Functional imaging with diffusion-weighted imaging (DWI) is a complementary tool to conventional diagnostic magnetic resonance imaging sequences. It is being increasingly investigated to predict tumor response and assess tumor recurrence. We elucidate the specific technical modifications of DWI preferred for gynecological imaging, including the different b-values and planes for image acquisition. Additionally, we discuss the problems and potential pitfalls encountered during DWI interpretation and ways to overcome them. DWI has a wide range of clinical applications in malignant and non-malignant gynecological conditions. It provides supplemental information helpful in diagnosing and managing tubo-ovarian abscess, uterine fibroids, endometriosis, adnexal torsion, and dermoid. Similarly, DWI has diverse applications in gynecological oncology in diagnosis, staging, detection of recurrent disease, and tumor response assessment. Quantitative evaluation with apparent diffusion coefficient (ADC) measurement is being increasingly evaluated for correlation with various tumor parameters in managing gynecological malignancies aiding in preoperative treatment planning. Newer advanced DWI techniques of diffusion tensor imaging (DTI) and whole body DWI with background suppression (DWIBS) and their potential uses in pelvic nerve mapping, preoperative planning, and fertility-preserving surgeries are briefly discussed. Full article

Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations. Full article

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL). At present, knowledge of genetic changes in early-stage MF is insufficient. Additionally, low tumor cell fraction renders calling of copy-number variations as the predominant mutations in MF challenging, thereby impeding further investigations. We show that enrichment of T cells from a biopsy of a stage I MF patient greatly increases tumor fraction. This improvement enables accurate calling of recurrent MF copy-number variants such as ARID1A and CDKN2A deletion and STAT5 amplification, undetected in the unprocessed biopsy. Furthermore, we demonstrate that application of long-read nanopore sequencing is especially useful for the structural variant rich CTCL. We detect the structural variants underlying recurrent MF copy-number variants and show phasing of multiple breakpoints into complex structural variant haplotypes. Additionally, we record multiple occurrences of templated insertion structural variants in this sample. Taken together, this study suggests a workflow to make the early stages of MF accessible for genetic analysis, and indicates long-read sequencing as a major tool for genetic analysis for MF. Full article

Gynecologic carcinosarcomas, specifically of endometrial and ovarian origin, are aggressive and rare tumors. Treatment data are limited and are often extrapolated from other histologies and smaller retrospective studies. While the optimal therapy approach remains contentious, treatment is often multimodal and may include surgery, chemotherapy, radiation, or a combination of multiple strategies. However, despite aggressive treatment, these tumors fare worse than carcinomas of the same anatomic sites irrespective of their stage. Recent studies have described in-depth molecular characterizations of gynecologic carcinosarcomas. Although many molecular features mirror those seen in other uterine and ovarian epithelial tumors, the high prevalence of epithelial-mesenchymal transition is more unique. Recently, molecular descriptions have expanded to begin to characterize the tumor immune microenvironment. While the importance of the immune microenvironment has been well-established for other tumor types, it has been less systematically explored in gynecologic carcinosarcomas. Furthermore, the use of immunotherapy in patients with gynecologic carcinosarcomas has not been extensively evaluated. In this review, we summarize the available data surrounding gynecologic carcinosarcomas, with a focus on the immune microenvironment. We end with a discussion of potential immunotherapy uses and future directions for the field. Full article

It is unclear whether patients with cancer present inherently impaired responses to COVID-19 and vaccination due to their treatments, neoplastic diseases or both. To address this question, immune profiling was performed in three cohorts of healthy donors and oncologic patients: infected with SARS-CoV-2, BNT162b2-vaccinated, and with previous COVID-19 disease and subsequently vaccinated. Cancer patients showed good antibody responses to vaccination, but poor induction of T-cell responses towards the S protein when compared to infection. Following natural infection, the major targets for T-cells were the SARS-CoV-2 structural proteins M and S, but not the N protein. Similar to antibody titers, the T-cell responses quickly decayed after six months post-vaccination. Significant memory T-cell expansion was observed in vaccinated donors only if previously diagnosed with COVID-19 before undergoing vaccination. Oncologic patients with previous COVID-19 followed by vaccination exhibited potent IL-17+ CD4 and CD8 T-cell responses and elevated numbers of circulating neutrophils in peripheral blood. Full article

PTK7, a catalytically defective receptor protein tyrosine kinase, promotes angiogenesis by activating KDR through direct interaction and induction of KDR oligomerization. This study developed anti-PTK7 monoclonal antibodies (mAbs) to regulate angiogenesis by inhibiting PTK7 function. The effect of anti-PTK7 mAbs on vascular endothelial growth factor (VEGF)-induced angiogenic phenotypes in human umbilical vascular endothelial cells (HUVECs) was examined. Analysis of mAb binding with PTK7 deletion mutants revealed that mAb-43 and mAb-52 recognize immunoglobulin (Ig) domain 2 of PTK7, whereas mAb-32 and mAb-50 recognize Ig domains 6–7. Anti-PTK7 mAbs inhibited VEGF-induced adhesion and wound healing in HUVECs. mAb-32, mAb-43, and mAb-52 dose-dependently mitigated VEGF-induced migration and invasion in HUVECs without exerting cytotoxic effects. Additionally, mAb-32, mAb-43, and mAb-52 inhibited capillary-like tube formation in HUVECs, and mAb-32 and mAb-43 suppressed angiogenesis ex vivo (aortic ring assay) and in vivo (Matrigel plug assay). Furthermore, mAb-32 and mAb-43 downregulated VEGF-induced KDR activation and downstream signaling and inhibited PTK7–KDR interaction in PTK7-overexpressing and KDR-overexpressing HEK293 cells. Thus, anti-PTK7 mAbs inhibit angiogenic phenotypes by blocking PTK7–KDR interaction. These findings indicate that anti-PTK7 mAbs that neutralize PTK7 function can alleviate impaired angiogenesis-associated pathological conditions, such as cancer metastasis. Full article

The widespread diffusion of photodynamic therapy (PDT) as a clinical treatment for solid tumors is mainly limited by the patient’s adverse reaction (skin photosensivity), insufficient light penetration in deeply seated neoplastic lesions, unfavorable photosensitizers (PSs) biodistribution, and photokilling efficiency due to PS aggregation in biological environments. Despite this, recent preclinical studies reported on successful combinatorial regimes of PSs with chemotherapeutics obtained through the drugs encapsulation in multifunctional nanometric delivery systems. The aim of the present review deals with the punctual description of several nanosystems designed not only with the objective of co-transporting a PS and a chemodrug for combination therapy, but also with the goal of improving the therapeutic efficacy by facing the main critical issues of both therapies (side effects, scarce tumor oxygenation and light penetration, premature drug clearance, unspecific biodistribution, etc.). Therefore, particular attention is paid to the description of bio-responsive drugs and nanoparticles (NPs), targeted nanosystems, biomimetic approaches, and upconverting NPs, including analyzing the therapeutic efficacy of the proposed photo-chemotherapeutic regimens in in vitro and in vivo cancer models. Full article

This study aimed to predict early breast cancer recurrence in women under 40 years of age using radiomics signature and clinicopathological information. We retrospectively investigated 155 patients under 40 years of age with invasive breast cancer who underwent MRI and surgery. Through stratified random sampling, 111 patients were assigned as the training set, and 44 were assigned as the validation set. Recurrence-associated factors were investigated based on recurrence within 5 years during the total follow-up period. A Rad-score was generated through texture analysis (3D slicer, ver. 4.8.0) of breast MRI using the least absolute shrinkage and selection operator Cox regression model. The Rad-score showed a significant association with disease-free survival (DFS) in the training set (p = 0.003) and validation set (p = 0.020) in the Kaplan–Meier analysis. The nomogram was generated through Cox proportional hazards models, and its predictive ability was validated. The nomogram included the Rad-score and estrogen receptor negativity as predictive factors and showed fair DFS predictive ability in both the training and validation sets (C-index 0.63, 95% CI 0.45–0.79). In conclusion, the Rad-score can predict the disease recurrence of invasive breast cancer in women under 40 years of age, and the Rad-score-based nomogram showed reasonably high DFS predictive ability, especially within 2 years of surgery. Full article

Predicting patient response to treatment and the onset of chemoresistance are still major challenges in oncology. Chemoresistance is deeply influenced by the complex cellular interactions occurring within the tumor microenvironment (TME), including metabolic crosstalk. We have previously shown that ex vivo tumor tissue cultures derived from ovarian carcinoma (OvC) resections retain the TME components for at least four weeks of culture and implemented assays for assessment of drug response. Here, we explored ex vivo patient-derived tumor tissue cultures to uncover metabolic signatures of chemosensitivity and/or resistance. Tissue cultures derived from nine OvC cases were challenged with carboplatin and paclitaxel, the standard-of-care chemotherapeutics, and the metabolic footprints were characterized by LC-MS. Partial least-squares discriminant analysis (PLS-DA) revealed metabolic signatures that discriminated high-responder from low-responder tissue cultures to ex vivo drug exposure. As a proof-of-concept, a set of potential metabolic biomarkers of drug response was identified based on the receiver operating characteristics (ROC) curve, comprising amino acids, fatty acids, pyrimidine, glutathione, and TCA cycle pathways. Overall, this work establishes an analytical and computational platform to explore metabolic features of the TME associated with response to treatment, which can leverage the discovery of biomarkers of drug response and resistance in OvC. Full article

Despite several limitations, the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are still the gold standard in response evaluation of metastatic colorectal cancer (mCRC). The aim of the present study was to investigate hypermethylated neuropeptide Y circulating tumor DNA (meth-NPY) as an early biomarker for treatment effect and monitoring in 70 mCRC patients receiving first-line treatment in the FOLFOXIRI-Toco trial. Meth-NPY was analyzed using droplet digital PCR, and the response rate was defined as the fraction of patients converting from a baseline detectable level to an undetectable level after the first treatment cycle (responders). A significant increase in meth-NPY was defined as a value with no overlap between the 95% CI of the current and preceding measurement. Progression-free survival (PFS) was significantly longer in meth-NPY responders compared to non-responders, 10.1 and 7.6 months, respectively (p = 0.02, HR = 0.43). Patients with response according to RECIST 1.1 had a PFS of 10.1 compared to 7.3 months for non-responders (p = 0.17, HR = 0.65). A significant increase in meth-NPY was found with a median of 49 days before radiological progression. In conclusion, early meth-NPY response proved superior to response according to RECIST 1.1 with respect to predicting improved PFS. Meth-NPY is an early indicator of progression, allowing treatment reorientation at an earlier timepoint. Full article

Carcinoma of the cervix is one of the most common cancers that claims women’s lives every year. Despite preventive HPV vaccines and conventional cancer treatments, approximately 273,000 women succumb to cervical carcinoma every year. Immune system perturbations help malignant cells in immune evasion, tumor establishment, invasion, and metastasis. An insight into immune system players that promote or suppress cervical cancer is important for the development of more targeted therapies with the fewest side effects. Immunotherapy has emerged as the most compliant approach to target cancer because it utilizes a natural course of action to stimulate the immune system against cancer cells. The major immunotherapy approaches for cervical carcinoma include monoclonal antibodies, immune checkpoint blockade therapy, adoptive cell transfer therapies, and oncolytic viruses. In October 2021 the FDA approved pembrolizumab in combination with chemotherapy or bevacizumab as a first-line treatment for cervical cancer. A recent breakthrough has been made in the cancer immunotherapy regimen in which a monoclonal antibody dostarlimab was able to completely cure all colorectal cancer patients, with disease-free progression after 6 months and counting. This creates hope that immunotherapy may prove to be the final nail in the coffin of this centuries-long prevalent disease of “cancer”. Full article

(1) Background: Gliomas are the most common primary brain neoplasms accounting for roughly 40–50% of all malignant primary central nervous system tumors. We aim to develop a deep learning-based framework for automated segmentation and prediction of biomarkers and prognosis in patients with gliomas. (2) Methods: In this retrospective two center study, patients were included if they (1) had a diagnosis of glioma with known surgical histopathology and (2) had preoperative MRI with FLAIR sequence. The entire tumor volume including FLAIR hyperintense infiltrative component and necrotic and cystic components was segmented. Deep learning-based U-Net framework was developed based on symmetric architecture from the 512 × 512 segmented maps from FLAIR as the ground truth mask. (3) Results: The final cohort consisted of 208 patients with mean ± standard deviation of age (years) of 56 ± 15 with M/F of 130/78. DSC of the generated mask was 0.93. Prediction for IDH-1 and MGMT status had a performance of AUC 0.88 and 0.62, respectively. Survival prediction of <18 months demonstrated AUC of 0.75. (4) Conclusions: Our deep learning-based framework can detect and segment gliomas with excellent performance for the prediction of IDH-1 biomarker status and survival. Full article

Many studies have evaluated the clinical implications of lymph node ratio (LNR) as a prognostic factor in patients with oral squamous cell carcinoma (OSCC). The main purpose of this systematic review and meta-analysis was to address LNR as a prognosticator in patients with OSCC. A systematic search was conducted in the following databases: PubMed, EMBASE, Google Scholar, OpenGrey, Cochrane library, and ClinicalTrials.gov, and studies between 2009 and 2020 were sought. The pooled relative risk was calculated along with 95% confidence intervals for the following endpoints: overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), distant metastasis-free survival (DMFS), locoregional disease-free survival (LRDFS), local recurrence-free survival (LRFS), and recurrence-free survival (RFS) according to the random-effects model (Der Simonian–Laird approach). Subgroup and meta-regression analyses were performed as well. Finally, 32 cohort studies were eligible, which included 20,994 patients with OSCC. Patients were subdivided into two categories, group YES (studies that included in their analysis only patients with positive lymph nodes) and group NO (studies that did not exclude LNR = 0 patients). In the group YES, patients with high LNR had shorter OS (RR = 1.68, 95% CI: 1.47–1.91), DFS (RR = 1.68, 95% CI: 1.42–1.99), DSS (RR = 1.94, 95% CI: 1.56–2.42), DMFS (RR = 1.83, 95% CI: 1.13–2.96), LRDFS (RR = 1.55, 95% CI: 1.10–2.20), and LRFS (RR = 1.73, 95% CI: 1.41–2.13) compared to patients with low LNR. In the group NO, patients with high LNR in comparison had shorter OS (RR = 2.38, 95% CI: 1.99–2.85), DFS (RR = 2.04, 95% CI: 1.48–2.81), and DSS (RR = 2.90, 95% CI: 2.35–3.57) compared to patients with low LNR. Based on those findings, LNR might be an independent prognostic factor for OS in patients with OSCC and could be incorporated into future classification systems for better risk stratification. Full article

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe₂ and COTI-NMeCy), and the non-substituted analogue (COTI-NH₂) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe₂ as an interesting new drug candidate with improved anticancer activity and resistance profile. Full article

To explore the relationship between cancer cell SREBF1 expression, lipid droplets (LDs) formation, and the sensitivity to chemotherapies, we cultured lung adenocarcinoma cells H1299 (with LD) and H1563 (without LD) in a serum-free basal medium (BM) or neutrophil degranulation products containing medium (NDM), and tested cell responses to cisplatin and etoposide. By using the DESeq2 Bioconductor package, we detected 674 differentially expressed genes (DEGs) associated with NDM/BM differences between two cell lines, many of these genes were associated with the regulation of sterol and cholesterol biosynthesis processes. Specifically, SREBF1 markedly declined in both cell lines cultured in NDM or when treated with chemotherapeutics. Despite the latter, H1563 exhibited LD formation and resistance to etoposide, but not to cisplatin. Although H1299 cells preserved LDs, these cells were similarly sensitive to both drugs. In a cohort of 292 patients with non-small-cell lung cancer, a lower SREBF1 expression in tumors than in adjacent nontumor tissue correlated with overall better survival, specifically in patients with adenocarcinoma at stage I. Our findings imply that a direct correlation between SREBF1 and LD accumulation can be lost due to the changes in cancer cell environment and/or chemotherapy. The role of LDs in lung cancer development and response to therapies remains to be examined in more detail. Full article