Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold.

BACKGROUND AND AIMS: This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). METHODS: Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). RESULTS: EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). CONCLUSION: In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Genomics and emerging biomarkers for immunotherapy of colorectal cancer.

Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker-guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application.

COOLHAIR: a prospective randomized trial to investigate the efficacy and tolerability of scalp cooling in patients undergoing (neo)adjuvant chemotherapy for early breast cancer.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a distressing side effect for women with breast cancer undergoing chemotherapy. Scalp cooling is a method aiming to prevent CIA, but its efficacy is not well defined. Randomized trials until recently and at the time this trial was designed have been lacking. METHODS: Patients undergoing (neo)adjuvant chemotherapy for early breast cancer (EBC) were randomized to scalp cooling (CAP) or observation (NoCAP). All patients received 18-24 weeks of anthracycline- and/or taxane-based chemotherapy. The primary endpoint was patient-reported rate of alopecia according to a modified version of the Dean Scale. Hair preservation was defined as hair loss ≤ grade 2 (≤ 50%). Secondary endpoints were rate of alopecia determined by medical staff, rate of wig/scarf use, tolerability as well as quality of life (QoL). RESULTS: Seventy-nine patients were randomized. Hair preservation was observed in 39.3% of patients in the CAP arm versus 0% in the NoCAP arm (p < 0.001). Wig/scarf use was significantly less frequent in the CAP group (40.7% vs 95.5% outside home before cycle 3, p < 0.001). The drop-out rate was 31.7% and 34.2% in the CAP and NoCAP arm, respectively. Main reasons for drop-out were hair loss, adverse events (CAP), and randomization into control arm. We observed no differences in efficacy between anthracycline-based and non-anthracycline-based regimens. QoL did not differ between the study arms. CONCLUSIONS: This trial adds to the evidence that scalp cooling effectively prevents CIA in a meaningful number of patients. This option should be made available for patients undergoing (neo)adjuvant chemotherapy for EBC.

Randomized controlled trial of S-1 maintenance therapy in metastatic esophagogastric cancer - the multinational MATEO study.

BACKGROUND: The optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer. METHODS: The Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life. Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy. DISCUSSION: MATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy. TRIAL REGISTRATION: NCT02128243 (date of registration: 29-04-2014).

Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.

BACKGROUND: Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. METHODS: In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. FINDINGS: Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9-16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3-35·4) of 78 patients. Grade 3-4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. INTERPRETATION: Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. FUNDING: Bristol-Myers Squibb.

Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling.

BACKGROUND: Colorectal cancer is the third most common malignancy in humans and novel therapeutic approaches are urgently needed. Autophagy is an evolutionarily highly conserved cellular process by which cells collect unnecessary organelles or misfolded proteins and subsequently degrade them in vesicular structures in order to refuel cells with energy. Dysregulation of the complex autophagy signaling network has been shown to contribute to the onset and progression of cancer in various models. The Bcl-2 family of proteins comprises central regulators of apoptosis signaling and has been linked to processes involved in autophagy. The antiapoptotic members of the Bcl-2 family of proteins have been identified as promising anticancer drug targets and small molecules inhibiting those proteins are in clinical trials. METHODS: Flow cytometry and colorimetric assays were used to assess cell growth and cell death. Long term 3D cell culture was used to assess autophagy in a tissue mimicking environment in vitro. RNA interference was applied to modulate autophagy signaling. Immunoblotting and q-RT PCR were used to investigate autophagy signaling. Immunohistochemistry and fluorescence microscopy were used to detect autophagosome formation and autophagy flux. RESULTS: This study demonstrates that autophagy inhibition by obatoclax induces cell death in colorectal cancer (CRC) cells in an autophagy prone environment. Here, we demonstrate that pan-Bcl-2 inhibition by obatoclax causes a striking, late stage inhibition of autophagy in CRC cells. In contrast, ABT-737, a Mcl-1 sparing Bcl-2 inhibitor, failed to interfere with autophagy signaling. Accumulation of p62 as well as Light Chain 3 (LC3) was observed in cells treated with obatoclax. Autophagy inhibition caused by obatoclax is further augmented in stressful conditions such as starvation. Furthermore, our data demonstrate that inhibition of autophagy caused by obatoclax is independent of the essential pro-autophagy proteins Beclin-1, Atg7 and Atg12. CONCLUSIONS: The objective of this study was to dissect the contribution of Bcl-2 proteins to autophagy in CRC cells and to explore the potential of Bcl-2 inhibitors for autophagy modulation. Collectively, our data argue for a Beclin-1 independent autophagy inhibition by obatoclax. Based on this study, we recommend the concept of autophagy inhibition as therapeutic strategy for CRC.

Outcomes and risk factors for cancer patients undergoing endoscopic intervention of malignant biliary obstruction.

BACKGROUND: Malignant bile duct obstruction is a common problem among cancer patients with hepatic or lymphatic metastases. Endoscopic retrograde cholangiography (ERC) with the placement of a stent is the method of choice to improve biliary flow. Only little data exist concerning the outcome of patients with malignant biliary obstruction in relationship to microbial isolates from bile. METHODS: Bile samples were taken during the ERC procedure in tumor patients with biliary obstruction. Clinical data including laboratory values, tumor-specific treatment and outcome data were prospectively collected. RESULTS: 206 ERC interventions in 163 patients were recorded. In 43 % of the patients, systemic treatment was (re-) initiated after successful biliary drainage. A variety of bacteria and fungi was detected in the bile samples. One-year survival was significantly worse in patients from whom multiresistant pathogens were isolated than in patients, in whom other species were detected. Increased levels of inflammatory markers were associated with a poor one-year survival. The negative impact of these two factors was confirmed in multivariate analysis. In patients with pancreatic cancer, univariate analysis showed a negative impact on one-year survival in case of detection of Candida species in the bile. Multivariate analysis confirmed the negative prognostic impact of Candida in the bile in pancreatic cancer patients. CONCLUSION: Outcome in tumor patients with malignant bile obstruction is associated with the type of microbial biliary colonization. The proof of multiresistant pathogens or Candida, as well as the level of inflammation markers, have an impact on the prognosis of the underlying tumor disease.

Mapping the optimal forest road network based on the multicriteria evaluation technique: the case study of Mediterranean Island of Thassos in Greece.

The sustainable management of forest resources can only be achieved through a well-organized road network designed with the optimal spatial planning and the minimum environmental impacts. This paper describes the spatial layout mapping for the optimal forest road network and the environmental impacts evaluation that are caused to the natural environment based on the multicriteria evaluation (MCE) technique at the Mediterranean island of Thassos in Greece. Data analysis and its presentation are achieved through a spatial decision support system using the MCE method with the contribution of geographic information systems (GIS). With the use of the MCE technique, we evaluated the human impact intensity to the forest ecosystem as well as the ecosystem's absorption from the impacts that are caused from the forest roads' construction. For the human impact intensity evaluation, the criteria that were used are as follows: the forest's protection percentage, the forest road density, the applied skidding means (with either the use of tractors or the cable logging systems in timber skidding), the timber skidding direction, the visitors' number and truck load, the distance between forest roads and streams, the distance between forest roads and the forest boundaries, and the probability that the forest roads are located on sights with unstable soils. In addition, for the ecosystem's absorption evaluation, we used forestry, topographical, and social criteria. The recommended MCE technique which is described in this study provides a powerful, useful, and easy-to-use implement in order to combine the sustainable utilization of natural resources and the environmental protection in Mediterranean ecosystems.

Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue.

Tumors from colorectal cancer (CRC) are generally immunogenic and commonly infiltrated with T lymphocytes. However, the details of the adaptive immune reaction to these tumors are poorly understood. We have accrued both colon tumor samples and adjacent healthy mucosal samples from 15 CRC patients to study lymphocytes infiltrating these tissues. We apply a method for detailed sequencing of T-cell receptor (TCR) sequences from tumor-infiltrating lymphocytes (TILs) in CRC tumors at high throughput to probe T-cell clones in comparison with the TCRs from adjacent healthy mucosal tissue. In parallel, we captured TIL counts using standard immunohistochemistry. The variation in diversity of the TIL repertoire was far wider than the variation of T-cell clones in the healthy mucosa, and the oligoclonality was higher on average in the tumors. However, the diversity of the T-cell repertoire in both CRC tumors and healthy mucosa was on average 100-fold lower than in peripheral blood. Using the TCR sequences to identify and track clones between mucosal and tumor samples, we determined that the immune response in the tumor is different than in the adjacent mucosal tissue, and the number of shared clones is not dependent on distance between the samples. Together, these data imply that CRC tumors induce a specific adaptive immune response, but that this response differs widely in strength and breadth between patients.

Diarrhea is a positive outcome predictor for sorafenib treatment of advanced hepatocellular carcinoma.

OBJECTIVE: This study was performed to identify clinical predictors for better survival in patients with advanced hepatocellular carcinoma (HCC) under sorafenib treatment. METHODS: Between December 2007 and January 2010, 46 patients with advanced HCC were treated with sorafenib until significant tumor progression or intolerable toxicity. We prospectively collected clinical baseline data as well as data on the incidence and severity of toxic side effects of sorafenib to be correlated with progression-free survival and overall survival (OS), respectively. RESULTS: Only 26.1% (n = 12) of patients tolerated sorafenib without requiring dose reduction. The most frequent grade 3 toxicities were diarrhea (32.6%), hand-foot skin reaction (13.0%), fatigue (4.3%), and nausea/vomiting (2.2%). Eastern Cooperative Oncology Group performance status (p = 0.034) and portal vein infiltration (p = 0.021) significantly correlated with OS. Furthermore, we found a significant correlation between OS and appearance of grade 2 or 3 diarrhea with a median actuarial survival of 11.8 months (95% CI 6.9-16.6) compared to 4.2 months in patients with grade 0 or 1 diarrhea (95% CI 0.0-9.1; p = 0.009). In contrast, appearance of hand-foot skin reaction did neither correlate with progression-free survival nor with OS. CONCLUSION: Appearance of grade 2 or 3 diarrhea indicates a better OS of HCC patients undergoing sorafenib treatment.

The Role and Therapeutic Targeting of CCR5 in Breast Cancer.

The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse array of ligands initiating cell signaling that includes guided migration. Although well known to be expressed on immune cells, recent studies have shown the induction of CCR5 on the surface of breast cancer epithelial cells. The function of CCR5 on breast cancer epithelial cells includes the induction of aberrant cell survival signaling and tropism towards chemo attractants. As CCR5 is not expressed on normal epithelium, the receptor provides a potential useful target for therapy. Inhibitors of CCR5 (CCR5i), either small molecules (maraviroc, vicriviroc) or humanized monoclonal antibodies (leronlimab) have shown anti-tumor and anti-metastatic properties in preclinical studies. In early clinical studies, reviewed herein, CCR5i have shown promising results and evidence for effects on both the tumor and the anti-tumor immune response. Current clinical studies have therefore included combination therapy approaches with checkpoint inhibitors.

Impact of 68Ga-FAPI PET/CT on Staging and Oncologic Management in a Cohort of 226 Patients with Various Cancers.

Since the development of fibroblast activation protein-targeted radiopharmaceuticals, 68Ga-fibroblast activation protein inhibitor (FAPI) PET/CT has been found to be suitable for detecting primary and metastatic lesions in many types of tumors. However, there is currently a lack of reliable data regarding the clinical impact of this family of probes. To address this gap, the present study aimed to analyze the clinical impact of 68Ga-FAPI PET/CT by examining a large cohort of patients with various tumors. Methods: In total, 226 patients (137 male and 89 female) were included in this retrospective analysis. Pancreatic cancer and head and neck cancers were the most common tumor types in this cohort. TNM stage and oncologic management were initially determined with gold standard imaging, and these results were compared with 68Ga-FAPI PET/CT. Changes were classified as major and minor. Results: For 42% of all patients, TNM stage was changed by 68Ga-FAPI PET/CT results. Most of these changes resulted in upstaging. A change in clinical management occurred in 117 of 226 patients. Although a major change in management occurred in only 12% of patients, there was a significant improvement in the ability to accurately plan radiation therapy. In general, the highest clinical impact of 68Ga-FAPI PET/CT imaging was found in patients with lung cancer, pancreatic cancer, and head and neck tumors. Conclusion: 68Ga-FAPI PET/CT is a promising imaging probe that has a significant impact on TNM stage and clinical management. 68Ga-FAPI PET/CT promises to be a crucial new technology that will improve on conventional radiologic imaging methods such as contrast-enhanced CT and contrast-enhanced MRI typically acquired for cancer staging.

Outcome and prognostic factors in patients undergoing salvage therapy for recurrent esophagogastric cancer after multimodal treatment.

PURPOSE: Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. METHODS: Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. RESULTS: Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (< 6 months) had an inferior overall survival (OS 6.3 vs. 13.8 months, p < 0.001) after relapse than those with a late relapse (> 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p < 0.0001). Multivariate analysis confirmed the prognostic benefit of the MSI status and a local intervention. CONCLUSION: Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer - The PICCASSO phase I trial.

BACKGROUND: PD-1/PD-L1 inhibitors do not show activity in mismatch repair proficient (MMRp) colorectal cancer. Inhibition of C-C motif chemokine receptor 5 (CCR5) leads to an antitumoral activation of macrophages, affecting immune cell infiltrates. PICCASSO is a phase I trial exploring safety and efficacy of pembrolizumab and maraviroc in refractory MMRp CRC. METHODS: Twenty patients received pembrolizumab and maraviroc (core period, eight cycles), followed by pembrolizumab monotherapy. Primary endpoint was the feasibility rate (patients without treatment-related grade ≥3 immune-related adverse events, treatment-related grade ≥4 adverse events, or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Optional biopsies of liver metastases were performed for analyses of the micromilieu. RESULTS: The feasibility rate was 94.7% [90% CI 77.4-99.7%], with one grade 4 hyperglycemia and no additional ≥ grade 3 treatment-related toxicities. ORR according to RECIST was 5.3%. Median PFS according to RECIST was 2.10 months [95%CI 1.68-2.30], median OS 9.83 months [95% CI, 5.59-20.02]. Disease control rate of poststudy salvage treatment was >70%. Translational analyses showed an increase of antitumoral chemokines during treatment; eotaxin, a chemokine involved in chemotaxis, was identified as a biomarker linked to OS. CONCLUSIONS: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MMRp CRC patients was limited with prolonged disease stabilizations observed in single patients. Efficacy of poststudy salvage treatment and OS was higher than expected in this heavily pretreated population. THIS TRIAL IS REGISTERED AT CLINICALTRIALS.GOV: NCT03274804.

Predicting the Risk of Metastases by PSMA-PET/CT-Evaluation of 335 Men with Treatment-Naïve Prostate Carcinoma.

Men diagnosed with aggressive prostate cancer are at high risk of local relapse or systemic progression after definitive treatment. Treatment intensification is highly needed for that patient cohort; however, no relevant stratification tool has been implemented into the clinical work routine so far. Therefore, the aim of the current study was to analyze the role of initial PSMA-PET/CT as a prediction tool for metastases. In total, 335 men with biopsy-proven prostate carcinoma and PSMA-PET/CT for primary staging were enrolled in the present, retrospective study. The number and site of metastases were analyzed and correlated with the maximum standardized uptake value (SUVmax) of the intraprostatic, malignant lesion. Receiver operating characteristic (ROC) curves were used to determine sensitivity and specificity and a model was created using multiple logistic regression. PSMA-PET/CT detected 171 metastases with PSMA-uptake in 82 patients. A statistically significant higher SUVmax was found for men with metastatic disease than for the cohort without distant metastases (median 16.1 vs. 11.2; p < 0.001). The area under the curve (AUC) in regard to predicting the presence of any metastases was 0.65. Choosing a cut-off value of 11.9 for SUVmax, a sensitivity and specificity (factor 1:1) of 76.0% and 58.4% was obtained. The current study confirms, that initial PSMA-PET/CT is able to detect a relatively high number of treatment-naïve men with metastatic prostate carcinoma. Intraprostatic SUVmax seems to be a promising parameter for the prediction of distant disease and could be used for treatment stratification-aspects which should be verified within prospective trials.

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience.

OBJECTIVES: A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled. MATERIAL AND METHODS: Patients with resectable NSCLC stage II/IIIA were included. Two cycles of pembrolizumab (200 mg intravenously once every 3 weeks) were administered prior to surgery. The primary objectives were to assess the feasibility and safety of neoadjuvant pembrolizumab therapy and to evaluate antitumor activity. We analyzed the clinical parameters as well as pathological and radiological tumor response data. RESULTS: The NSCLC histology was adenocarcinoma for 13 patients and squamous cell carcinoma for 2 patients. All patients but two underwent 2 cycles of pembrolizumab prior to surgery. Four patients (27 %) presented a major pathologic response. Significant tumor target response in positron emission tomography computed tomography (PET-CT) was detected in all 4 pathologic responders. Nevertheless, the PET findings mismatched the tumor load in some patients. A PD-L1 expression ≥10 % in the pretreatment biopsy was associated with at least major pathologic response. Five patients (33 %) presented grade 2-3 treatment related adverse events (TRAE), the overall postoperative morbidity was 7 % and 30-day mortality was 0 %. CONCLUSION: Neoadjuvant pembrolizumab is a feasible therapy in surgical lung cancer patients. It was associated with tolerable toxicity and did not compromise tumor resection.

JunB is a key regulator of multiple myeloma bone marrow angiogenesis.

Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.

Cancer-related microangiopathic hemolytic anemia in patients with advanced gastric cancer: A retrospective single-center analysis.

BACKGROUND: Microangiopathic hemolytic anemia (MAHA) with thrombocytopenia and organ failure caused by tumor-associated thrombotic microangiopathy (TMA) is a life-threatening oncological emergency. Rapid diagnosis and precise distinction from other forms of TMA is crucial for appropriate therapy, which aims at treating the underlying malignancy. However, the prognosis of patients with cancer-related (CR)-MAHA is limited. To date, less than 50 patients with gastric cancer and CR-MAHA have been reported, mainly as single case reports, and detailed information on treatment strategies and outcome are scarce. We analyzed the characteristics and outcomes data of CR-MAHA patients with gastric cancer treated at our center between 2012 and 2019. AIM: To gain knowledge about CR-MAHA and the course of disease. METHODS: We retrospectively analyzed patients using an institutional prospectively maintained database. Patients who had CR-MAHA but other cancer types or cancer of unknown primary were excluded. The basic requirements for inclusion were: Histologically proven gastric adenocarcinoma; and clinical diagnosis of hemolytic anemia with schistocytes with or without thrombocytopenia. The observation period for each patient started with the first day of documented symptoms. The follow-up period for this analysis ended on February 1, 2020. RESULTS: We identified eight patients with a median age of 54 years. Histologically, all patients had (partial) diffuse subtypes of gastric adenocarcinoma with partial or complete signet cell morphology. All patients had metastatic disease and one patient had a microsatellite instability-high (MSI-H) tumor. In three patients, clinical signs of MAHA preceded the diagnosis of cancer, and in two patients, CR-MAHA indicated recurrent disease. All patients had severe hemolytic anemia and thrombocytopenia. Six patients experienced severe bone pain, and five patients had dyspnea. Systemic, 5-fluorouracil-based combination chemotherapy was initiated in six patients, which resulted in rapid initial response with significant improvement of clinical symptoms and blood values. Progression-free survival (PFS) of the whole cohort was 1.9 wk and median overall survival (OS) was 1.9 wk. For patients with chemotherapy, PFS was 9.0 wk and OS was 10.3 wk. The patient with the MSI-H tumor has been undergoing immunotherapy for more than 3 years. CONCLUSION: The benefit of chemotherapy in CR-MAHA patients is limited. Immunotherapy for patients with MSI-H tumors may lead to long-term tumor control even in CR-MAHA patients.

The Role of 68Ga-FAPI PET/CT for Patients with Malignancies of the Lower Gastrointestinal Tract: First Clinical Experience.

For oncologic management or radiotherapy planning, reliable staging tools are essential. The recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitor (FAPI) PET/CT as a first clinical analysis for primary malignancies within the lower gastrointestinal tract (LGT). Methods:68Ga-FAPI PET/CT was performed on a cohort of 22 patients with LGT tumors, including 15 patients with metastatic disease, 1 patient with suspected local relapse, and 6 treatment-naïve patients. Uptake of 68Ga-FAPI-04 and 68Ga-FAPI-46 was quantified by SUVmax and SUVmean After comparison with standard imaging, changes in tumor stage or localization and in oncologic or radiooncologic management were recorded. Results: The highest uptake of FAPI tracer was observed in liver metastases and anal cancer, with an SUVmax of 9.1 and 13.9, respectively. Because of low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50%, whereas in patients with metastases, new findings occurred in 47%. In total, FAPI imaging caused a high, medium, and low change in oncologic or radiooncologic management in 19%, 33%, and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by 68Ga-FAPI PET/CT. Conclusion: The present study demonstrated that both primary and metastatic LGT tumors were reliably detected by 68Ga-FAPI PET/CT, leading to relevant changes in TNM status and oncologic or radiooncologic management. 68Ga-FAPI PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT tumors, potentially opening new applications for tumor staging or restaging.

Targeted and immuno-biology driven treatment strategies for triple-negative breast cancer: current knowledge and future perspectives.

Introduction: Accounting for about 15% of breast cancer patients, triple-negative breast cancer (TNBC) is responsible for 25% of disease related deaths, more frequent distant spread and visceral metastasis. However, improving survival in TNBC failed and primary resistance, immunological ignorance and tumor heterogeneity limit clinical activity of novel therapies. In view of recent molecular, genetic and immunologic insights, this review aims to describe the current status of immunological and targeted treatments from a hypothesis driven perspective. Areas covered: Recent preclinical studies and ongoing clinical trials for immune directed and targeted treatments of TNBC are summarized, including immune-checkpoint blockade, resistance mechanisms, inhibition of poly (ADP-ribose) polymerase (PARP), combinatorial strategies as well as preclinical, hypothesis generating studies. Expert commentary: Sustained responses have been observed with immune-checkpoint blockade and PARP inhibitors demonstrated remarkable efficacy in germline BRCA mutated TNBC. In order to generate clinical success of many other, to date ineffective, targeted and immune therapies, the integration of multidimensional, large amounts of data, will be essential and likely accelerate treatment progress of TNBC.