Cancers, Volume 16, Issue 9 (May-1 2024) – 175 articles

(1) Background: There is a huge unmet clinical need for novel treatment strategies in advanced and recurrent cervical cancer. Several cell membrane-bound molecules are up-regulated in cancer cells as compared to normal tissue and have revived interest with the introduction of antibody–drug conjugates (ADCs). (2) Methods: In this study, we characterize the expression of 10 potential ADC targets, TROP2, mesotheline, CEACAM5, DLL3, folate receptor alpha, guanylatcyclase, glycoprotein NMB, CD56, CD70 and CD138, on the gene expression level. Of these, the three ADC targets TROP2, CEACAM5 and CD138 were further analyzed on the protein level. (3) Results: TROP2 shows expression in 98.5% (66/67) of cervical cancer samples. CEACAM5 shows a stable gene expression profile and overall, 68.7% (46/67) of cervical cancer samples are CEACAM-positive with 34.3% (23/67) of cervical cancer samples showing at least moderate or high expression. Overall, 73.1% (49/67) of cervical cancer samples are CD138-positive with 38.8% (26/67) of cervical cancer samples showing at least moderate or high expression. (4) Conclusions: TROP2, CEACAM5 or CD138 do seem suitable for further clinical research and the data presented here might be used to guide further clinical trials with ADCs in advanced and recurrent cervical cancer patients. Full article

Modern chemotherapies offer a broad approach to cancer treatment but eliminate both cancer and non-cancer cells indiscriminately and, thus, are associated with a host of side effects. Advances in precision oncology have brought about new targeted therapeutics, albeit mostly limited to a subset of patients with an actionable mutation. They too come with side effects and, ultimately, ‘self-resistance’ to the treatment. There is recent interest in the modulation of ion channels, transmembrane proteins that regulate the flow of electrically charged molecules in and out of cells, as an approach to aid treatment of cancer. Phytochemicals have been shown to act on ion channels with high specificity regardless of the tumor’s genetic profile. This paper explores the use of phytochemicals in cancer symptom management and treatment. Full article

There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment. Full article

Background: Awake craniotomy (AC) is recommended for the resection of tumors in eloquent areas. It is traditionally performed under monitored anesthesia care (MAC), which relies on hypnotics and opioids. Hypnosis-assisted AC (HAAC) is an emerging technique that aims to provide psychological support while reducing the need for pharmacological sedation and analgesia. We aimed to compare the characteristics and outcomes of patients who underwent AC under HAAC or MAC. Methods: We retrospectively analyzed the clinical, anesthetic, surgical, and neuropsychological data of patients who underwent awake surgical resection of eloquent brain tumors under HAAC or MAC. We used Mann–Whitney U tests, Wilcoxon signed-rank tests, and repeated-measures analyses of variance to identify statistically significant differences at the 0.05 level. Results: A total of 22 patients were analyzed, 14 in the HAAC group and 8 in the MAC group. Demographic, radiological, and surgical characteristics as well as postoperative outcomes were similar. Patients in the HAAC group received less remifentanil (p = 0.047) and propofol (p = 0.002), but more dexmedetomidine (p = 0.025). None of them received ketamine as a rescue analgesic. Although patients in the HAAC group experienced higher levels of perioperative pain (p < 0.05), they reported decreasing stress levels (p = 0.04) and greater levels of satisfaction (p = 0.02). Conclusion: HAAC is a safe alternative to MAC as it reduces perioperative stress and increases overall satisfaction. Further research is necessary to assess whether hypnosis is clinically beneficial. Full article

There is limited information on whether the COVID-19 pandemic was associated with decreased breast cancer screening uptake and if COVID-19 vaccination was associated with an increase in screening uptake. Our study explored the uptake of breast cancer screening in Japan after the COVID-19 pandemic and assessed its association with the COVID-19 vaccination. We analyzed data from the Japan COVID-19 and Society Internet Survey (JACSIS), a web-based prospective cohort survey, and we included 6110 women without cancer history who were aged 40 to 74 years that participated in the 2012 and 2022 surveys. We examined the regular breast cancer screening uptake before and after the pandemic and employed a multivariable Poisson regression model to seek any association between COVID-19 vaccination and screening uptake. Of 6110, 38.2% regularly participated in screening before the pandemic and 46.9% did so after the pandemic. Individuals unvaccinated due to health reasons (incidence rate ratio (IRR) = 0.47, 95% CI: 0.29–0.77, p = 0.003) and for other reasons (IRR = 0.73, 95% CI: 0.62–0.86, p < 0.001) were less likely to undergo screening compared to fully vaccinated individuals. There was no long-term decrease in breast cancer screening uptake after the pandemic in Japan. Vaccination was linked to increased uptake, but there was no dose relationship. Full article

Introduction: Spinal intradural tumors account for 15% of all CNS tumors. Typical tumor entities include ependymomas, astrocytomas, meningiomas, and neurinomas. In cases of multiple affected segments, extensive approaches may be necessary to achieve the gold standard of complete tumor resection. Methods: We performed a bicentric, retrospective cohort study of all patients equal to or older than 14 years who underwent multi-segment surgical treatment for spinal intradural tumors between 2007 and 2023 with approaches longer than four segments without instrumentation. We assessed the surgical technique and the clinical outcome regarding signs of symptomatic spinal instability. Children were excluded from our cohort. Results: In total, we analyzed 33 patients with a median age of 44 years and interquartile range IQR of 30–56 years, including the following tumors: 21 ependymomas, one subependymoma–ependymoma mixed tumor, two meningiomas, two astrocytomas, and seven patients with other entities. The median length of the approach was five spinal segments with a range of 4–14 and with the foremost localization in the cervical or thoracic spine. Laminoplasty was the most chosen approach (72.2%). The median time to follow-up was 13 months IQR (4–56 months). Comparing pre- and post-surgery outcomes, 72.2% of the patients (n = 24) reported pain improvement after surgery. The median modified McCormick scores pre- and post surgery were equal to II IQR (I–II) and II IQR (I–III), respectively. Discussion: We achieved satisfying results with long-segment approaches. In general, patients reported pain improvement after surgery and received similar low modified McCormick scores pre- and post surgery and did not undergo secondary dorsal fixation. Thus, we conclude that intradural tumor resection via extensive approaches does not seem to impair long-term spinal stability in our cohort. Full article

Among women, ovarian cancer ranks as the fifth most common cause of cancer-related deaths. This study examined the impact of Hippo signaling pathway on ovarian carcinogenesis. Therefore, the signatures related to Hippo signaling pathway were derived from the molecular signatures database (MSigDB) and were used for further analysis. The Z score-based pathway activation scoring method was employed to investigate the expression patterns of these signatures in the mRNA expression profiles of ovarian cancer cohorts. Compared to other subtype tumors, the results of this study show that the Hippo signaling pathway signatures are dysregulated prominently in serous subtype-specific ovarian carcinogenesis. A receiver operating characteristic (ROC) curve-based results of the Hippo gene set, yes-associated protein 1 (YAP1), and mammalian sterile 20-like kinases 1 (MST1) genes can predict the serous subtype tumors by higher specificity and sensitivity with significant areas under the curve values also further reconfirmed these signaling dysregulations. Moreover, these gene sets were studied further for mutation analysis in the profile of high-grade serous ovarian adenocarcinoma in the cBioPortal database. The OncoPrint results reveal that these Hippo signaling pathway genes are amplified highly during the grade three and stage third or fourth of serous type ovarian tumors. In addition, the results of the Dependency Map (DepMap) plot also clearly show that these genes are amplified significantly across the ovarian cancer cell lines. Finally, overall survival (OS) curve plot investigations also revealed that these gene expressions show poor survival patterns linked to highly expressed conditions in serous subtypes of ovarian cancer patients with significant p-values (p < 0.05). Thus, the current finding would help to develop the targeted therapies treatment for serous subtype ovarian carcinogenesis. Full article

In the past decade, the therapeutic arsenal for metastatic bladder cancer has expanded considerably, with the development of immune checkpoint inhibitors (ICIs), antibody–drug conjugates such as enfortumab vedotin, and anti-fibroblast growth factor receptor agents. Clinical trials evaluating ICIs as neoadjuvants, adjuvants, or first- or second-line treatments have produced conflicting results. However, first-line therapeutic strategies have been redefined by the recent publication of results from two clinical trials: CheckMate-901, which demonstrated the superiority of combined treatment with nivolumab and chemotherapy in extending overall survival, and EV-302, which demonstrated that combined treatment with pembrolizumab and enfortumab vedotin reduced the risk of death by 53%. In this review, we discuss the role of ICIs, alone or in combination, in bladder cancer management in the metastatic and adjuvant settings in 2024, considering the latest published trials. The potential role of ICIs as neoadjuvants is also discussed. Full article

Neuroblastoma (NB), the most common cancer in infants and the most common solid tumor outside the brain in children, grows aggressively and responds poorly to current therapies. We have identified a new drug (opaganib, also known as ABC294640) that modulates sphingolipid metabolism by inhibiting the synthesis of sphingosine 1-phosphate (S1P) by sphingosine kinase-2 and elevating dihydroceramides by inhibition of dihydroceramide desaturase. The present studies sought to determine the potential therapeutic activity of opaganib in cell culture and xenograft models of NB. Cytotoxicity assays demonstrated that NB cells, including cells with amplified MYCN, are effectively killed by opaganib concentrations well below those that accumulate in tumors in vivo. Opaganib was shown to cause dose-dependent decreases in S1P and hexosylceramide levels in Neuro-2a cells, while concurrently elevating levels of dihydroceramides. As with other tumor cells, opaganib reduced c-Myc and Mcl-1 protein levels in Neuro-2a cells, and also reduced the expression of the N-Myc protein. The in vivo growth of xenografts of human SK-N-(BE)2 cells with amplified MYCN was suppressed by oral administration of opaganib at doses that are well tolerated in mice. Combining opaganib with temozolomide plus irinotecan, considered the backbone for therapy of relapsed or refractory NB, resulted in increased antitumor activity in vivo compared with temozolomide plus irinotecan or opaganib alone. Mice did not lose additional weight when opaganib was combined with temozolomide plus irinotecan, indicating that the combination is well tolerated. Opaganib has additive antitumor activity toward Neuro-2a tumors when combined with the checkpoint inhibitor anti-CTLA-4 antibody; however, the combination of opaganib with anti-PD-1 or anti-PD-L1 antibodies did not provide increased antitumor activity over that seen with opaganib alone. Overall, the data demonstrate that opaganib modulates sphingolipid metabolism and intracellular signaling in NB cells and inhibits NB tumor growth alone and in combination with other anticancer drugs. Amplified MYCN does not confer resistance to opaganib, and, in fact, the drug attenuates the expression of both c-Myc and N-Myc. The safety of opaganib has been established in clinical trials with adults with advanced cancer or severe COVID-19, and so opaganib has excellent potential for treating patients with NB, particularly in combination with temozolomide and irinotecan or anti-CTLA-4 antibody. Full article

Richter transformation is a rare phenomenon characterized by the transformation of cell chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma variant. The early identification of CLLs with a high risk of RT is fundamental. In this field, 2-deoxy-2-[¹⁸F]-fluoro-D-glucose positron emission tomography/computed tomography (2-[¹⁸F]FDG PET/CT) has been shown to be a non-invasive and promising tool, but apparently, unclear data seem to be present in the literature. This systematic review and bivariate meta-analysis aimed to investigate the diagnostic performance of 2-[¹⁸F]FDG PET/CT and its parameters in predicting RT. Between 2006 and 2024, 15 studies were published on this topic, including 1593 CLL patients. Among semiquantitative variables, SUV_max was the most investigated, and the best threshold derived for detecting RT was five. With this cut-off value, a pooled sensitivity of 86.8% (95% CI: 78.5–93.3), a pooled specificity of 48.1% (95% CI: 27–69.9), a pooled negative predictive value of 90.5% (95% CI: 88.4–92.4), a pooled negative likelihood ratio of 0.35 (95% CI: 0.17–0.70), a pooled positive likelihood ratio of 1.8 (95% CI: 1.3–2.4), and a pooled diagnostic odds ratio of 6.7 (3.5–12.5) were obtained. With a higher cut-off (SUV_max = 10), the specificity increased while the sensitivity reduced. The other metabolic features, like metabolic tumor volume, total lesion glycolysis, and radiomic features, were only marginally investigated with controversial evidence. Full article

Widespread adoption of mpMRI has led to a decrease in the number of patients requiring prostate biopsies. ⁶⁸Ga-PSMA-11 PET/CT has demonstrated added benefits in identifying csPCa. Integrating the use of these imaging techniques may hold promise for predicting the presence of csPCa without invasive biopsy. A retrospective analysis of 42 consecutive patients who underwent mpMRI, ⁶⁸Ga-PSMA-11 PET/CT, prostatic biopsy, and radical prostatectomy (RP) was carried out. A lesion-based model (n = 122) using prostatectomy histopathology as reference standard was used to analyze the accuracy of ⁶⁸Ga-PSMA-11 PET/CT, mpMRI alone, and both in combination to identify ISUP-grade group ≥ 2 lesions. ⁶⁸Ga-PSMA-11 PET/CT demonstrated greater specificity and positive predictive value (PPV), with values of 73.3% (vs. 40.0%) and 90.1% (vs. 82.2%), while the mpMRI Prostate Imaging Reporting and Data System (PI-RADS) 4–5 had better sensitivity and negative predictive value (NPV): 90.2% (vs. 78.5%) and 57.1% (vs. 52.4%), respectively. When used in combination, the sensitivity, specificity, PPV, and NPV were 74.2%, 83.3%, 93.2%, and 51.0%, respectively. Subgroup analysis of PI-RADS 3, 4, and 5 lesions was carried out. For PI-RADS 3 lesions, ⁶⁸Ga-PSMA-11 PET/CT demonstrated a NPV of 77.8%. For PI-RADS 4–5 lesions, ⁶⁸Ga-PSMA-11 PET/CT achieved PPV values of 82.1% and 100%, respectively, with an NPV of 100% in PI-RADS 5 lesions. A combination of ⁶⁸Ga-PSMA-11 PET/CT and mpMRI improved the radiological diagnosis of csPCa. This suggests that avoidance of prostate biopsy prior to RP may represent a valid option in a selected subgroup of high-risk patients with a high suspicion of csPCa on mpMRI and ⁶⁸Ga-PSMA-11 PET/CT. Full article

Cholangiocarcinoma (CCA) is a rare cancer of bile ducts. It is associated with a poor prognosis. The incidence of CCA is rising worldwide. Anatomical subgroups have been used to classify patients for treatment and prognosis. There is a growing understanding of clinically important distinctions based on underlying genetic differences that lead to different treatment options and outcomes. Its management is further complicated by a heterogeneous population and relative rarity, which limits the conduct of large trials to guide management. Surgery has been the primary method of therapy for localized disease; however, recurrence and death remain high with or without surgery. Therefore, there have been concerted efforts to investigate new treatment options, such as the use of neoadjuvant treatments to optimize surgical outcomes, targeted therapy, leveraging a new understanding of immunobiology and stereotactic radiation. In this narrative review, we address the evidence to improve suboptimal outcomes in unresectable CCA with radiation, as well as the role of radiation in neoadjuvant and postoperative treatment. We also briefly discuss the recent developments in systemic treatment with targeted therapies and immune checkpoint inhibitors. Full article

With the rapid increase in computer processing capacity over the past two decades, machine learning techniques have been applied in many sectors of daily life. Machine learning in therapeutic settings is also gaining popularity. We analysed current studies on machine learning in robotic urologic surgery. We searched PubMed/Medline and Google Scholar up to December 2023. Search terms included “urologic surgery”, “artificial intelligence”, “machine learning”, “neural network”, “automation”, and “robotic surgery”. Automatic preoperative imaging, intraoperative anatomy matching, and bleeding prediction has been a major focus. Early artificial intelligence (AI) therapeutic outcomes are promising. Robot-assisted surgery provides precise telemetry data and a cutting-edge viewing console to analyse and improve AI integration in surgery. Machine learning enhances surgical skill feedback, procedure effectiveness, surgical guidance, and postoperative prediction. Tension-sensors on robotic arms and augmented reality can improve surgery. This provides real-time organ motion monitoring, improving precision and accuracy. As datasets develop and electronic health records are used more and more, these technologies will become more effective and useful. AI in robotic surgery is intended to improve surgical training and experience. Both seek precision to improve surgical care. AI in ‘’master–slave’’ robotic surgery offers the detailed, step-by-step examination of autonomous robotic treatments. Full article

Because of the high prevalence of bone destruction in patients with multiple myeloma (MM), physical exercise is oftentimes discouraged by healthcare providers. The goal of this prospective trial was to investigate the feasibility of two six-month exercise interventions in patients with MM (N = 42): a remotely prompted home-based walking intervention or a supervised strength training intervention. Physical function and pain were assessed with the Activity Measure for Post-Acute Care (AM-PAC) Basic Mobility Short Form raw score, a six-minute walk test (6 MWT), a 30-second sit-to-stand test (30 SST), a timed up-and-go (TUG) test, a visual analog scale (VAS) for pain, handheld dynamometer tests, heart rate at rest, blood oxygen saturation at rest, and body mass index. No intervention-related serious adverse events were observed. Adverse events mostly affected the musculoskeletal system. In the resistance training group (n = 24), patients showed significant improvements in AM-PAC, TUG, 6 MWT, and 30 SST, with all effects but the 6 MWT sustained six months after the intervention. The walking group (n = 18) saw improvements in the AM-PAC, TUG, 6 MWT, and 30 SST, with a sustained change in the AM-PAC and TUG. This trial shows the feasibility of both exercise interventions with a sustained beneficial effect on the physical functioning of a six-month strength training intervention and, to a lesser extent, a six-month unsupervised walking intervention. A larger study building on these findings is currently underway. Full article

Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk of developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there is a great need for the identification of reliable predictive biomarkers for response and toxicity. The cytokine MIF (macrophage migration inhibitory factor) and its cognate receptor CD74 are intimately connected with cancer progression and have previously been proposed as prognostic biomarkers for patient outcome in various cancers, including solid tumors such as malignant melanoma. Here, we assess their potential as predictive biomarkers for response to ICB therapy and irAE development. We provide a brief overview of their function and roles in the context of cancer and autoimmune disease. We also review the evidence showing that MIF and CD74 may be of use as predictive biomarkers of patient response to ICB therapy and irAE development. We also highlight that careful consideration is required when assessing the potential of serum MIF levels as a biomarker due to its reported circadian expression in human plasma. Finally, we suggest future directions for the establishment of MIF and CD74 as predictive biomarkers for ICB therapy and irAE development to guide further research in this field. Full article

Liver cancer is one of the leading causes of cancer-related mortality. Hepatocellular carcinoma and cholangiocarcinoma are the most common types, and despite numerous advances, therapeutic options still remain poor for these cancer patients. Tumor development and progression strictly depend on a supportive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant immune cells population within a tumorigenic liver; they sustain cancer cells’ growth and invasiveness, and their presence is correlated with a poor prognosis. Furthermore, TAM cross-talk with cells and components of the TME promotes immunosuppression, a desmoplastic response, and angiogenesis. In this review, we summarize the latest advances in understanding TAM heterogeneity and function, with a particular focus on TAM modulation of the TME. We also discuss the potential of targeting macrophage subpopulations and how this is now being exploited in current clinical trials for the treatment of liver cancer. Full article

Sex differences in cancer are well-established. However, less is known about sex differences in diagnosis of brain metastasis and outcomes among patients with advanced melanoma. Using a United States nationwide electronic health record-derived de-identified database, we evaluated patients diagnosed with advanced melanoma from 1 January 2011–30 July 2022 who received an oncologist-defined rule-based first line of therapy (n = 7969, 33% female according to EHR, 35% w/documentation of brain metastases). The odds of documented brain metastasis diagnosis were calculated using multivariable logistic regression adjusted for age, practice type, diagnosis period (pre/post-2017), ECOG performance status, anatomic site of melanoma, group stage, documentation of non-brain metastases prior to first-line of treatment, and BRAF positive status. Real-world overall survival (rwOS) and progression-free survival (rwPFS) starting from first-line initiation were assessed by sex, accounting for brain metastasis diagnosis as a time-varying covariate using the Cox proportional hazards model, with the same adjustments as the logistic model, excluding group stage, while also adjusting for race, socioeconomic status, and insurance status. Adjusted analysis revealed males with advanced melanoma were 22% more likely to receive a brain metastasis diagnosis compared to females (adjusted odds ratio [aOR]: 1.22, 95% confidence interval [CI]: 1.09, 1.36). Males with brain metastases had worse rwOS (aHR: 1.15, 95% CI: 1.04, 1.28) but not worse rwPFS (adjusted hazard ratio [aHR]: 1.04, 95% CI: 0.95, 1.14) following first-line treatment initiation. Among patients with advanced melanoma who were not diagnosed with brain metastases, survival was not different by sex (rwOS aHR: 1.06 [95% CI: 0.97, 1.16], rwPFS aHR: 1.02 [95% CI: 0.94, 1.1]). This study showed that males had greater odds of brain metastasis and, among those with brain metastasis, poorer rwOS compared to females, while there were no sex differences in clinical outcomes for those with advanced melanoma without brain metastasis. Full article

Non-small-cell lung cancer (NSCLC) is the most prevalent type of lung cancer, with extensively characterized mutational spectra. Several biomarkers (such as EGFR, BRAF, KRAS gene mutations, etc.) have emerged as predictive and prognostic markers for NSCLC. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, prompting the search for alternatives. Cell-free DNA (cfDNA) found in plasma is emerging as a highly promising avenue or a supplementary method for assessing the efficacy of cancer treatments. This is especially valuable in instances where conventional biopsy specimens, like formalin-fixed, paraffin-embedded (FFPE), or freshly frozen tumor tissues prove inadequate for conducting molecular pathology analyses subsequent to the initial diagnostic procedures. By leveraging cfDNA from plasma, clinicians gain an additional tool to gauge the effectiveness of cancer therapies, thereby enhancing their ability to optimize tailored treatment strategies. In this study, 51 Lithuanian females with NSCLC were analyzed, with adenocarcinoma being the predominant pathology diagnosis in 40 cases (78%). Target mutations were identified in 38 out of 51 patients (74.5%) in tumor tissue samples, while in plasma samples, they were identified in only 10 patients’ samples (19.6%). Even though we did not have enough voluminous plasma samples in our study, gene mutations were detected in plasma from ten women, three of whom were diagnosed with early stages of lung cancer (stages I and II). For these patients, the following mutations were detected: deletion in exon 19 of the EGFR gene and single nucleotide polymorphisms in the TP53 and MET genes. All other women were diagnosed with stages III or IV of lung cancer. This indicates that the later stages of cancer contribute more cfDNA in plasma, making extraction less complicated. Full article

The prevention and appropriate management of venous thromboembolism in cancer patients is of paramount importance. However, the literature data report an underestimation of this major problem in patients with gynecological cancers, with an inconsistent venous thromboembolism risk assessment and prophylaxis in this patient setting. This narrative review provides a comprehensive overview of the available evidence regarding the management of venous thromboembolism in cancer patients, focusing on the specific context of gynecological tumors, exploring the literature discussing risk factors, risk assessment, and pharmacological prophylaxis. We found that the current understanding and management of venous thromboembolism in gynecological malignancy is largely based on studies on solid cancers in general. Hence, further, larger, and well-designed research in this area is needed. Full article

Cancer cells expand rapidly in response to altered intercellular and signaling interactions to achieve the hallmarks of cancer. Impaired cell polarity combined with activated oncogenes is known to promote several hallmarks of cancer, e.g., activating invasion by increased activity of Jun N-terminal kinase (JNK) and sustained proliferative signaling by increased activity of Hippo effector Yorkie (Yki). Thus, JNK, Yki, and their downstream transcription factors have emerged as synergistic drivers of tumor growth through pro-tumor signaling and intercellular interactions like cell competition. However, little is known about the signals that converge onto JNK and Yki in tumor cells and enable tumor cells to achieve the hallmarks of cancer. Here, using mosaic models of cooperative oncogenesis (Ras^V12,scrib⁻) in Drosophila, we show that Ras^V12,scrib⁻ tumor cells grow through the activation of a previously unidentified network comprising Wingless (Wg), Dronc, JNK, and Yki. We show that Ras^V12,scrib⁻ cells show increased Wg, Dronc, JNK, and Yki signaling, and all these signals are required for the growth of Ras^V12,scrib⁻ tumors. We report that Wg and Dronc converge onto a JNK–Yki self-reinforcing positive feedback signal-amplification loop that promotes tumor growth. We found that the Wg–Dronc–Yki–JNK molecular network is specifically activated in polarity-impaired tumor cells and not in normal cells, in which apical-basal polarity remains intact. Our findings suggest that the identification of molecular networks may provide significant insights into the key biologically meaningful changes in signaling pathways and paradoxical signals that promote tumorigenesis. Full article

Elevated levels of peripheral blood and tumor tissue neutrophils are associated with poorer clinical response and therapy resistance in melanoma. The underlying mechanism and the role of neutrophils in targeted therapy is still not fully understood. Serum samples of patients with advanced melanoma were collected and neutrophil-associated serum markers were measured and correlated with response to targeted therapy. Blood neutrophils from healthy donors and patients with advanced melanoma were isolated, and their phenotypes, as well as their in vitro functions, were compared. In vitro functional tests were conducted through nonadherent cocultures with melanoma cells. Protection of melanoma cell lines by neutrophils was assessed under MAPK inhibition. Blood neutrophils from advanced melanoma patients exhibited lower CD16 expression compared to healthy donors. In vitro, both healthy-donor- and patient-derived neutrophils prevented melanoma cell apoptosis upon dual MAPK inhibition. The effect depended on cell–cell contact and melanoma cell susceptibility to treatment. Interference with protease activity of neutrophils prevented melanoma cell protection during treatment in cocultures. The negative correlation between neutrophils and melanoma outcomes seems to be linked to a protumoral function of neutrophils. In vitro, neutrophils exert a direct protective effect on melanoma cells during dual MAPK inhibition. This study further hints at a crucial role of neutrophil-related protease activity in protection. Full article

Significant health disparities exist in relation to pathogenic variants in BRCA1/2. This study aimed to better understand the barriers and facilitators to BRCA1/2 genetic testing and intrafamilial communication of risk in racially and ethnically diverse individuals. We conducted qualitative interviews with non-Hispanic White (n = 11) and Black, Indigenous, People of Color (BIPOC) individuals (n = 14) who underwent testing for pathogenic BRCA1/2 variants. We employed template analysis, case study analysis, and comparative case study analysis to examine healthcare experiences related to genetic testing as well as intrafamilial communication of risk. Applying an intersectional lens, we sought to inform more person-centered approaches to precision healthcare and help dismantle disparities in genomic healthcare. Template analysis revealed salient factors at the individual (psychosocial well-being), interpersonal/familial, and healthcare system levels. A two-part case study analysis provided insights into how race/ethnicity, cultural norms, and socioeconomic status interact with systemic and structural inequities to compound disparities. These findings underscore the need for person-centered, tailored, and culturally sensitive approaches to understanding and addressing the complexities surrounding testing and the communication of BRCA risk. Applying an intersectional lens can inform more person-centered approaches to precision healthcare and may help to surmount existing disparities. Full article

Background: Colorectal cancer remains the second leading cause of cancer-related death in the US. As early-onset colorectal cancer (EO-CRC) becomes more prevalent in the US, research attention has shifted towards identifying at-risk populations. Previous studies have highlighted the rising rate of early-onset adenocarcinoma (ADC) and neuroendocrine tumors (NET) in the US. However, data on geographical variations of EO-CRC are scarce. Hence, our study aims to analyze time trends in EO-CRC incidence rates across various US regions and to assess these trends by sex and histopathological subtypes (ADC and NET). Methods: We analyze data spanning from 2001 to 2020 from the United States Cancer Statistics (USCS) database, covering nearly 98% of the US population. Using SEER*Stat software version (8.4.2, NCI), we calculated EO-CRC incidence rates among adults aged 20–54 years, adjusting for the age standard 2000 US population. The rates were categorized by sex and US geographical regions into west, midwest, northeast, and south. Time trends, reported as annual percentage change (APC) and average APC (AAPC), were generated via Joinpoint Regression software (v.5.0.2, NCI) utilizing the weighted Bayesian Information Criteria “BIC” method to generate the best-fit trends with a two-sided p-value cutoff at 0.05. The rates were also stratified by histopathology into ADC and NET. Results: Between 2001 and 2020, a total of 514,875 individuals were diagnosed with early-onset CRC in the US, with 54.78% being men. Incidence rates and trends varied across geographical regions. In the western region (comprising 106,685 patients, 54.85% men), incidence rates significantly increased in both women (AAPC = 1.37, p < 0.001) and men (AAPC = 1.34, p < 0.001). Similarly, in the midwestern region (with 110,380 patients, 55.46% men), there were significant increases in incidence rates among women (AAPC = 1.06, p < 0.001) and men (AAPC = 1.35, p < 0.001). The northeastern region (with 94,758 patients, 54.53% men) also witnessed significant increases in incidence rates for both women (AAPC = 0.71, p < 0.001) and men (AAPC = 0.84, p < 0.001). In contrast, the southern region (with 203,052 patients, 54.48% men) experienced slower increases in incidence rates among both women and men (AAPC = 0.25, p < 0.05 in women; AAPC = 0.66, p < 0.05 in men). When stratified by histopathology, incidence rates for adenocarcinomas (ADC) increased in all regions, most notably in the west (AAPC = 1.45, p < 0.05), and least in the south (AAPC = 0.46, p < 0.05). Conversely, for neuroendocrine tumors (NET), while incidence rates increased similarly across all regions, the pace was notably faster compared to ADC, particularly in the west (AAPC = 3.26, p < 0.05) and slower in the south (AAPC = 2.24, p < 0.05) Discussion: Our analysis of nationwide US data spanning two decades and encompassing over half a million early-onset CRC patients, representing nearly 98% of the US population, highlights significant temporal variation in incidence rates across various geographical regions. The most substantial increases in incidence rates were observed in the west, while the least pronounced changes were noted in the south, affecting both men and women. These trends persisted across the main CRC histopathological subtypes, with NET exhibiting a notably swifter pace of increase compared with ADC. These findings hold important implications for public health strategies and underscore the need for targeted interventions to address the rising burden of early-onset CRC across different regions in the US. Full article

Lung cancer (LC) is a serious health problem worldwide. Survival outcomes have improved over time due to the widespread use of novel therapeutic agents, including immune checkpoint inhibitors (ICIs). Endocrine immune-related adverse events (e-irAEs) are common in LC patients treated with ICIs. We performed a retrospective study of patients with LC who received treatment with ICIs at a tertiary referral center between January 2014 and October 2023. In total, 983 LC patients were included in the study. E-irAEs presented at a median time of 4.1 months and included hypothyroidism (15.6%), hyperthyroidism (4.3%), adrenal insufficiency (0.4%), hypophysitis (0.4%), and diabetes mellitus (0.2%). These toxicities were not related to the duration of treatment or the type of ICIs. Most (97.6%) e-irAEs were mild (grade 1–2). Median overall survival (OS) was higher in LC patients who experienced e-irAEs (31.6 months) compared to those who did not (10.8 months). The difference remained statistically significant in the 3-month (HR: 0.42) and 6-month landmark analysis (HR: 0.51). The OS advantage was observed in both patients with NSCLC (HR: 0.36) and SCLC (HR: 0.27). Additional research is needed to validate the role of e-irAEs as an independent predictor of survival outcomes in patients with LC. Full article

Background: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. Purpose: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. Methods: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. Results: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. Conclusions: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors. Full article

Preserving maximum lung function is a fundamental goal of parenchymal-sparing pulmonary laser surgery. Long-term studies for follow-up of lung function after pulmonary laser metastasectomy are lacking. However, a sufficient postoperative lung function is essential for quality of life and reduces potential postoperative complications. In this study, we investigate the extent of loss in lung function following pulmonary laser resection after three, six, and twelve months. We conducted a retrospective analysis using a prospective database of 4595 patients, focusing on 126 patients who underwent unilateral pulmonary laser resection for lung metastases from 1996 to 2022 using a 1318 nm Nd:YAG laser or a high-power pure diode laser. Results show that from these patients, a median of three pulmonary nodules were removed, with 75% presenting central lung lesions and 25% peripheral lesions. The median preoperative FEV₁ was 98% of the predicted value, decreasing to 71% postoperatively but improving to 90% after three months, 93% after six months, and 96% after twelve months. Statistical analysis using the Friedman test indicated no significant difference in FEV₁ between preoperative levels and those at six and twelve months post-surgery. The findings confirm that pulmonary laser surgery effectively preserves lung function over time, with patients generally regaining their preoperative lung function within a year, regardless of the metastases’ location. Full article

Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings. Full article

Background: The quest to comprehend the real-world efficacy of CDK4/6 inhibitors (CDKis) in breast cancer continues, as patient responses vary significantly. Methods: This single-center retrospective study evaluated CDKi use outside the trial condition from November 2016 to May 2020. Progression-free survival (PFS), time-to-treatment failure (TTF), short-term and prolonged treatment benefit (≥4 and ≥10 months), as well as prognostic and predictive markers were assessed with Kaplan–Meier and multivariate regression analyses. Results: Out of 86 identified patients, 58 (67.4%) had treatment failure of which 40 (46.5%) were due to progression. Median PFS and TTF were 12 and 8.5 months, respectively. A total of 57 (66.3%) and 42 (48.8%) patients experienced short-term and prolonged treatment benefit. Independent, significant predictors for PFS were progesterone receptor expression (HR: 0.88), multiple metastatic sites (HR: 2.56), and hepatic metastasis (HR: 2.01). Significant predictors for TTF were PR expression (HR: 0.86), multiple sites (HR: 3.29), adverse events (HR: 2.35), and diabetes (HR: 2.88). Aside from tumor biology and adverse events, treatment modifications like pausing and switching of CDKi were predictive for short-term (OR: 6.73) and prolonged (OR: 14.27) therapeutic benefit, respectively. Conclusions: These findings emphasize the importance of tailored treatment strategies, highlighting the role of PR expression, metastatic burden, and therapeutic adjustments in optimizing patient outcomes in real-world breast cancer management. Full article

Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study’s findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity. Full article

Background: Established barriers to general exercise and physical activity among individuals with head and neck cancer include dry mouth, difficulty eating, weight loss, fear of injury, comorbidities, and treatment-related symptoms of pain and fatigue. Methods/Design: A 12-week pragmatic randomized controlled trial was conducted followed by an optional supported exercise transition phase. Eligible participants were individuals with head and neck cancers who had undergone surgery and/or radiation therapy to lymph node regions in the neck. Participants were randomized to a comparison group involving a shoulder and neck physiotherapeutic exercise protocol, or to a combined experimental group comprising the shoulder and neck physiotherapeutic exercise protocol and lower-body resistance exercise training. The primary outcome of this study was fatigue-related quality of life. Results: Sixty-one participants enrolled, 59 (97%) completed the randomized trial phase, 55 (90%) completed the 24-week follow-up, and 52 (85%) completed the one-year follow-up. Statistically significant between-group differences were found in favor of the combined experimental group for the fatigue-related quality of life, fitness outcomes, and overall physical activity. Paired comparisons confirmed significant within-group improvements for both groups from baseline to one-year follow-up across most outcomes. Discussion: A group-based combined physiotherapeutic and lower-body resistance exercise program was feasible and effective. Findings are limited to individuals who had undergone a surgical neck dissection procedure. Given the complexity of head and neck cancer, further pragmatic interdisciplinary research is warranted. Full article