Sabine Schmid

Microsatellite analysis in serous tumors of the ovary.

Thirty-four serous ovarian neoplasms were analyzed for microsatellite instability (MIN) and loss of heterozygosity (LOH) at 20 chromosomal loci of eight different chromosomes, including the map positions of the six known mismatch repair genes. Twelve of the 20 (60%) serous ovarian tumors of low malignant potential (LMP) and 13 of 15 (87%) samples of serous ovarian carcinomas, taken from 14 patients, showed LOH at one or more of the analyzed microsatellite loci. In serous carcinomas, LOH of the dinucleotide repeat D7S521 was most frequent. Six of 20 (30%) LMP tumors were also affected by MIN at more than one locus, whereas in the carcinomas MIN was found only sporadically (p < 0.025). No correlation between increased occurrence of MIN and LOH at the chromosomal loci of the known mismatch repair genes were discovered for these LMP tumors. Although our observation regarding LOH frequency in serous LMP tumors and serous carcinomas is compatible with the hypothesis that serous LMP tumors might represent precursor lesions of invasive carcinomas, the results concerning the occurrence of MIN suggest that the mechanisms of tumorigenesis of some tumors of LMP are distinct from those in invasive serous carcinomas.

Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab

OBJECTIVESnImmunotherapy with the programmed death receptor-1 (PD-1) antibody nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC) treatment. Nivolumab shows better outcome compared to standard second line chemotherapy, but reliable prognostic markers are lacking. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and associated with worse overall survival (OS) in several tumor types, but have not been analysed extensively in lung cancer in the era of immunotherapy.nnnMETHODSnPatients with metastatic NSCLC treated with nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. Cox regression analyses were conducted to study the prognostic role of NLR and PLR on OS and progression free survival (PFS). Logistic regression was used to study the association of NLR and PLR. The combined impact of NLR and other known prognostic factors was explored with multivariable regression.nnnRESULTSnFifty-two patients were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64, 95% CI 1.78-7.46, p<0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI 0.04-0.68, p=0.013). There was no significant association with PFS (HR for log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month survival using log(NLR) was 0.738, the AUC for the prediction of response to nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didnt correlate with other known prognostic factors (i.e histology, tobacco use, ECOG performance status,) in our cohort. Inclusion of NLR in multivariable models with these other factors significantly improved the prediction of OS.nnnCONCLUSIONnElevated pre-treatment NLR and PLR are associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.

Response to dabrafenib after progression on vemurafenib in a patient with advanced BRAF V600E-mutant bronchial adenocarcinoma

We present the case of a patient with rapidly accelerated fibrosarcoma gene F (BRAF) mutated adenocarcinoma of the lung, responding to BRAF inhibitor dabrafenib after progressing on vemurafenib followed by docetaxel. The present case illustrates the potential benefit of successful rechallenge with a BRAF inhibitor, a well known phenomenon observed in other oncogenic driven molecular subtypes of non-small cell lung cancer (NSCLC) such as epidermal growth factor receptor mutation. Rechallenge with a BRAF inhibitor in BRAF mutated NSCLC should be considered, particularly in the absence of alternative therpateutic options.

Management of von Hippel-Lindau Disease: An Interdisciplinary Review

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumour predisposition syndrome with an incidence of 1:36,000 newborns, the estimated prevalence in Europe is about 1-9/100,000. It is associated with an increased risk of developing various benign and malignant tumours, thus affecting multiple organs at different time points in the life of a patient. Disease severity and diversity as well as age at first symptoms vary considerably, and diagnostic delay due to failure of recognition is a relevant issue. The identification of a disease-causing VHL germline mutation subsequently allows family members at risk to undergo predictive genetic testing after genetic counselling. Clinical management of patients and families should optimally be offered as an interdisciplinary approach. Prophylactic screening programs are a cornerstone of care, and have markedly improved median overall survival of affected patients. The aim of this review is to give an overview of the heterogeneous manifestations of the VHL syndrome and to highlight the diagnostic and therapeutic challenges characteristic for this orphan disease. A comprehensive update of the underlying genetic and molecular principles is additionally provided. We also describe how the St. Gallen VHL multidisciplinary group is organised as an example of interdisciplinary cooperation in a tertiary hospital in Switzerland.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration of an Intravascular Sarcoma Metastasis

The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of endovascular lesions has rarely been described. We report a case of EBUS-TBNA of a solid mass in the left pulmonary artery in a patient with synovial sarcoma of the kidney, which was performed without complications and led to the diagnosis of metastatic disease. EBUS-TBNA seems to be a rapid, minimally invasive, safe and effective diagnostic procedure in selected cases of endovascular lesions.

Clinical Outcome of ALK-Positive Non–Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs)

Introduction NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co‐occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood. Methods Outcomes of patients with metastatic NSCLC de novo co‐alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed. Results A total of 14 patients with adenocarcinoma were identified. Five patients had ALK/EGFR co‐alterations and nine had ALK/KRAS co‐alterations. Six of seven patients with ALK/KRAS co‐alterations (86%) were primary refractory to crizotinib. One patient has had ongoing disease stabilization for 26 months. Of the patients with ALK/EGFR co‐alterations, one immediately progressed after receiving crizotinib for 1.3 months and two had a partial response for 5.7 and 7.3 months, respectively. Three of four patients with ALK/EGFR co‐alterations treated with an EGFR TKI achieved one or more responses in different lines of therapy: four patients had a partial response, three with afatinib and one with osimertinib. One patient achieved a complete remission with osimertinib, and one patient was primary refractory to erlotinib. Median PFS during treatment with a first EGFR TKI was 5.8 months (range 3.0–6.9 months). Conclusions De novo concurrent ALK/KRAS co‐alterations were associated with resistance to ALK TKI treatment in seven out of eight patients. In patients with ALK/EGFR co‐alterations, outcomes with ALK and EGFR TKIs seem inferior to what would be expected in patients with either alteration alone, but further studies are needed to clarify which patients with ALK/EGFR co‐alterations may still benefit from the respective TKI.

Pulmonary Embolism in a Patient with Primary Renal Synovial Sarcoma: The Important Differential Diagnosis of Tumor Embolism and Its Therapeutic Implications

Pulmonary tumor embolism rarely occurs in epithelial-derived tumors, but it has been described in different tumor entities. Microscopic pulmonary tumor embolisms are often only discovered on autopsy. Pulmonary thromboembolism, on the other hand, is a frequent complication in cancer patients, and surgery in patients with a malignant tumor is an additional risk factor. The differential diagnosis between pulmonary thromboembolism and pulmonary tumor embolism can be challenging. In this case report, we describe the rare case of a patient with primary renal synovial sarcoma and the workup for a thrombus in the left pulmonary artery.

Assessment of anticancer-treatment outcome in patients with metastatic castration-resistant prostate cancer—going beyond PSA and imaging, a systematic literature review

BACKGROUNDnIn the past years, there has been significant progress in anticancer drug development for patients with metastatic castration-resistant prostate cancer (CRPC). However, the current instruments to assess clinical treatment response have limitations and may not sufficiently reflect patient benefit. Our objective was to systematically identify tools to evaluate both patient benefit and clinical anticancer-treatment response as basis for an international consensus process and development of a specific pragmatic instrument for men with CRPC.nnnMETHODSnPubMed, Embase and CINAHL were searched to identify currently available tools to assess anticancer-treatment benefit, other than standard imaging procedures and prostate-specific antigen measurements, namely quality of life (QoL), detailed pain assessment, physical function and objective measures of other complex cancer-related syndromes in patients with CRPC. Additionally, all CRPC phase III trials published in the last 5 years were reviewed as well as studies using physical function tools in a general cancer population. The PRIMSA statement was followed for the systematic review process.nnnRESULTSnThe search generated 1096 hits, 185 full-text papers were screened and finally 73 publications were included. Additional 89 publications were included by hand-search. We identified a total of 98 tools used in CRPC trials and grouped these into three categories: 22 tools assessing QoL domains and subgroups, 47 tools for pain assessment and 29 tools for objective measures, mainly physical function and assessment of skeletal disease burden.nnnCONCLUSIONnA wide variety of assessment tools and also efforts to standardize and harmonize patient-reported outcomes and pain assessment were identified. However, the specific needs of the increasing CRPC population living longer with their incurable cancer are insufficiently captured and objective physical outcome measures are under-represented. In the age of new anticancer drug targets and principles, new methods to monitor patient relevant outcomes of antineoplastic therapy are of utmost importance.

Is There a Flare Phenomenon on Bone Scintigraphy in Men With Advanced Prostate Cancer Treated With Radium-223?

Micro‐Abstract Radium‐223 is an approved survival‐prolonging treatment option in men with castration‐resistant prostate cancer and bone metastases, but data on treatment monitoring by imaging are scarce. We systematically evaluated imaging data of 19 patients treated with radium‐223. On bone scintigraphy a flare phenomenon on therapy with radium‐223 may be observed; this should be taken into consideration when evaluating men receiving therapy with radium‐223. Introduction Radium‐223 is an approved survival‐prolonging treatment option in men with castration‐resistant prostate cancer (mCRPC) and bone metastases. In the registration trial (ALSYMPCA), no regular imaging was mandated. We aimed to analyze men with metastatic mCRPC treated with radium‐223 who had bone scintigraphy for staging and treatment monitoring. Patients and Methods Retrospective chart review was performed of mCRPC patients who received 6 cycles of radium‐223 and who underwent bone scintigraphy before start of radium‐223 and after 3 and 6 cycles of treatment. Results Nineteen patients with a median age of 74 years met the selection criteria and were included in the analysis. On bone scintigraphy, 4 of 19 patients showed a total of ≥ 2 new lesions after 3 cycles of radium‐223 therapy, but 3 of 4 patients did not have ≥ 2 new lesions after 6 cycles, meeting the criteria for bone scintigraphy flare. Of these 4 patients, 2 received radium‐223 before docetaxel therapy, and all 4 had concomitant treatment with denosumab. In the entire cohort, 3 of 19 patients showed soft tissue progression on computed tomography after 3 cycles of radium‐223. Conclusion Bone scintigraphy flare in patients undergoing therapy with radium‐223 was observed. Bone scintigraphy data acquired during treatment with radium‐223 should be interpreted with caution, and treatment should not be changed according to increase in number of lesions on bone scintigraphy alone after 3 cycles of radium‐223.

Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC)

BackgroundResponse to immune checkpoint inhibitors depends on tumor intrinsic properties and also on host factors in the tumour microenvironment including the presence of immune cells (IC). We hypothesized that nivolumab efficacy varies across different metastatic sites.MethodsWe retrospectively analyzed computed tomography scans of patients with metastatic non-small cell lung carcinoma (NSCLC) receiving nivolumab. RECIST 1.1 criteria were applied to assess the overall response rate (ORR) and organ-specific response rate (OSRR).ResultsWe analyzed 52 patients including 44% females, 58% adenocarcinoma and 8% never smokers. Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%). ORR and disease control rate (DCR) were 20% and 45%, respectively. Median overall survival, progression-free survival and duration of response were 11.9, 2.3 and 10.3 months. OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases. Nine out of 12 patients with bone metastases had progressive lesions. The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases.ConclusionIn conclusion, the efficacy of immunotherapy is dependent on the metastatic location. Treatment appears more active in lymph nodes compared to other organ sites such as liver, adrenals and bone. Future strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.