One of the foundational elements of enhanced recovery after surgery (ERAS) guidelines is early postoperative mobilization. For patients undergoing head and neck cancer (HNC) surgery with free flap reconstruction, the ERAS guideline recommends patients be mobilized within 24 h postoperatively. The objective of this study was to evaluate compliance with the ERAS recommendation for early postoperative mobilization in 445 consecutive patients who underwent HNC surgery in the Calgary Head and Neck Enhanced Recovery Program. This retrospective analysis found that recommendation compliance increased by 10% despite a more aggressive target for mobilization (from 48 to 24 h). This resulted in a decrease in postoperative mobilization time and a stark increase in the proportion of patients mobilized within 24 h (from 10% to 64%). There was a significant relationship between compliance with recommended care and time to postoperative mobilization (Spearman’s rho = −0.80; p < 0.001). Hospital length of stay was reduced by a median of 2 days, from 12 (1QR = 9–16) to 10 (1QR = 8–14) days (z = 3.82; p < 0.001) in patients who received guideline-concordant care. Engaging the clinical team and changing the order set to support clinical decision-making resulted in increased adherence to guideline-recommended care for patients undergoing major HNC surgery with free flap reconstruction. Full article

Cold atmospheric plasma (CAP) has emerged as a highly selective anticancer agent, most recently in the form of plasma-activated medium (PAM). Since epithelial–mesenchymal transition (EMT) has been implicated in resistance to various cancer therapies, we assessed whether EMT status is associated with PAM response. Mesenchymal breast cancer cell lines, as well as the mesenchymal variant in an isogenic EMT/MET human breast cancer cell system (PMC42-ET/LA), were more sensitive to PAM treatment than their epithelial counterparts, contrary to their responses to other therapies. The same trend was seen in luminal muscle-invasive bladder cancer model (TSU-Pr1/B1/B2) and the non-muscle-invasive basal 5637 bladder cancer cell line. Three-dimensional spheroid cultures of the bladder cancer cell lines were less sensitive to the PAM treatment compared to their two-dimensional counterparts; however, incrementally better responses were again seen in more mesenchymally-shifted cell lines. This study provides evidence that PAM preferentially inhibits mesenchymally-shifted carcinoma cells, which have been associated with resistance to other therapies. Thus, PAM may represent a novel treatment that can selectively inhibit triple-negative breast cancers and a subset of aggressive bladder cancers, which tend to be more mesenchymal. Our approach may potentially be utilized for other aggressive cancers exhibiting EMT and opens new opportunities for CAP and PAM as a promising new onco-therapy. Full article

Leptomeningeal metastases (LM) from solid tumors represent an unmet need of increasing importance due to an early use of MRI for diagnosis and improvement of outcome of some molecular subgroups following targeted agents and immunotherapy. In this review, we first discussed factors limiting the efficacy of targeted agents in LM, such as the molecular divergence between primary tumors and CNS lesions and CNS barriers at the level of the normal brain, brain tumors and CSF. Further, we reviewed pathogenesis and experimental models and modalities, such as MRI (with RANO and ESO/ESMO criteria), CSF cytology and liquid biopsy, to improve diagnosis and monitoring following therapy. Efficacy and limitations of targeted therapies for LM from EGFR-mutant and ALK-rearranged NSCLC, HER2-positive breast cancer and BRAF-mutated melanomas are reported, including the use of intrathecal administration or modification of traditional cytotoxic compounds. The efficacy of checkpoint inhibitors in LM from non-druggable tumors, in particular triple-negative breast cancer, is discussed. Last, we focused on some recent techniques to improve drug delivery. Full article

The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases. Full article

CA125 is widely used as an initial investigation in women presenting with symptoms of possible ovarian cancer. We sought to develop CA125-based diagnostic prediction models and to explore potential implications of implementing model-based thresholds for further investigation in primary care. This retrospective cohort study used routinely collected primary care and cancer registry data from symptomatic, CA125-tested women in England (2011–2014). A total of 29,962 women were included, of whom 279 were diagnosed with ovarian cancer. Logistic regression was used to develop two models to estimate ovarian cancer probability: Model 1 consisted of age and CA125 level; Model 2 incorporated further risk factors. Model discrimination (AUC) was evaluated using 10-fold cross-validation. The sensitivity and specificity of various model risk thresholds (≥1% to ≥3%) were compared with that of the current CA125 cut-off (≥35 U/mL). Model 1 exhibited excellent discrimination (AUC: 0.94) on cross-validation. The inclusion of additional variables (Model 2) did not improve performance. At a risk threshold of ≥1%, Model 1 exhibited greater sensitivity (86.4% vs. 78.5%) but lower specificity (89.1% vs. 94.5%) than CA125 (≥35 U/mL). Applying the ≥1% model threshold to the cohort in place of the current CA125 cut-off, 1 in every 74 additional women identified had ovarian cancer. Following external validation, Model 1 could be used as part of a ‘risk-based triage’ system in which women at high risk of undiagnosed ovarian cancer are selected for urgent specialist investigation, while women at ‘low risk but not no risk’ are offered non-urgent investigation or interval CA125 re-testing. Such an approach has the potential to expedite ovarian cancer diagnosis, but further research is needed to evaluate the clinical impact and health–economic implications. Full article

The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease. Full article

Pancreatic cancer (PaC) induces a prothrombotic and hypercoagulable state. The aim of this study was to investigate the effect of tinzaparin in combination with chemotherapy. The PaCT (pancreatic cancer and tinzaparin) study was a retrospective observational study that collected data regarding progression free survival (PFS) in advanced or metastatic PaC patients who received thromboprophylaxis with tinzaparin during chemotherapy with nab-paclitaxel (N) and gemcitabine (G). The primary end point was to compare, from already published data, the PFS of patients receiving thromboprophylaxis with tinzaparin with the PFS of patients receiving chemotherapy with N–G but no thromboprophylaxis. Secondary end points were efficacy and safety of anticoagulation. In total, 110 PaC patients, 93% with advanced or metastatic disease, treated with N–G and tinzaparin (10,291 ± 1176 Anti-Xa IU, OD, median duration 8.7, IQR: 5.6–11.9 months) were enrolled. Of these, 52% were males and; the median age was 68 (40–86 years). The tumor was located to in the pancreatic head at in 45% of the patients. The median PFS was 7.9 months (IQR: 5.0–11.8 months). Out of 14 similar studies (involving 2994 patients) identified via systematic search, it was determined that the weighted PFS of patients receiving N–G but no anticoagulation was 5.6 months. Therefore, patients receiving tinzaparin had 39.54% higher PFS than patients without thromboprophylaxis (p < 0.05). During the follow-up period of 18.3 ± 11.7 months, three (2.7%) thrombotic events were recorded while two clinically relevant non-major bleeding events occurred (1.9%). In conclusion, PFS in advanced PaC patients undergoing chemotherapy is positively impacted by anticoagulation. Thromboprophylaxis with tinzaparin in treatment dose is efficient and safe. Full article

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells. Full article

The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin–radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III–IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted. Full article

Background: Adult patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) have prolonged survival but face the risk of treatment-induced impaired fertility. This systematic review, conducted by Fondazione Italiana Linfomi (FIL) researchers, aims to evaluate the incidence of treatment-related infertility, fertility preservation options, fertility assessment measures, and the optimal interval between the end of treatment and conception. Methods: MEDLINE, the Cochrane Library, and EMBASE were systematically searched up to September 2020 for published cohort, case–control, and cross-sectional studies on fertility issues. Results: Forty-five eligible studies were identified. Gonadotoxicity was related to sex, type and dosage of treatment, and, in females, to age. After receiving alkylating-agent-containing regimens, less than 30% of males recovered spermatogenesis, and 45% of females ≥30 years in age retained regular menstrual cycles. Sperm cryopreservation was offered to the majority of patients; sperm utilization resulted in a 33–61% pregnancy rate. After ovarian tissue transplantation, the spontaneous pregnancy and live birth rates were 38% and 23%; after IVF, the live birth rate was 38.4%. No data could be extracted on the utilization rate of cryopreserved mature oocytes. The results of studies on GnRH analogs are controversial; therefore, their use should not be considered an alternative to established cryopreservation techniques. Sperm count, FSH, and inhibin-B levels were appropriate measures to investigate male fertility; serum AMH levels and antral follicle count were the most appropriate markers for ovarian reserve. No data could be found regarding the optimal interval between the end of treatment and conception. Conclusions: The risk of infertility should be discussed with adult lymphoma patients at the time of diagnosis, and fertility preservation options should be proposed before first-line treatment with alkylating-agent-containing regimens. Full article

We investigate the robustness of adaptive chemotherapy schedules over repeated cycles and a wide range of tumor sizes. Using a non-stationary stochastic three-component fitness-dependent Moran process model (to track frequencies), we quantify the variance of the response to treatment associated with multidrug adaptive schedules that are designed to mitigate chemotherapeutic resistance in an idealized (well-mixed) setting. The finite cell (N tumor cells) stochastic process consists of populations of chemosensitive cells, chemoresistant cells to drug 1, and chemoresistant cells to drug 2, and the drug interactions can be synergistic, additive, or antagonistic. Tumor growth rates in this model are proportional to the average fitness of the tumor as measured by the three populations of cancer cells compared to a background microenvironment average value. An adaptive chemoschedule is determined by using the $N\to \infty$ limit of the finite-cell process (i.e., the adjusted replicator equations) which is constructed by finding closed treatment response loops (which we call evolutionary cycles) in the three component phase-space. The schedules that give rise to these cycles are designed to manage chemoresistance by avoiding competitive release of the resistant cell populations. To address the question of how these cycles perform in practice over large patient populations with tumors across a range of sizes, we consider the variances associated with the approximate stochastic cycles for finite N, repeating the idealized adaptive schedule over multiple periods. For finite cell populations, the distributions remain approximately multi-Gaussian in the principal component coordinates through the first three cycles, with variances increasing exponentially with each cycle. As the number of cycles increases, the multi-Gaussian nature of the distribution breaks down due to the fact that one of the three sub-populations typically saturates the tumor (competitive release) resulting in treatment failure. This suggests that to design an effective and repeatable adaptive chemoschedule in practice will require a highly accurate tumor model and accurate measurements of the sub-population frequencies or the errors will quickly (exponentially) degrade its effectiveness, particularly when the drug interactions are synergistic. Possible ways to extend the efficacy of the stochastic cycles in light of the computational simulations are discussed. Full article

Neoantigens are derived from tumor-specific somatic mutations. Neoantigen-based synthesized peptides have been under clinical investigation to boost cancer immunotherapy efficacy. The promising results prompt us to further elucidate the effect of neoantigen expression on patient survival in breast cancer. We applied Kaplan–Meier survival and multivariable Cox regression models to evaluate the effect of neoantigen expression and its interaction with T-cell activation on overall survival in a cohort of 729 breast cancer patients. Pearson’s chi-squared tests were used to assess the relationships between neoantigen expression and clinical pathological variables. Spearman correlation analysis was conducted to identify correlations between neoantigen expression, mutation load, and DNA repair gene expression. ERCC1, XPA, and XPC were negatively associated with neoantigen expression, while BLM, BRCA2, MSH2, XRCC2, RAD51, CHEK1, and CHEK2 were positively associated with neoantigen expression. Based on the multivariable Cox proportional hazard model, patients with a high level of neoantigen expression and activated T-cell status showed improved overall survival. Similarly, in the T-cell exhaustion and progesterone receptor (PR) positive subgroups, patients with a high level of neoantigen expression showed prolonged survival. In contrast, there was no significant difference in the T-cell activation and PR negative subgroups. In conclusion, neoantigens may serve as immunogenic agents for immunotherapy in breast cancer. Full article

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed. Full article

Aberrant angiogenesis is a hallmark for cancer and inflammation, a key notion in drug repurposing efforts. To delineate the anti-angiogenic properties of amifostine in a human adult angiogenesis model via 3D cell metabolomics and upon a stimulant-specific manner, a 3D cellular angiogenesis assay that recapitulates cell physiology and drug action was coupled to untargeted metabolomics by liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. The early events of angiogenesis upon its most prominent stimulants (vascular endothelial growth factor-A or deferoxamine) were addressed by cell sprouting measurements. Data analyses consisted of a series of supervised and unsupervised methods as well as univariate and multivariate approaches to shed light on mechanism-specific inhibitory profiles. The 3D untargeted cell metabolomes were found to grasp the early events of angiogenesis. Evident of an initial and sharp response, the metabolites identified primarily span amino acids, sphingolipids, and nucleotides. Profiles were pathway or stimulant specific. The amifostine inhibition profile was rather similar to that of sunitinib, yet distinct, considering that the latter is a kinase inhibitor. Amifostine inhibited both. The 3D cell metabolomics shed light on the anti-angiogenic effects of amifostine against VEGF-A- and deferoxamine-induced angiogenesis. Amifostine may serve as a dual radioprotective and anti-angiogenic agent in radiotherapy patients. Full article

Background: Despite that the unfavorable prognostic role of a high Total Metabolic Tumor Volume (TMTV) in Follicular Lymphoma has been demonstrated, the role of SUV_max alone at baseline PET/CT could have a different prognostic role. Patients and Methods: We performed a retrospective observational monocentric cohort study. All patients affected by FL who underwent a basal PET/CT were included. Two subgroups were identified and compared in terms of PFS and OS: (A) Basal SUV_max ≤ 6; and (B) Basal SUV_max > 6. Results: Ninety-four patients were included, 34 in group A (36.2%) and 60 in group B (63.8%). The PFS at two years was comparable in the two groups (97%). The five-year PFS was 73.5% for group A and 95% for group B (p 0.005). The five-year PFS in the whole cohort was 87.5%. A clear advantage was confirmed in group A in the absence of other risk factors. Patients with SUV_max ≤ 6 and no risk factors showed a 5-year PFS of 73% against 83% for patients with SUV_max > 6 and at least two risk factors. Conclusion: A high FDG uptake favorably correlated with PFS. A low basal SUV_max reflected a higher rate of late relapse requiring a prolonged follow-up. The basal SUV_max is an approachable parameter with prognostic implications. Full article