Large Tumor Group Research Articles

Lung neuroendocrine tumors

Neuroendocrine tumors are a large and heterogeneous group of tumors that develop from neuroendocrine cells. To define this type of tumor, the well-established term “carcinoid” continues to be used in clinical practice for years. In accordance with the characteristics of embryogenesis, three groups of neuroendocrine tumors are distinguished. The source of these tumors are neuroendocrine cells, which are located in almost all organs. The term itself and the concept of “neuroendocrine cell” have historically been repeatedly reassessed. In 1969 A. Pearse, based on the ability of these cells to utilize and decarboxylate amine precursors, introduced the term “APUD system” (aminoprecursor uptake and decarboxylation). Neuroendocrine cells, although they can secrete the same substances as neurons, but, unlike the latter, they participate not in topical, but in paracrine regulation of organs and tissues. They are located in all human organs and are the most important tool for maintaining homeostasis.In recent years, more and more publications have appeared about the frequent localization of neuroendocrine tumors in the lungs, and new approaches to the diagnosis of this pathology. This review presents the diagnostic features and clinical course of pulmonary neuroendocrine tumors.

Explorative case control study on the associations of serum vitamin D3, folic acid and vitamin B12 levels on Kawasaki disease and coronary artery lesions.

Kawasaki Disease (KD) is a pediatric vasculitic disorder characterized by systemic small vasculitis, notably coronary arteritis, with unclear pathogenesis. This explorative case-control study investigated the association between folic acid (FA), vitamin D3 (VD3), and vitamin B12 (VB12) levels and the different types of Kawasaki Disease, as well as the incidence of coronary artery lesions (CALs). In this explorative case control study, 365 KD children admitted to our hospital from January 1, 2022 to June 30, 2023 were included as the KD group. Simultaneously, 365 healthy children who received physical examination during the same period were included as the control group. The KD group was divided into typical KD group and incomplete KD group (IKD group), CALs group and non-CALS group, and IVIG sensitive group and IVIG resistant group. The children with CALs were divided into small tumor group, medium tumor group and large tumor group. Serum levels of FA, VB12, and VD3 were compared across all groups. Serum levels of FA and VD3 were significantly decreased in both the KD and CALs groups (p < 0.05), and both factors were identified as independent risk factors for KD and CALs. Similarly, reduced serum VD3 levels were observed in the IKD and IVIG-resistant groups (p < 0.05), with VD3 also being an independent risk factor for both IKD and IVIG resistance. Additionally, lower serum FA levels were noted in the group with large aneurysms (p < 0.05), establishing FA as an independent risk factor for aneurysm size. Serum levels of folic FA and vitamin VD3 were significantly reduced in children with KD. Furthermore, these reductions were more pronounced in children with IKD and CALs. This pattern suggests that lower FA and VD3 levels may increase the risk of more severe coronary lesions in KD patients. Therefore, monitoring these biomarkers could provide valuable insights for early clinical diagnosis and intervention.

Expression of Forkhead Box M1 and Anticancer Effects of FOXM1 Inhibition in Epithelioid Sarcoma

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1–protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), sex (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1–protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.

Epidemiology of Cancer.

Cancers are a large and heterogeneous group of malignant tumors that collectively accounted for approximately 600 000 US deaths in 2020; only heart disease claimed more lives. A large amount of knowledge has accumulated regarding the epidemiology of most cancer types, including their causes. The cancer types most frequently diagnosed among adults in most high-income countries are lung, colorectal, female breast, cutaneous melanoma, and prostate. In general cancer incidence and mortality is very low in children and adolescents, rising exponentially with increasing age during adulthood. There is marked international variation in the incidence of most cancers. The most important causes of cancer are tobacco use (primarily cigarette use), excess alcohol consumption, obesity, lack of physical activity, diets low in fruits and vegetables, infectious agents, and sun exposure. Early detection can reduce the chances that a person will die of cancers of the female breast, uterine cervix, colon and rectum, lung, and prostate. Although the most common cancers in the United States continue to have a substantial impact on public health, they are caused in whole or part by factors over which people and governments have control through choices they make. Among these are tobacco and alcohol use, obesity, diets low in fruits and vegetables and lack of physical activity, and sun exposure. Thus, a very large proportion of cancer's impact could be ameliorated if more people avoided these exposures.

Long-term outcomes after minimal right lateral thoracotomy for the resection of cardiac tumors

ObjectivesCardiac tumors are a rare and heterogeneous entity, with a cumulative incidence of up to 0.02%. This study aimed to investigate one of the largest patient cohorts for long-term outcomes after minimally-invasive cardiac surgery using right-anterior thoracotomy and femoral cardiopulmonary bypass (CPB) cannulation. MethodsBetween 2009 and 2021, patients who underwent minimally-invasive cardiac tumor removal at our department were included. The diagnosis was confirmed postoperatively by (immune-) histopathological analysis. Preoperative baseline characteristics, intraoperative data, and long-term survival were analyzed. ResultsBetween 2009 and 2021, 183 consecutive patients underwent surgery for a cardiac tumor at our department. Of these, n = 74 (40%) were operated on using a minimally-invasive approach. The majority, n = 73 (98.6%), had a benign cardiac tumor, and 1 (1.4%) had a malignant cardiac tumor. The mean age was 60 ± 14 years, and n = 45 (61%) of patients were female. The largest group of tumors was myxoma (n = 62; 84%). Tumors were predominantly located in the left atrium in 89% (n = 66). CPB-time was 97 ± 36min and aortic cross-clamp time 43 ± 24 min s. The mean hospital stay was 9.7 ± 4.5 days. The perioperative mortality was 0%, and all-cause mortality after ten years was 4.1%. ConclusionMinimally-invasive tumor excision is feasible and safe, predominantly in benign cardiac tumors, even in combination with concurrent procedures. Patients who require cardiac tumor removal should be evaluated for minimally-invasive cardiac surgery at a specialized center, as it is highly effective and associated with good long-term survival.

RadioLigand Therapy with [177Lu]Lu-PSMA-617 for Salivary Gland Cancers: Literature Review and First Compassionate Use in France.

Salivary gland cancers are rare tumors comprising a large group of heterogeneous tumors with variable prognosis. Their therapeutic management at a metastatic stage is challenging due to the lack of therapeutic lines and the toxicity of treatments. [177Lu]Lu-PSMA-617 (prostate-specific membrane antigen) is a vectored radioligand therapy (RLT) initially developed to treat castration-resistant metastatic prostate cancer with encouraging results in terms of efficacy and toxicity. Many malignant cells could be treated with [177Lu]Lu-PSMA-617 as long as they express PSMA as a consequence of androgenic pathway activation. RLT may be used when anti-androgen hormonal treatment has failed, particularly in prostate cancer. [177Lu]Lu-PSMA-617 has been proposed in certain salivary gland cancers, though the expression of PSMA is demonstrated by a significant uptake using [68Ga]Ga-PSMA-11 PET scan. This theranostic approach could be a new therapeutic option, warranting prospective investigation in a larger cohort. We review the literature on this subject and offer a clinical illustration of compassionate use in France as a perspective for administering [177Lu]Lu-PSMA-617 in salivary gland cancer.

Abstract 1407: Refining endometrial carcinoma of no-specific molecular subtype by sources of estrogen signaling

Abstract Introduction: Endometrial carcinomas (ECs) of no-specific molecular profile (NSMP-EC) are a large and heterogenous group of tumors. These cancers, in particular endometrioid carcinomas, are thought to be dependent on or benefit from estrogen receptor (ER) signaling. In this study, we sought to determine the sources of ER signaling in patients with NSMP-EC. Methods: We compiled a retrospective database of EC patients who received their primary treatment at our institution from 2014 to 2022, and who had ECs of NSMP based on a surrogate of The Cancer Genome Atlas (TCGA) prognostic EC molecular subtype. We used ovarian volume (binarized using a cutoff of 40 cm3), menopausal status, body mass index (BMI&amp;gt;25), and ESR1 hotspot mutations as surrogate markers for ER signaling. Results: A total of 171 patients with NSMP-EC were included in this study. As expected, menopausal status was correlated with ovarian volume (right ovarian volume median 12.3 cm3 vs 32.8 cm3, p=0.001; left ovarian volume median 10.6 cm3 vs 37.7 cm3, p&amp;lt;0.001). Of these 171 patients, 135 (79%) had an identifiable source of ER signaling. Tumors with ER signaling sources tended to be endometrioid carcinomas (125/135, 93%) whereas a lower proportion of ECs without ER signaling were of endometrioid histology (24/36, 67%; p=0.001). ESR1 hotspot mutations almost exclusively occurred in post-menopausal (11/12 mutated cases) and older patients (median age 69 vs 61 years, p=0.012). PTEN mutations tended to be more frequent in ECs with ER signaling source (70% vs. 50%, P=0.036); in contrast, KRAS hotspot mutations were more common in cases without an identifiable ER source (42% vs. 24%, p=0.067). Additionally, the presence of PTEN mutations was associated with a higher BMI (median 31.1 vs 28.3, p=0.012), whereas FBXW7 mutations were associated with a lower BMI (median 24 vs 30.6, p=0.047). Log-rank survival analysis showed that patients whose ECs lacked an identifiable ER signaling source had a markedly worse survival outcome (p=0.0024). Discussion: We demonstrate that the majority of NSMP-ECs have an identifiable ER signaling source. The minority of NSMP-ECs lacking an ER signaling source may not only represent a hormonally independent tumorigenesis but are also markedly distinct at the molecular, pathologic, and clinical levels. ER protein immunohistochemistry may help in further defining these groups. Citation Format: Clarissa Lam, Carol Aghajanian, Nadeem Abu-Rustum, Britta Weigelt, Lora Ellenson, Amir Momeni Boroujeni. Refining endometrial carcinoma of no-specific molecular subtype by sources of estrogen signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1407.

The In Vitro and In Vivo Anticancer Effect of Photomed for Photodynamic Therapy: Comparison with Photofrin and Radachlorin.

To overcome the limitation of conventional cancer treatments, photodynamic therapy (PDT) has been introduced as another treatment option. PDT provides a non-invasive, non-surgical way with reduced toxicity. To improve the antitumor efficacy of PDT, we synthesized a novel photosensitizer, a 3-substituted methyl pyropheophorbide-a derivative (Photomed). The purpose of the study was to evaluate the antitumor effect of PDT with Photomed comparing with the clinically approved photosensitizers Photofrin and Radachlorin. The cytotoxicity assay against SCC VII cells (murine squamous cell carcinoma) was performed to determine whether Photomed is safe without PDT and whether Photomed is effective against cancer cells with PDT. An in vivo anticancer efficacy study was also performed using SCC VII tumor-bearing mice. The mice were divided into small-tumor and large-tumor groups to identify whether Photomed-induced PDT is effective for not only small tumors but also large tumors. From in vitro and in vivo studies, Photomed was confirmed to be (1) a safe photosensitizer without laser irradiation, (2) the most effective photosensitizer with PDT against cancers compared to Photofrin and Radachlorin and (3) effective with PDT in treating not only small tumors but also large tumors. In conclusion, Photomed may contribute as a novel, potential photosensitizer for use in PDT cancer treatment.

Clinical differences between small and large pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors, most of which are characterized by the release of catecholamine, and range in diameters from less than 1 cm to 10 cm or more. However, knowledge of the differences in clinical features between small and large PPGLs is insufficient. A retrospective analysis of patients with PPGLs treated at our institution between January 2018 and June 2020 was performed. The clinical characteristics of patients were investigated, and comparisons were made between patients with large and small PPGLs. The logistic regression analysis was used to confirm the risk factors, and the receiver operating characteristic curve was used to evaluate the diagnostic performance of the variables. Totally 263 patients were included, including 110 patients in small tumor group and 153 patients in large tumor group. There were more male patients in the large tumor group (p=0.009). More patients had hypertension (p<0.001) and diabetes (p=0.002) in the large tumor group. The 24-h urinary epinephrine (24hU-E) (p < 0.001) and 24-h urinary norepinephrine (24hU-NE) (p=0.002) concentrations were higher in the large tumor group. In terms of tumor location, adrenal-PPGLs were more frequent in the large tumor group (p<0.001). Multivariate logistic regression analysis showed that male sex [odds ratio (OR): 2.871, 95% confidence interval (CI): 1.444-5.711, p=0.003], 24hU-E concentrations (OR: 1.025, 95% CI:1.004-1.047, p=0.020), 24hU-NE concentrations (OR: 1.002, 95%CI: 1.001-1.004, p=0.045), and adrenal-PPGLs (OR: 2.510, 95% CI:1.256-5.018, p=0.009) were positive risk factors for large tumors. Taking above variables into the same model, the area under the receiver operating characteristic curve of the model for predicting the large tumor was 0.772 (95% CI: 0.706-0.834). After the short-term follow-up, there was no significant difference in tumor recurrence between the two groups (p=0.681). Significant differences in numerous clinical characteristics exist between large and small PPGLs. The male patients were more likely to be with large tumors, and such tumors were more likely to reside on the adrenal glands. Catecholamine measurements also help predict tumor size of PPGLs. Clinical decision-making will benefit from this information.

World health organization classification of bone tumors (fifth edition): What a radiologist needs to know?

Since 1967, the World Health Organization (WHO) classification of tumors is regarded as a reference standard and practical guide and provides a precious resource not only for the histopathologists and oncosurgeons but also for the radiologists involved in cancer care. Primary bone tumors are a rare and heterogeneous group of neoplasms that have a broad spectrum of morphological, biological, genetic, and radiological features. Appropriate imaging workup and accurate histopathological diagnosis are crucial for appropriate management and prognostication. The fourth edition of the WHO classification of tumors of soft tissue and bone was introduced in 2013. In the past 7 years, there have been considerable advances in the understanding of this large and diverse group of tumors. With technological advances and the introduction of new molecular and genetic data about some bone tumors, there has been reorganization in the classification and introduction of a few new entities. The new WHO classification of soft tissue and bone tumors introduced in 2020 (fifth edition) has made essential refinements in the classification and has also introduced many new entities. Newly identified genetic alterations and corresponding immunohistochemical markers are included in the new classification, and this has helped in the reclassification of the existing tumor entities. These novel genetic alterations not only help in prognostication but are a target for potential therapeutic options which can bring a paradigm shift in the chemotherapeutic regimen for these entities in the future. The sole basis for the classification of bone tumors is histopathological. Although radiologists are not expected to know about the exquisite pathological details of bone tumors, a broad knowledge of the recent updates, including the reclassification of a few entities or the introduction of some, is vital for narrowing the differentials in imaging. A multidisciplinary approach including an orthopedic oncologist, radiologist, pathologist, surgical, and medical oncologist is required for accurate diagnosis and management of primary bone tumors. We hereby present a simplified review for the radiologists comprising the relevant details of the updates in bone tumors along with a simplified diagnostic algorithm to characterize these lesions.

The Choice of 2D-Brachytherapy or 3D-Brachytherapy for Cervical Cancer Patients after External Beam Radiation Based on Residual Gross Tumor Volume

<h3>Purpose/Objective(s)</h3> The purpose of this study was to analyze the choice of 2-dimensional brachytherapy (2D-BT) or 3-dimensional brachytherapy (3D-BT) for cervical cancer patients after external beam radiotherapy (EBRT), based on residual gross tumor volume (GTV res). <h3>Materials/Methods</h3> Between September 2019 and April 2020, 106 local advanced cervical cancer patients (FIGO stage IB3-IVA) who received primary radiation or chemoradiation followed by BT were analyzed retrospectively. We divided patients into large tumor group (GTV res > 30 mm³ or the width ≥ 4 cm) and small tumor group (GTV res ≤ 30 mm³). Point A and high-risk clinical target volume (CTV_HR) planning were designed for each patient; all patients received 4–5 fractions of intra-cavity BT with a single dose of 6 Gy. The CTV_HR, the bladder, and rectum were delineated, respectively, the D2cc (minimum dosage to the most irradiated 2 cc of an organ at risk) of bladder and rectum, D90 (dose to 90% of a target) of the target, vaginal dose point, and vaginal reference length (VRL) were compared. <h3>Results</h3> The patients who received BT fewer than 4 times (n = 2), had double primary tumors (n = 1), or had incomplete data (n = 3) were excluded. Thus, 106 patients were eligible and analyzed in this study. Of the 106 patients, 45 (42.5%) had an initial tumor size of > 4 cm before EBRT. After EBRT, 92 (86.8%) patients had small GTV res, the median of GTV res and CTV_HR were 2 cm³ and 17.85 cm³. The CTV_HR does not change with GTV res (r² = 0.16, <i>P</i> < 0.001), no matter the size of GTV res, both the point A dose and CTV_HR can satisfactorily reach the prescribed tumor coverage dose. However, when evaluated by volume dose, the CTV-_HR D90 was higher than the Point A dose; with reduced organs at risk (OARs) dose (bladder, rectum-, and vaginal dose point) (<i>P</i> < 0.05). The remainder of the patients had large GTV res, with a median of 64cm³, which is not covered by the Point A dose. While evaluated by volume dose, the median of CTV_HR was 71.6 cm³; as GTV res increased, the CTV_HR increased significantly (r² = 0.68, <i>P</i> < 0.001). The CTV_HR D90 to Point A dose ratio was negatively correlated with GTV res (r = -0.61, <i>P</i> < 0.001), and the Point A dose typically varied between 47% and 230% of the CTV_HR D90. In the OARs dose evaluation, only the vaginal dose points were lower in the CTV_HR plan. The 1-year and 2-year local controls for small and large tumor groups were 94.3% versus 78.6% and 91.9% versus 70.7%, respectively. <h3>Conclusion</h3> After EBRT, 86.8% of locally advanced cervical cancer (LACC) patients had small residual tumors, and 2D-BT can achieve adequate prescription dose coverage and meet treatment needs. Only 13.2% of patients had large residual tumors, and these patients should receive 3D-BT or treatment combined with interstitial needles to deliver a higher dose to the CTV_HR. To protect the OARs and reduce radiation damage in small resident tumor patients, 3D-BT would be the best choice.

Comparison of an Auto-Segmentation Model Using a Dual-Path Convolutional Neural Network to Intra- and Inter-Operator High-Risk Clinical Target Volumes for Tandem-and-Ovoid Brachytherapy

<h3>Purpose/Objective(s)</h3> To compare an auto-segmentation model for defining high-risk clinical target volumes (HR-CTVs) for tandem-and-ovoid (T&O) brachytherapy to intra- and inter-operator volumes. <h3>Materials/Methods</h3> Pre-implant T2-weighted MRI and post-implant CT images for 65 (48 for training, 8 for validation, and 9 for testing) patients who underwent T&O brachytherapy for FIGO IB-IIIC cervical cancer were included. The post-implant CT was aligned to the MRI using rigid registration and HR-CTVs were manually contoured or reviewed by a fellowship trained radiation oncologist (FRO) on both the CT and MRI. A dual-path 3D asymmetric convolutional neural network (CNN) architecture was built to extract CT (entire CT volume) and MRI features (masked HR-CTV_MR volume), and was optimized with an asymmetric weighting of 18:6 for CT:MRI. Voxel-based dice similarity coefficients (DSC_V) were used to evaluate the model performance and cross-validation was performed to assess model stability. The study cohort was divided into a small (< 20 cc), medium (20-40 cc), and large (> 40 cc) tumor group based on the HR-CTV_CT for further model evaluation. To determine intra-operator variability, 10 patients were randomly selected from each of the volume groups and contours from the first two fractions of treatment were reviewed. For inter-operator variability, four patients were randomly selected from each of the volume groups and were independently contoured by two additional radiation oncologists (RO1 and RO2). DSC_V were analyzed between the intra-operator contours, inter-operator contours (RO1 vs FRO and RO2 vs FRO), and auto-segmentation contours (auto-segmentation vs FRO). <h3>Results</h3> The dual-path asymmetric auto-segmentation model yielded a favorable contouring result with a mean DSC_V (auto-segmentation vs. FRO) of 0.76 ± 0.06. This result was numerically superior to inter-operator uncertainties for RO1 vs FRO (DSC_inter=0.68 ± 0.11) and RO2 vs FRO (DSC_inter=0.69 ± 0.07), as well as the mean intra-operator agreement of FRO (DSC_intra=0.74 ± 0.07). However, the differences were statistically insignificant with p values of 0.14, 0.08, 0.72, respectively. DSC_V of volumetric subgroups of small, medium, and large tumors are shown in Table 1<b>.</b> <h3>Conclusion</h3> An asymmetric dual-path CNN model utilizing pre-implant MRI (masked by HR-CTV_MR) and post-implant CT images was successfully developed for auto-segmentation of HR-CTV_CT for tandem-and-ovoid brachytherapy patients with a similar DSC_V compared to intra-operator and inter-operator contours.

Benign and malignant cardiac masses: long-term outcomes after surgical resection

Background Cardiac tumors represent a rare and heterogenous pathologic entity, with a cumulative incidence of up to 0.02%. This study aimed to investigate one of the largest patient cohorts published for clinical presentation and long-term outcomes after surgical resection. Research design Between 2009 and 2021, 183 consecutive patients underwent surgery for tumor excision in our center. Preoperative baseline characteristics, intraoperative data, and long-term survival were analyzed. The diagnosis was confirmed postoperatively by histology and Immunohistochemical investigations. Kaplan-Meier curves assessed survival, and the Cox, proportional hazards model, was used to identify prognostic factors for overall survival. Results This series included 183 consecutive patients; most (n=169, 92.3%) were diagnosed with benign cardiac masses. The mean age of patients was 60 ± 16 years, and 48% (n=88) were females. The largest group of tumors is represented by myxoma (n = 98; 54%). The most common malignant tumor was sarcomas (n = 5; 2.7%). The mean hospital stay was 11 ± 6.5 days, and all-cause mortality after ten years was 14%. Conclusion Surgery represents the gold standard in treating primary cardiac tumors; in benign tumors, it is highly effective and curative, whereas, in malignant tumors, it remains associated with more prolonged survival.

Aldosterone-Producing Adenomas of Increased Size Are Associated With Higher Steroidogenic Activity.

There are inconsistent results and insufficient evidence as to whether an association exists between the size and aldosterone-producing ability of aldosterone-producing adenomas. We further investigated this possible association retrospectively. A total of 142 cases of primary aldosteronism diagnosed as unilateral by adrenal venous sampling at 2 referral centers between 2009 and 2019 were included. We classified these individuals into small and large tumor groups using a diameter of 14 mm as a cutoff. This size was the median diameter of the tumor on the affected side of the adrenal gland. We compared plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC to PRA ratio, PAC from a saline infusion test (SIT), urinary aldosterone secretion (uAld), and serum potassium as indices of aldosterone-producing ability between the 2 groups. In some cases, we conducted histopathological evaluations and detection of the KCNJ5 mutation. PAC, PAC to PRA ratio, PAC from SIT, and uAld were higher and serum potassium was lower in the large tumor group. PAC, PAC from SIT, uAld, and serum potassium significantly correlated with tumor diameter. PRA was not associated with tumor diameter. Clear cell-dominant cases were more common in the large tumor group, while cases showing a strong expression of CYP11B2 were not significantly different between the groups. KCNJ5 mutations tended to be more common in the large tumor group. The higher aldosterone-producing ability in larger adenomas can be used to infer the responsible lesion and disease type.

Laparoscopic parenchyma-sparing liver resection for large (≥ 50 mm) colorectal metastases

BackgroundTraditionally, patients with large liver tumors (≥ 50 mm) have been considered for anatomic major hepatectomy. Laparoscopic resection of large liver lesions is technically challenging and often performed by surgeons with extensive experience. The current study aimed to evaluate the surgical and oncologic safety of laparoscopic parenchyma-sparing liver resection in patients with large colorectal metastases.MethodsPatients who primarily underwent laparoscopic parenchyma-sparing liver resection (less than 3 consecutive liver segments) for colorectal liver metastases between 1999 and 2019 at Oslo University Hospital were analyzed. In some recent cases, a computer-assisted surgical planning system was used to better visualize and understand the patients’ liver anatomy, as well as a tool to further improve the resection strategy. The surgical and oncologic outcomes of patients with large (≥ 50 mm) and small (< 50 mm) tumors were compared. Multivariable Cox-regression analysis was performed to identify risk factors for survival.ResultsIn total 587 patients met the inclusion criteria (large tumor group, n = 59; and small tumor group, n = 528). Median tumor size was 60 mm (range, 50–110) in the large tumor group and 21 mm (3–48) in the small tumor group (p < 0.001). Patient age and CEA level were higher in the large tumor group (8.4 μg/L vs. 4.6 μg/L, p < 0.001). Operation time and conversion rate were similar, while median blood loss was higher in the large tumor group (500 ml vs. 200 ml, p < 0.001). Patients in the large tumor group had shorter 5 year overall survival (34% vs 49%, p = 0.027). However, in the multivariable Cox-regression analysis tumor size did not impact survival, unlike parameters such as age, ASA score, CEA level, extrahepatic disease at liver surgery, and positive lymph nodes in the primary tumor.ConclusionLaparoscopic parenchyma-sparing resections for large colorectal liver metastases provide satisfactory short and long-term outcomes.Graphical abstract

The Lund Molecular Taxonomy Applied to Non–Muscle-Invasive Urothelial Carcinoma

The precise classification of tumors into relevant molecular subtypes will facilitate both future research and optimal treatment. Here, the Lund Taxonomy system for molecular classification of urothelial carcinoma was applied to two large and independent cohorts of non-muscle-invasive tumors. Of 752 tumors classified, close to 100% were of the luminal subtypes, 95% urothelial-like (Uro; UroA, UroB, or UroC) and 5% genomically unstable. The obtained subtype structure organized the tumors into groups with specific and coherent gene mutation, genomic, and clinical profiles. The intrasubtype variability in the largest group of tumors, UroA, was caused by infiltration and proliferation, not considered as cancer cell type-defining properties. Within the UroA subtype, a HOXB/late cell-cycle gene expression polarity was found, strongly associated with FGFR3, STAG2, and TP53 mutations, as well as with chromosome 9 losses. Kaplan-Meier analyses identified the genomically unstable subtype as a progression high-risk group, also valid in the subgroup of T1 tumors. Almost all progression events occurred within 12 months in this subtype. Also, a general progression gene signature was derived that identifies high- and low-risk tumors. All findings were demonstrated in two independent cohorts. The Lund Taxonomy system is applicable to both non-muscle- and muscle-invasive tumors and may be a useful biological framework for translational studies.

Complex Elucidation of Cells-of-Origin in Pediatric Soft Tissue Sarcoma: From Concepts to Real Life, Hide-and-Seek through Epigenetic and Transcriptional Reprogramming.

Soft tissue sarcoma (STS) comprise a large group of mesenchymal malignant tumors with heterogeneous cellular morphology, proliferative index, genetic lesions and, more importantly, clinical features. Full elucidation of this wide diversity remains a central question to improve their therapeutic management and the identity of cell(s)-of-origin from which these tumors arise is part of this enigma. Cellular reprogramming allows transitions of a mature cell between phenotypes, or identities, and represents one key driver of tumoral heterogeneity. Here, we discuss how cellular reprogramming mediated by driver genes in STS can profoundly reshape the molecular and morphological features of a transformed cell and lead to erroneous interpretation of its cell-of-origin. This review questions the fact that the epigenetic context in which a genetic alteration arises has to be taken into account as a key determinant of STS tumor initiation and progression. Retracing the cancer-initiating cell and its clonal evolution, notably via epigenetic approach, appears as a key lever for understanding the origin of these tumors and improving their clinical management.

Transcription Factors with Targeting Potential in Gliomas.

Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-1/2/3, E2F1–8, STAT3, and HIF-1/2) and tumor suppressor (NFI-A/B, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy.

Automatic segmentation of high-risk clinical target volume for tandem-and-ovoids brachytherapy patients using an asymmetric dual-path convolutional neural network.

Preimplant diagnostic magnetic resonance imaging is the gold standard for image-guided tandem-and-ovoids (T&O) brachytherapy for cervical cancer. However, high dose rate brachytherapy planning is typically done on postimplant CT-based high-risk clinical target volume (HR-CTVCT ) because the transfer of preimplant Magnetic resonance (MR)-based HR-CTV (HR-CTVMR ) to the postimplant planning CT is difficult due to anatomical changes caused by applicator insertion, vaginal packing, and the filling status of the bladder and rectum. This study aims to train a dual-path convolutional neural network (CNN) for automatic segmentation of HR-CTVCT on postimplant planning CT with guidance from preimplant diagnostic MR. Preimplant T2-weighted MR and postimplant CT images for 65 (48 for training, eight for validation, and nine for testing) patients were retrospectively solicited from our institutional database. MR was aligned to the corresponding CT using rigid registration. HR-CTVCT and HR-CTVMR were manually contoured on CT and MR by an experienced radiation oncologist. All images were then resampled to a spatial resolution of 0.5× 0.5 × 1.25mm. A dual-path 3D asymmetric CNN architecture with two encoding paths was built to extract CT and MR image features. The MR was masked by HR-CTVMR contour while the entire CT volume was included. The network put an asymmetric weighting of 18:6 for CT: MR. Voxel-based dice similarity coefficient (DSCV ), sensitivity, precision, and 95% Hausdorff distance (95-HD) were used to evaluate model performance. Cross-validation was performed to assess model stability. The study cohort was divided into a small tumor group(<20 cc), medium tumor group (20-40cc), and large tumor group(>40cc) based on the HR-CTVCT for model evaluation. Single-path CNN models were trained with the same parameters as those in dual-path models. For this patient cohort, the dual-path CNN model improved each of our objective findings, including DSCV , sensitivity, and precision, with an average improvement of 8%, 7%, and 12%, respectively. The 95-HD was improved by an average of 1.65mm compared to the single-path model with only CT images as input. In addition, the area under the curve for different networks was 0.86 (dual-path with CT and MR) and 0.80 (single-path with CT), respectively. The dual-path CNN model with asymmetric weighting achieved the best performance with DSCV of 0.65 ± 0.03 (0.61-0.70), 0.79 ± 0.02 (0.74-0.85), and 0.75 ± 0.04 (0.68-0.79) for small, medium, and large group. 95-HD were 7.34 (5.35-10.45) mm, 5.48 (3.21-8.43) mm, and 6.21 (5.34-9.32) mm for the three size groups, respectively. An asymmetric CNN model with two encoding paths from preimplant MR (masked by HR-CTVMR ) and postimplant CT images was successfully developed for automatic segmentation of HR-CTVCT for T&O brachytherapy patients.

The Effect of Lymph Node Dissection According to the Tumor Size in Surgery for Intrahepatic Cholangiocarcinoma

Introduction: Although surgical resection is considered as the treatment of choice for intrahepatic cholangiocarcinoma (IHCC), the role of lymph node dissection during hepatectomy is still under debate. The aim of this study was to evaluate the effect of lymph node dissection (LND) according to the size of the tumor. Method: The medical records of patients who underwent hepatectomy for IHCC between Aug 2004 to Dec 2020 were retrospectively reviewed. Excluding patients who underwent R1/R2 resection, 119 patients were enrolled in this study. Based on the maximal tumor size, patients were divided into two groups: small tumor group < 5cm (Group S, n=83) and large tumor group ≥ 5cm (Group L, n=36). The association of LND and survival rates was investigated in each group. Results: Eighty patients (67.2%) were male, and the others were female. Laparoscopic hepatectomy was done in 38 patients (31.9%). Although LND did not improve patient and disease-free survivals in Group L (p=0.356 and 0.217, respectively), it tended to improve disease-free survivals in Group S, which was statistically insignificant (5-year disease-free survival rates: 41.0% with LND, 27.8% without LND, p=0.091). Moreover, its effect was more definite in laparoscopic subgroup of Group S (5-year disease-free survival rates: 61.2% with LND, 20.3% without LND, p=0.049). However, the difference of patient survival rate did not achieve statistical significancy even in laparoscopic subgroup (p=0.199). Conclusions: LND might not be helpful on surgery for large IHCC. However, it should be positively considered in surgery for small IHCC < 5cm to decrease tumor recurrence.