59 %; T3, 60 %/64 %; T4, 100 %/4 %. Negative predictive values for T3/T4 were 80 %/100 %. MDCT accurately predicted complete histopathological response in 20 % (accuracy 74 %) and overstaged in 80 %. Tumour regression grade was predicted correctly in only 8 % (2/25) and underestimated in 68 % (17/25). Accurate N stage was noted in 69 % (24/35). CONCLUSION: Although MDCT tends to be able to exclude advanced tumour stages (T3, T4) with a higher likelihood, the diagnostic accuracy of high resolution MDCT for restaging oesophageal cancer and assessing the response to neoadjuvant therapy has not improved in comparison to older-generation CT. Therefore, the future assessment of oesophageal tumour response should focus on combined morphologic and metabolic imaging. KEY POINTS: • Multidetector CT (MDCT) has been beneficial for the evaluation of many tumours. • However diagnostic accuracy for restaging oesophageal cancer has not improved with MDCT. • MDCT tends to be able to exclude advanced tumour stages (T3/T4). • MDCT has a low accuracy for determining lymph node metastasis. • Oesophageal tumour response should be assessed by combined morphological and metabolic imaging.

Efficacy of Cetuximab in Combination with FOLFIRI in a Patient with KRAS Wild-Type Metastatic Anal Cancer.

Anal canal cancer is a rare tumor without clear treatment evidence in the metastatic setting. In terms of the bad prognosis of patients with metastatic anal cancer, further therapeutic options are urgently needed. In this paper we present the case of a 64-year-old man suffering from undifferentiated squamous cell carcinoma with liver metastases. After progression on cisplatin and fluorouracil, tumor tissue was analyzed with respect to anti-EGFR therapy with cetuximab. There was no KRAS mutation and the EGFR expression level in the tumor tissue was 2+; ideal conditions for the immunotherapy. Encouraged by these results we started a therapy using FOLFIRI in combination with cetuximab. Fortunately the patient showed a partial response after 6 cycles. On patient's preference we did a therapy break of 6 weeks. Within this time period the disease was progressive indicating its aggressiveness. However, the same immunotherapy was able to stabilize the disease for a further 3 months. The patient died 21 months after diagnosis because of liver failure. Nevertheless, from our perspective the combination of FOLFIRI and cetuximab is quite a promising therapeutic option for patients with metastatic anal cancer. Potential predictive factors of the immunochemotherapy are discussed in this paper.

Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes.

BACKGROUND: Reductions in transfusion requirements/improvements in hematologic parameters have been associated with iron chelation therapy in transfusion-dependent patients, including those with myelodysplastic syndromes; data on there reductions/improvements have been limited to case reports and small studies. DESIGN AND METHODS: To explore this observation in a large population of patients, we report a post-hoc analysis evaluating hematologic response to deferasirox in a cohort of iron-overloaded patients with myelodysplastic syndromes enrolled in the Evaluation of Patients' Iron Chelation with Exjade(®) (EPIC) study using International Working Group 2006 criteria. RESULTS: Two-hundred and forty-seven, 100 and 50 patients without concomitant medication for myelodysplastic syndromes were eligible for analysis of erythroid, platelet and neutrophil responses, respectively. Erythroid, platelet and neutrophil responses were observed in 21.5% (53/247), 13.0% (13/100) and 22.0% (11/50) of the patients after a median of 109, 169 and 226 days, respectively. Median serum ferritin reductions were greater in hematologic responders compared with non-responders at end of study, although these differences were not statistically significant. A reduction in labile plasma iron to less than 0.4 µmol/L was observed from week 12 onwards; this change did not differ between hematologic responders and non-responders. CONCLUSIONS: This analysis suggests that deferasirox treatment for up to 1 year could lead to improvement in hematologic parameters in some patients with myelodysplastic syndromes.

A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy.

BACKGROUND: The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts. DESIGN AND METHODS: To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m(2) total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m(2)) infused over 1 hour on 3 consecutive days every 4-6 weeks. RESULTS: The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic. CONCLUSIONS: Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.

Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.

PURPOSE: Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. PATIENTS AND METHODS: Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 µg/m2/24 hours. RESULTS: Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. CONCLUSION: Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.

Cerebrospinal fluid pleocytosis: pitfalls and benefits of combined analysis using cytomorphology and flow cytometry.

BACKGROUND: Cerebrospinal fluid samples with doubtful morphologic interpretation are a common problem in the workup of patients with clinical signs for leptomeningeal disease. The authors report on the combination of morphology and flow cytometry in the diagnosis of leptomeningeal disease in patients with radiological, clinical, or cytological findings suspicious for leukemia or lymphoma with spread into the cerebrospinal fluid. METHODS: The authors defined a set of antibodies for flow cytometric analysis, which is capable of distinguishing between malignant and nonmalignant hematopoietic cells. One hundred twenty-seven cases were analyzed with both methods. RESULTS: The additional application of flow cytometry resulted in an improvement of diagnostic reliability in 29 of 127 cases. Diagnostic sensitivity was raised from 73% (cytology) to 96% (flow cytometry), specificity from 94% to 97%, the positive predictive value from 88% to 96%, and the negative predictive value from 76% to 97%. CONCLUSIONS: Because the appropriate selection of markers is crucial to successful analysis, the authors suggested a highly selected panel of antibodies for flow cytometry analysis of cerebrospinal fluid samples. The authors were able to demonstrate that leptomeningeal disease caused by leukemia or lymphoma can be diagnosed by flow cytometry and discriminated from reactive pleocytosis in most cases of doubtful morphology.

Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study.

The prospective 1-year EPIC study enrolled 341 patients with myelodysplastic syndromes (MDS); although baseline iron burden was >2500ng/mL, approximately 50% were chelation-naïve. Overall median serum ferritin decreased significantly at 1 year (p=0.002). Decreases occurred irrespective of whether patients were chelation-naïve or previously chelated; changes were dependent on dose adjustments and ongoing iron intake. Sustained reductions in labile plasma iron were observed. Discontinuation rate (48.7%) and adverse event profile were consistent with previously reported deferasirox data in MDS. Alanine aminotransferase levels decreased significantly; change correlated significantly with reduction in serum ferritin (p<0.0001). This large dataset prospectively confirms the efficacy and well characterizes the safety profile of deferasirox in MDS.