External validation of risk prediction scores in patients undergoing anatomic video-assisted thoracoscopic resection.

BACKGROUND: EuroLung Risk scores were established to predict postoperative morbidity and mortality in patients undergoing anatomic lung resections. We aimed to perform an external validation of the EuroLung scores, which were calculated from data of the European Society of Thoracic Surgeons database, in our video-assisted thoracoscopic surgery cohort. METHODS: All available EuroLung scores were calculated for 718 patients scheduled for anatomic video-assisted thoracoscopic surgery resections between 2009 and 2019. Morbidity and mortality according to the definitions of the EuroLung scores were analyzed in a prospectively maintained database. RESULTS: Overall observed complication rate was 10.45%. Scores showed weak individual correlation (η = 0.155-0.174). The EuroLung1 app score showed the biggest area under the receiver operative characteristic (ROC) curve with 0.660. Binary logistic regression analysis showed that predicted postoperative forced expiratory volume in 1 s was associated with increased complications in both EuroLung1 and parsimonious EuroLung1 scores. Thirty-day mortality was 0.7% (predicted 1.10-1.40%) and was associated with predicted postoperative forced expiratory volume in 1 s for both EuroLung2 and parsimonious EuroLung2 scores. The EuroLung2 (2016) showed the biggest area under the ROC curve with 0.673. Only a very weak eta correlation between predicted and observed mortality was found for both aggregate EuroLung2, EuroLung2 (2016), EuroLung2 (2019), and parsimonious EuroLung2 (2016) (η = 0.025/0.015/0.011/0.009). CONCLUSION: EuroLung scores help to estimate postoperative morbidity. However, even with the highest aggregate EuroLung scores possible only 50% suffer from postoperative morbidity. Although calibration of the scores was acceptable, discrimination between predicted and observed events was poor. Therefore, individual correlation between predicted and observed events is weak. Therefore, EuroLung scores may be best used to compare institutional quality of care to the European Society of Thoracic Surgeons database but should not be used to preclude patients from surgical treatment.

Angiogenesis inhibition in non-small cell lung cancer: a critical appraisal, basic concepts and updates from American Society for Clinical Oncology 2019.

PURPOSE OF REVIEW: Recently, the combination of antiangiogenic agents, chemotherapy and immunotherapy has shown synergistic anticancer effects in non-small cell lung cancer (NSCLC). The future for this approach appears bright in lung cancer treatment; however, many challenges remain to be overcome regarding its true potential, optimal sequence and timing of therapy, and safety profile. In this review, we will discuss the current status and future direction of antiangiogenic therapy for the treatment of NSCLC, and highlight emerging strategies, such as tumor vessel normalization (TVN). RECENT FINDINGS: Bevacizumab was the first antiangiogenic agent approved for the treatment of advanced NSCLC. Recently, the combination of chemotherapy/antiangiogenic therapy with immunotherapy showed high efficacy in first-line settings. A subgroup of patients with liver metastasis and driver mutation-addicted tumors benefited most, suggesting that the metastatic location, as well as the genetic background of the tumor, are key determinants for therapy responses. SUMMARY: The efficacy of antiangiogenic therapies in unselected patients is rather limited. The tumor microenvironment has appeared to be more complex and heterogeneous than previously assumed. Only a contextual rather than a cell-specific approach might provide valuable insights towards the clinical validation of combinational therapies.

Lessons learned from immunoadsorption for hyperviscosity in IgM multiple myeloma-A case report.

We report the case of a 63-year-old Caucasian woman with multiple relapsed IgM multiple myeloma (MM) and elevated free kappa light chains (fκLC). Due to hyperviscosity syndrome with visual impairment, regular plasma exchanges were performed. As part of her 11th line of therapy, an experimental protocol consisting of pembrolizumab, pomalidomide, and dexamethasone was initiated. To reduce fκLC and immunoglobulin (Ig) M, we performed immunoadsorption (IA) using columns containing recombinant single domain camelid antibody fragments as ligands. We measured pembrolizumab (humanized IgG4 kappa anti-PD1 antibody) levels before and after each IA session and found a 98.1% reduction from baseline with five sessions of IA. Comparable elimination kinetics were observed for serum IgG, whereas fκLC and IgM were eliminated to a substantially lesser extent. These findings highlight that in hyperviscosity syndrome due to IgM MM, broad spectrum IA columns might be only moderately effective compared to total plasma exchange or double filtration plasmapheresis. Monoclonal antibodies are efficiently reduced by extracorporeal therapies and re-dosing is necessary to provide sufficient efficacy. In the case of serious adverse events such as immune-related adverse events, IA might be used to eliminate the monoclonal antibody. Measuring IgG levels might be a reasonable strategy for monitoring drug levels of monoclonal antibodies during IA.

VATS Partial Pleurectomy Versus VATS Pleural Abrasion: Significant Reduction in Pneumothorax Recurrence Rates After Pleurectomy.

INTRODUCTION: Surgical treatment of primary spontaneous pneumothorax (PSP) usually consists of bullectomy and any form of pleurodesis to reduce risk of disease recurrence. Whether pleurectomy is superior to pleural abrasion is still a matter of debate with recurrence rates especially high when performed with a video-assisted thoracoscopic (VATS) approach. Aim of this study was to compare the efficacy of the two methods in prevention of recurrence of pneumothorax in a minimally invasive setting. MATERIALS AND METHODS: Between 01/2005 and 12/2015, 107 patients younger than 40 years with PSP underwent VATS bullectomy and either partial pleurectomy or pleural abrasion. Medical records of patients were reviewed retrospectively. RESULTS: Pleural abrasion was performed in 34/107 patients, 73/107 patients underwent partial pleurectomy. There were no statistically significant differences in age, sex, body mass index or smoking history at time of surgery. There was no significant difference in major postoperative complications (p = 0.3022). Nine (8.4%) patients had a recurrence of pneumothorax during follow-up. Incidence of recurrence in those undergoing pleural abrasion was significantly higher than those undergoing apical pleurectomy (8/34 vs. 1/73, p < 0.001). Surgical technique was the only factor associated with a recurrence of PSP after surgical intervention. DISCUSSION: In our analysis, a VATS partial pleurectomy proved to be effective for prevention of recurrent PSP. Recurrence rates were low despite a minimally invasive approach and significantly lower than in the pleural abrasion group. According to these findings, VATS pleurectomy might be considered as the primary choice for surgical pleurodesis in patients with PSP.

What's new in small cell lung cancer - extensive disease? An overview on advances of systemic treatment in 2016.

Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials. Furthermore, a potential benefit of new agents targeting DLL3, Aurora A kinase and PARP-inhibitor was reported. In this review we summarize new developments and critically highlight the most important and promising data in the relapsed small cell lung cancer disease.

Predominant expression of truncated EpCAM is associated with a more aggressive phenotype and predicts poor overall survival in colorectal cancer.

Regulated intramembrane proteolysis (RIP) has been shown to be an important mechanism for oncogenic activation of EpCAM through nuclear translocation of the intracellular domain EpICD. Recently, we identified two different membranous EpCAM variants namely EpCAM(MF) (full-length) and EpCAM(MT) (truncated) to be expressed in the majority of human epithelial tumors. The aim of our study was to evaluate the potential role of these two protein variants as additional prognostic biomarkers in colorectal cancer. In most studies only one antibody targeting the extracellular domain of EpCAM (EpEX) has been used, whereas in the present study additionally an antibody which detects the intracellular domain (EpICD) was applied to discriminate between different EpCAM variants. Using immunohistochemistry, we analyzed the expression of EpCAM(MF) and EpCAM(MT) variants in 640 patients with colorectal cancer and determined their correlations with other prognostic factors and clinical outcome. A statistically significant association was observed for EpCAM(MT) with advanced tumor stage (p < 0.001), histological grade (p = 0.01), vascular (p < 0.001) and marginal (p = 0.002) invasion. Survival analysis demonstrated reduced overall survival (p < 0.004) in patients with tumors expressing the EpCAM(MT) phenotype when compared to patients with tumors expressing the EpCAM(MF) variant. In conclusion, this study for the first time indicates that expression of EpCAM(MT) is associated with a more aggressive phenotype and predicts poor survival in patients with colorectal cancer.

NSCLC without Antineoplastic Treatment: Incidence, Characteristics, and Outcome as Outlined in the TYROL Study.

BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) has become more and more individualized with the availability of potent and less toxic therapies. However, there are still patients who do not receive antineoplastic treatment. The aim of this study was to investigate the incidence of 'no treatment', its reasons, and the outcome of untreated NSCLC patients in recent years. PATIENTS AND METHODS: Medical files of 1,256 consecutive NSCLC patients diagnosed between 2001 and 2009 at the Medical University of Innsbruck and affiliated hospitals were retrospectively analyzed. RESULTS: In 66 of the 1,256 patients (5.3%), the absence of antineoplastic treatment could be ascertained. The median age was 72.1 years, and 42 patients (63.3%) were males. The majority of patients presented with stage IV (n=45; 68.2%). Treatment was omitted due to physical deterioration in 41 patients (62.1%), and 25 patients (37.9%) refused any treatment. The median overall survival of the untreated patients was 3.1 months (refusal: 9.7 months; physical deterioration: 2.1 months). CONCLUSION: This study provides information on the incidence of NSCLC patients without antineoplastic treatment and gives a detailed description of the characteristics and comorbidities. These data might help clinicians in the survival estimations of their NSCLC patients in scenarios like therapy refusal or poor physical condition.

Non-pegylated liposomal doxorubicin in lymphoma: patterns of toxicity and outcome in a large observational trial.

The anthracycline doxorubicin plays a major role in the treatment of lymphoproliferative disorders. However, its use is often limited due to cardiac toxicity, which seems to be much less in the liposomal non-pegylated formulation (Myocet®). The aim of this study was the evaluation of efficacy and toxicity of Myocet®-containing treatment regimens, with a focus on cardiotoxicity during treatment in lymphoma patients. A total of 326 consecutive patients, treated between March 2008 and December 2013 in 11 Austrian and 1 Italian cancer centers, were retrospectively assessed. Patients' baseline and treatment-related parameters were obtained by reviewing hospital records. Median age was 74 years (range 26-93). The most common histology was DLBCL (60 %), followed by FL (13 %) and MCL (8 %). At least one cardiovascular comorbidity was present in 72 % of patients. Most common grade 3/4 toxicities were hematologic, namely, leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia in 44, 40, 17, and 16 %. Overall, 43 patients suffered a cardiac event (any grade) with most patients developing congestive heart failure. Parameters significantly associated with severe cardiac events (grades 3-5) were the presence of cardiovascular comorbidities, chronic obstructive pulmonary disease, and elevated baseline NT-proBNP. Treatment response after first line Myocet®-containing therapy was ≥58 % among all entities (range 58-86 %) and therefore comparable to those of conventional therapeutic regimens. Herein, we provide a detailed toxicity profile of Myocet®-containing chemotherapy regimens. Despite the high rate of patients with preexisting comorbidities, the number of adverse events was encouraging. However, these results need to be confirmed in a prospective randomized trial.

CXCR3 Expression Is Associated with Advanced Tumor Stage and Grade Influencing Survival after Surgery of Localised Renal Cell Carcinoma.

BACKGROUND: Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8+ T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8+ T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. METHODS: CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. RESULTS: Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8+ T cell expression (p < 0.001). Patients with CXCR3high RCCs had also a significant shorter RFS compared to CXCR3low (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. CONCLUSION: CXCR3high cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC.

Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy.

INTRODUCTION: Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. MATERIAL AND METHODS: Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17ß-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. RESULTS: Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039). CONCLUSION: Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings.

Urothelial carcinoma (UC) presents as aggressive disease with a greater incidence in men, yet a more aggressive course of disease in women. Patients with metastatic UC receive a chemotherapy regimen as the gold standard, based on an included platin substance. In the case of having contraindications to chemotherapy, checkpoint immunotherapy, priming the immune system to the tumor, is the treatment of choice. Furthermore, immunotherapy is used as second line therapy in progressive disease after chemotherapy and as maintenance therapy in stable tumor conditions after completing the chemotherapy regimen.Evidence shows that sex hormones of the hypothalamus­hypophysis axis influence development and course of UC. The sex hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate estrogen (E2) production with a negative feedback function on the LH and FSH secretion. High levels of E2 present with a protective effect against UC. Sex has furthermore shown to predict potential response to immunotherapy. This study therefore focused on monitoring and correlating changes of sex hormone levels in 28 patients during therapy with checkpoint inhibitors.This first study assessing changes in sex hormones and the influence of baseline sex hormone values on survival in UC shows that responders to immunotherapy had significantly increased FSH levels. FSH furthermore increased in male patients receiving second line immunotherapy. High values of LH and a high LH/FSH ratio at baseline correlated with better overall survival in female patients. High E2 levels were indicative of better survival in male patients. The study results represent first suggestive prognostic and predictive results to the response of immunotherapy in UC.

Optimization of postoperative surveillance protocols in upper tract urothelial cancer: A retrospective cohort study.

Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is managed by radical or organ-sparing surgery. High recurrence rates require early detection and strict follow-up (FU) protocols. Recommendations are assigned to a low level of evidence. Our aim was to identify time-to-tumor recurrence, analyze the temporal relation to recommended FU regimens, and provide a critical proposal for further surveillance. This retrospective study included 54 patients receiving radical nephroureterectomy (RNU) in high-risk UTUC and 14 patients assigned to kidney-sparing surgery (KSS) with low-risk disease. FU surveillance protocols consisted of close intervals irrespective of the received type of surgery. In total, 68 patients were included with a median FU of 23 months. Mean overall survival (OS) was significantly shorter in RNU compared to KSS (P = .027). Recurrence in the bladder and/or upper urinary tract (UUT) was 57.1% in KSS and 38.9% after RNU (P = .241). Mean recurrence-free survival (RFS) was significantly shorter in RNU patients compared to KSS (22.4 vs. 47.9 months, P = .013), and 76.2% of the recurrences in the RNU group occurred in the first postoperative year. UUT recurrence was diagnosed after a median of 3.0 (RNU) and 25.0 (KSS) months. There was a frequent onset of metastases in the RNU group, with 85.7% in the first year compared to the KSS group with 50%. Multivariable regression analysis showed that the tumor stage was the parameter independently related to OS (P = .002), RFS (P = .008), and metastasis-free survival (MFS, P = .002). In conclusion, surveillance of UTUC should be adapted to real-time occurrence patterns. Strict imaging protocols are recommended in the first two years irrespective of the method of surgery. As recurrence is equally distributed over the years after KSS, cystoscopy should be offered regularly for five years and diagnostic URS for three years. After RNU, cystoscopies should be decreased to yearly intervals after year three. Contralateral UUT should also be examined after RNU.

Sarcopenia and Mediastinal Adipose Tissue as a Prognostic Marker for Short- and Long-Term Outcomes after Primary Surgical Treatment for Lung Cancer.

Surgical resection remains the gold standard of treatment for early-stage lung cancer. Several risk models exist to predict postoperative morbidity and mortality. Psoas muscle sarcopenia has already successfully been used for morbidity prediction in lung transplantation and is not yet included in the available risk scores for pulmonary resections. We hypothesized that the skeletal muscle index and mediastinal adipose tissue might also have an impact on postoperative outcomes after primary surgery for primary lung cancer. The institutional database was queried for patients with primary lung cancer who were treated with primary lobectomy or segmentectomy between February 2009 and November 2018. In total, 311 patients were included for analysis. Patients receiving neo-/adjuvant chemotherapy or with a positive nodal status were excluded to rule out any morbidity or mortality due to (neo-)adjuvant treatment. Sarcopenia was defined as a skeletal muscle index of <34.4 cm2/m2 for women and <45.4 cm2/m2 for men. Mediastinal adipose tissue was defined with a radiodensity of -150 to -30 Hounsfield units. Sarcopenia was diagnosed in 78 (25.1%) of the 311 patients. Male patients were significantly more likely to suffer from sarcopenia (31.5% vs. 18.1%, p = 0.009). Comorbidities, lung function, tumour histology, pathologic tumour staging, mediastinal adipose tissue and age did not differ between groups with or without sarcopenia. Sarcopenic patients had a significantly longer length of stay, with 13.0 days vs. 9.5 (p = 0.003), and a higher rate of any postoperative complications (59.0% vs. 44.6%, p = 0.036). There was no difference in recurrence rate. Five-year overall survival was significantly better in the patient cohort without sarcopenia (75.6% vs. 64.5%, p = 0.044). Mediastinal adipose tissue showed no significant impact on length of stay, postoperative complications, recurrence rate, morbidity or survival. Sarcopenia, quantified with the skeletal muscle index, is shown to be a risk factor for postoperative morbidity and reduced survival in primary lung cancer. Efforts should be taken to pre-emptively screen for sarcopenia and start countermeasures (e.g., physical prehabilitation, protein-rich nutrition, etc.) during the preoperative workup phase.

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Radiomic Assessment of Radiation-Induced Alterations of Skeletal Muscle Composition in Head and Neck Squamous Cell Carcinoma within the Currently Clinically Defined Optimal Time Window for Salvage Surgery-A Pilot Study.

Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) frequently require primary radiochemotherapy (RCT). Despite intensity modulation, the desired radiation-induced effects observed in HNSCC may also be observed as side effects in healthy tissue, e.g., the sternocleidomastoid muscle (SCM). These side effects (e.g., tissue fibrosis) depend on the interval between the completion of RCT and restaging CT. For salvage surgery, the optimal time window for surgery is currently clinically postulated at between 6 and 12 weeks after completion of RCT. Thus, no extensive tissue fibrosis is to be expected. This interval is based on clinical studies exploring surgical complications. Studies directly exploring radiation-induced changes of the SCM in HNSCC patients are sparse. The present study quantified tissue alterations in the SCM and paravertebral musculature (PVM) after RCT, applying radiomics to determine the optimal time window for salvage surgery. Three radiomic key parameters, (1) volume, (2) mean positivity of pixels (MPP), and (3) uniformity, were extracted with mint LesionTM in the staging CTs and restaging CTs of 98 HNSCC patients. Of these, 25 were female, the mean age was 62 (±9.6) years, and 80.9% were UICC Stage IV. The mean restaging interval was 55 (±28; range 29-229) days. Only the mean volume significantly decreased after RCT, from 9.0 to 8.4 and 96.5 to 91.9 mL for the SCM and PVM, respectively (both p = 0.007, both Cohen's d = 0.28). In addition, the mean body mass index (BMI) decreased from 23.9 (±4.2) to 21.0 (±3.6) kg/m² (p < 0.001; Cohen's d = 0.9). The mean BMI decreased significantly and was correlated with the volume decrease for the SCM (r = 0.27; p = 0.007) and PVM (r = 0.41; p < 0.001). If t-test p-values were adjusted for the BMI decrease, no significant change in volumes for the SCM and PVM was observed (both p > 0.05). The present data support the clinically postulated optimal interval for salvage surgery of 6 to 12 weeks.

PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system.

Polybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821-1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1-mut BTCs.

Multi-omic Characterization of Pancreatic Ductal Adenocarcinoma Relates CXCR4 mRNA Expression Levels to Potential Clinical Targets.

PURPOSE: Chemokines are essential for immune cell trafficking and are considered to have a major impact on the composition of the tumor microenvironment. CX-chemokine receptor 4 (CXCR4) is associated with poor differentiation, metastasis, and prognosis in pancreatic ductal adenocarcinoma (PDAC). This study provides a comprehensive molecular portrait of PDAC according to CXCR4 mRNA expression levels. EXPERIMENTAL DESIGN: The Cancer Genome Atlas database was used to explore molecular and immunologic features associated with CXCR4 mRNA expression in PDAC. A large real-word dataset (n = 3,647) served for validation and further exploratory analyses. Single-cell RNA analyses on a publicly available dataset and in-house multiplex immunofluorescence (mIF) experiments were performed to elaborate cellular localization of CXCR4. RESULTS: High CXCR4 mRNA expression (CXCR4high) was associated with increased infiltration of regulatory T cells, CD8+ T cells, and macrophages, and upregulation of several immune-related genes, including immune checkpoint transcripts (e.g., TIGIT, CD274, PDCD1). Analysis of the validation cohort confirmed the CXCR4-dependent immunologic TME composition in PDAC irrespective of microsatellite instability-high/mismatch repair-deficient or tumor mutational burden. Single-cell RNA analysis and mIF revealed that CXCR4 was mainly expressed by macrophages and T-cell subsets. Clinical relevance of our finding is supported by an improved survival of CXCR4high PDAC. CONCLUSIONS: High intratumoral CXCR4 mRNA expression is linked to a T cell- and macrophage-rich PDAC phenotype with high expression of inhibitory immune checkpoints. Thus, our findings might serve as a rationale to investigate CXCR4 as a predictive biomarker in patients with PDAC undergoing immune checkpoint inhibition.

Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer.

PURPOSE: Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer. Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared with wild-type (WT) colorectal cancers to gain insights into potential rationales for therapeutic strategies. EXPERIMENTAL DESIGN: A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and IHC. An independent cohort was used to validate our findings. RESULTS: The discovery cohort consisted of 7,245 colorectal cancer samples. RSPOfp and RNF43 mutations were detected in 1.3% (n = 94) and 6.1% (n = 443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g., IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison with WT colorectal cancers, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A, and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared with WT cases (4.4% vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared with WT samples. Although RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a tumor mutation burden ≥10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings. CONCLUSIONS: This is the largest series of RSPOfp/RNF43-mut colorectal cancers reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy.

Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives.

Mutated germline alleles in the DNA damage repair (DDR) genes "breast cancer gene 1" (BRCA1) and BRCA2 have originally been identified as major susceptibility genes in breast and ovarian cancers. With the establishment and approval of more cost-effective gene sequencing methods, germline and somatic BRCA mutations have been detected in several cancers. Since the approval of poly (ADP)-ribose polymerase inhibitors (PARPi) for BRCA-mutated cancers, BRCA mutations gained rising therapeutic implications. The impact and significance of BRCA mutations have been evaluated extensively in the last decades. Moreover, other genes involved in the DDR pathway, such as ATM, ATR, or CHK1, have emerged as potential new treatment targets, as inhibitors of these proteins are currently under clinical investigation. This review gives a concise overview on the emerging clinical implications of mutations in the DDR genes in gastrointestinal cancers with a focus on BRCA mutations.

Cardiotoxic mechanisms of cancer immunotherapy - A systematic review.

Cancer immunotherapy is a success story of translational medicine that has led to improved survival in patients with different difficult-to-treat types of cancer, such as metastasized melanoma, non-small cell lung cancer or renal cell carcinoma. These novel therapeutic agents exert their antitumor effects by activating the patients' immune system against cancer cells. Immunotherapy can be divided into active agents, such as anti-tumour vaccines or adoptive T-cell transfer, and passive immunotherapies like monoclonal antibodies, checkpoint inhibitors, cytokine therapy, bispecific T-cell engagers. After initial experimental use, broad clinical application revealed a number of important cardiovascular side effects of immunotherapeutics, which limit treatment options and decrease patients' prognosis and quality of life. With the rising rate of new immunotherapeutics at a hand, the number of patients receiving cancer immunotherapy will constantly increase, resulting in improved long-term survival rates. This review aims to summarize available cancer immunotherapies, their mechanism of action, currently known cardiovascular toxicities and their treatment. Further optimization of patient care will depend on the combined efforts by oncologists, cardiologists and cardiac surgeons to identify patients at risk and the implementation of interdisciplinary screening and treatment strategies. It is therefore crucial to familiarize heart specialists with novel cancer therapeutics and their potential adverse effects.