Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC (n = 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort (n = 202), first-line validation cohort (n = 118), second-line cohort (n = 56), and surgery cohort (n = 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08–1.46) and IL-15 (HR = 2.23, 95% CI 1.48–3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (<6 months) and long survival (>18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds. Full article

Myeloproliferative neoplasms (MPNs) arise from the uncontrolled proliferation of hematopoietic stem and progenitor cells in bone marrow. As with all tumors, the development of MPNs is a consequence of alterations in malignant cells and their interaction with other extrinsic factors that support and promote tumor progression. Since the discovery of driver mutations, much work has focused on studying and reviewing the genomic features of the disease but has neglected to delve into the important role that many other mechanisms may play. This review discusses the genetic component of MPNs but focuses mainly on some of the most relevant work investigating other non-genetic factors that may be crucial for the disease. The studies summarized here address MPN cell-intrinsic or -extrinsic factors and the interaction between them through transcriptomic, proteomic and microbiota studies, among others. Full article

Immunogenic cell death (ICD) can switch immunologically “cold” tumors “hot”, making them sensitive to immune checkpoint inhibitor (ICI) therapy. Many therapeutic platforms combine multiple modalities such as oncolytic viruses (OVs) and low-dose chemotherapy to induce ICD and improve prognostic outcomes. We previously detailed many unique properties of oncolytic bovine herpesvirus type 1 (oBHV) that suggest widespread clinical utility. Here, we show for the first time, the ability of oBHV monotherapy to induce bona fide ICD and tumor-specific activation of circulating CD8⁺ T cells in a syngeneic murine model of melanoma. The addition of low-dose mitomycin C (MMC) was necessary to fully synergize with ICI through early recruitment of CD8⁺ T cells and reduced infiltration of highly suppressive PD-1⁺ Tregs. Cytokine and gene expression analyses within treated tumors suggest that the addition of MMC to oBHV therapy shifts the immune response from predominantly anti-viral, as evidenced by a high level of interferon-stimulated genes, to one that stimulates myeloid cells, antigen presentation and adaptive processes. Collectively, these data provide mechanistic insights into how oBHV-mediated therapy modalities overcome immune suppressive tumor microenvironments to enable the efficacy of ICI therapy. Full article

We recruited 50 patients with unresectable stage III NSCLC who received CCRT between March 2020 and March 2021. Durvalumab consolidation (DC) was administered to patients (n = 23) without progression after CCRT and programmed death-ligand 1 (PD-L1) ≥ 1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated by the CD-PRIME^TM system, exhibited EpCAM/CK+/CD45− phenotype in BioViewCCBS^TM. At median follow-up of 27.4 months, patients with residual CTC clusters at C1 had worse median PFS than those without a detectable CTC cluster (11.0 vs. 27.8 months, p = 0.032), and this trend was noted only in the DC group (p = 0.034). Patients with high platelets at C1 (PLT^hi, >252 × 10³/µL) had worse median PFS than those with low platelets (PLT^lo) (5.9 vs. 17.1 months, p < 0.001). In multivariable analysis, PLT^hi and residual CTC clusters at C1 were independent risk factors for PFS, and DC group with PLT^hi and residual CTC clusters at C1 showed the worst median PFS (2.6 months, HR 45.16, p = 0.001), even worse than that of the CCRT alone group with PLT^hi (5.9 months, HR 15.39, p = 0.001). The comprehensive analysis of CTCs and PBCs before and after CCRT revealed that the clearance of CTC clusters and platelet counts at C1 might be potential biomarkers for predicting survival. Full article

In the present study, we show that the inhibitor of the apoptosis-stimulating protein of p53 (iASPP) physically interacts with the hyaluronan receptor CD44 in normal and transformed cells. We noticed that the CD44 standard isoform (CD44s), but not the variant isoform (CD44v), bound to iASPP via the ankyrin-binding domain in CD44s. The formation of iASPP-CD44s complexes was promoted by hyaluronan stimulation in fibroblasts but not in epithelial cells. The cellular level of p53 affected the amount of the iASPP-CD44 complex. iASPP was required for hyaluronan-induced CD44-dependent migration and adhesion of fibroblasts. Of note, CD44 altered the sub-cellular localization of the iASPP-p53 complex; thus, ablation of CD44 promoted translocation of iASPP from the nucleus to the cytoplasm, resulting in increased formation of a cytoplasmic iASPP-p53 complex in fibroblasts. Overexpression of iASPP decreased, but CD44 increased the level of intracellular reactive oxygen species (ROS). Knock-down of CD44s, in the presence of p53, led to increased cell growth and cell density of fibroblasts by suppression of p27 and p53. Our observations suggest that the balance of iASPP-CD44 and iASPP-p53 complexes affect the survival and migration of fibroblasts. Full article

Background: The deregulated expression of the c-MYC oncogene activates p53, which is presumably mediated by ARF/INK4, as well as replication-stress-induced DNA damage. Here, we aimed to determine whether the c-MYC-inducible AP4 transcription factor plays a role in this context using a genetic approach. Methods: We used a CRISPR/Cas9 approach to generate AP4- and/or p53-deficient derivatives of MCF-7 breast cancer cells harboring an ectopic, inducible c-MYC allele. Cell proliferation, senescence, DNA damage, and comprehensive RNA expression profiles were determined after activation of c-MYC. In addition, we analyzed the expression data from primary breast cancer samples. Results: Loss of AP4 resulted in elevated levels of both spontaneous and c-MYC-induced DNA damage, senescence, and diminished cell proliferation. Deletion of p53 in AP4-deficient cells reverted senescence and proliferation defects without affecting DNA damage levels. RNA-Seq analyses showed that loss of AP4 enhanced repression of DREAM and E2F target genes after p53 activation by c-MYC. Depletion of p21 or the DREAM complex component LIN37 abrogated this effect. These p53-dependent effects were conserved on the level of clinical and gene expression associations found in primary breast cancer tumors. Conclusions: Our results establish AP4 as a pivotal factor at the crossroads of c-MYC, E2F, and p53 target gene regulation. Full article

The study was conducted in the era when maintenance immunotherapy with durvalumab was not available in clinical practice after chemoradiotherapy (CRT) in unresectable non-small-cell lung cancer (NSCLC). The main aim of the study was to check whether the presence of cardiovascular diseases (CVD) and their pharmacotherapy affects the overall survival (OS) in such NSCLC patients undergoing sequential CRT. The group of 196 patients were analyzed: 101 patients with CVD (51.53%) and 95 patients with other reasons of qualification for sequential CRT (decreased performance status, older age, and other non-cardiovascular co-morbidities). Although patients with CVD were more often in older age, and they more often experienced cardiac and nephrological complications (p < 0.05 for all), there was a statistically nonsignificant trend for lower all-cause mortality in patients with CVD. The lowest all-cause mortality was observed in patients treated with beta-blockers and statins after two (HR = 0.31; 95%CI: 0.1–0.98; p = 0.047), three (HR = 0.33; 95%CI: 0.13–0.81; p = 0.015) and even four (HR = 0.45; 95%CI: 0.22–0.97; p = 0.027) years of follow-up. The benefit in OS remained significant in 101 patients with CVD treated with beta-blockers (HR = 0.65; 95%CI: 0.43–0.99; p = 0.045), and eventually statin, throughout the whole follow-up (log-rank p < 0.05). Further prospective studies are necessary to confirm the role of beta-blockers and statins in reduction of mortality in NSCLC patients undergoing radical CRT. Full article

Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133−/CD44− cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby (cis or trans) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with “hub” SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC. Full article

Sarcomas represent a heterogeneous group of mesenchymal malignancies that most commonly occur in the extremities, retroperitoneum, and head and neck. Intra-abdominal manifestations are rare and prove particularly difficult to treat when peritoneal sarcomatosis is present. Because of the overall poor prognosis of the disease, a tailored approach to surgical management is essential to achieve satisfactory outcomes with limited morbidity. We present the perioperative and long-term outcomes of 19 cases of sarcoma with peritoneal sarcomatosis treated surgically at our hospital. Treatment pathways were reviewed and clinical follow-up was performed. Patient characteristics, medical history, tumor subtype, surgical approach, hospital stay, complications, follow-up, and overall survival (OS) were assessed. Our patients were 9 women and 10 men with a median age of 45.9 years (18–88) and a median survival of 30 months (0–200). In most cases, peritoneal sarcomatosis was either discovered during surgery or the procedure was performed with palliative intent from the beginning. The surgical approach in these cases is very heterogeneous and should consider a variety of factors to tailor an approach for each patient. Sharing our experiences will help to increase knowledge about this rare disease and provide insight into the management of future cases. Full article

Although radiotherapy is the standard treatment for Helicobacter pylori (Hp)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy using antibiotics and an acid secretion suppressor can sometimes induce complete remission. We explored predictive markers for the response to eradication therapy for gastric MALT lymphoma that were negative for both API2-MALT1 and Hp infection using comprehensive RNA sequence analysis. Among 164 gastric MALT lymphoma patients who underwent eradication therapy as primary treatment, 36 were negative for both the API2-MALT1 fusion gene and Hp infection. Based on eradication therapy efficacy, two groups were established: complete response (CR) and no change (NC). The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that cancer-related genes and infection-related genes were highly expressed in the NC and CR groups, respectively. Based on this finding and transcription factor, gene ontology enrichment, and protein–protein interaction analyses, we selected 16 candidate genes for predicting eradication therapy efficacy. Real-time PCR validation in 36 Hp-negative patients showed significantly higher expression of olfactomedin-4 (OLFM4) and the Nanog homeobox (NANOG) in the CR and NC groups, respectively. OLFM4 and NANOG could be positive and negative predictive markers, respectively, for eradication therapy efficacy against gastric MALT lymphoma that is negative for both API2-MALT1 and Hp infection. Full article

Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients’ outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed 118 patients (median age at diagnosis 58.3, range 14.3–82.3 years) harboring FLT3-ITD, of whom 94 patients were consolidated with an allogeneic HSCT and included in outcome analyses. A high FLT3-ITD allelic ratio was associated with a higher white blood cell count, higher blood and bone marrow blasts, and worse ELN2017 risk at diagnosis. Patients with a high FLT3-ITD allelic ratio more often had NPM1 mutations, while patients with a low allelic ratio more often had FLT3-TKD mutations. Patients with a high FLT3-ITD allelic ratio were less likely to achieve a measurable residual disease (MRD)-negative remission prior to allogeneic HSCT and had a trend for a shorter time to relapse. However, there was no distinct cumulative incidence of relapse, non-relapse mortality, or overall survival according to the FLT3-ITD allelic ratio in transplanted patients. While co-mutated FLT3-TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high FLT3-ITD allelic ratio, comparative studies are needed to evaluate which FLT3-ITD mutated patients benefit from which consolidation strategy. Full article

Background: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. Methods: The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. Results: Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. Conclusions: Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram. Full article

The COVID-19 pandemic disrupted conventional medical education for surgical trainees with respect to clinical training, didactics, and research. While the effects of the COVID-19 pandemic on surgical trainees were variable, some common themes are identifiable. As hordes of COVID-19 patients entered hospitals, many surgical trainees stepped away from their curricula and were redeployed to other hospital units to care for COVID-19 patients. Moreover, the need for social distancing limited traditional educational activities. Regarding clinical training, some trainees demonstrated reduced case logs and decreased surgical confidence. For residents, fellows, and medical students alike, most didactic education transitioned to virtual platforms, leading to an increase in remote educational resources and an increased emphasis on surgical simulation. Resident research productivity initially declined, although the onset of virtual conferences provided new opportunities for trainees to present their work. Finally, the pandemic was associated with increased anxiety, depression, and substance use for some trainees. Ultimately, we are still growing our understanding of how the COVID-19 pandemic has redefined surgical training and how to best implement the lessons we have learned. Full article

With the development of RNA modification research, N6-methyladenosine (m6A) is regarded as one of the most important internal epigenetic modifications of eukaryotic mRNA. It is also regulated by methylase, demethylase, and protein preferentially recognizing the m6A modification. This dynamic and reversible post-transcriptional RNA alteration has steadily become the focus of cancer research. It can increase tumor stem cell self-renewal and cell proliferation. The m6A-modified genes may be the primary focus for cancer breakthroughs. Although some endocrine cancers are rare, they may have a high mortality rate. As a result, it is critical to recognize the significance of endocrine cancers and identify new therapeutic targets that will aid in improving disease treatment and prognosis. We summarized the latest experimental progress in the m6A modification in endocrine cancers and proposed the m6A alteration as a potential diagnostic marker for endocrine malignancies. Full article

(Multi-)Morbidity shares common biological mechanisms or risk factors with breast cancer. This study aimed to investigate the association between the number of morbidities and patterns of morbidity and the risk of female breast cancer. Among 239,436 women (40–69 years) enrolled in the UK Biobank cohort who had no cancer history at baseline, we identified 35 self-reported chronic diseases at baseline. We assigned individuals into morbidity patterns using agglomerative hierarchical clustering analysis. We fitted Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer risk. In total, 58.4% of women had at least one morbidity, and the prevalence of multi-morbidity was 25.8%. During a median 7-year follow-up, there was no association between breast cancer risk (5326 cases) and either the number of morbidities or the identified clinically relevant morbidity patterns: no-predominant morbidity (reference), psychiatric morbidities (HR = 1.04, 95%CI 0.94–1.16), respiratory/immunological morbidities (HR = 0.98, 95%CI 0.90–1.07), cardiovascular/metabolic morbidities (HR = 0.93, 95%CI 0.81–1.06), and unspecific morbidities (HR = 0.98, 95%CI 0.89–1.07), overall. Among women younger than 50 years of age only, however, there was a significant association with psychiatric morbidity patterns compared to the no-predominant morbidity pattern (HR = 1.25, 95%CI 1.02–1.52). The other associations did not vary when stratifying by age at baseline and adherence to mammography recommendations. In conclusion, multi-morbidity was not a key factor to help identify patients at an increased risk of breast cancer. Full article