Residual Tumor Mass Research Articles

Ultra-Low Anti-Müllerian Hormone Levels in Recurrent Cystic Ovarian Neoplasm: A Case Report

Fertility has been a major issue in the management of cystic ovarian neoplasm. This case report presents an extreme case of ultra-low AMH levels in a young female with recurrent cystic ovarian neoplasm and analyzes the potential causes. A twenty-two-year-old female presented with stomach discomfort. The patient had undergone two surgeries for ovarian neoplasm within the last six years. The patient had another abdominal lump suspected to be a residual tumor mass. After further examination, the patient was diagnosed with cystic ovarian neoplasm. The laboratory findings showed low T4 levels, increased TSH levels, and ultra-low AMH levels (0.023 ng/mL). Management of cystic ovarian neoplasm should concern the effect on fertility. The AMH level can be used for pre-treatment counseling in these patients.

Neoadjuvant chemo- or chemo-radiation-therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, often diagnosed at stages that dis-qualify for surgical resection. Neoadjuvant therapies offer potential tumor regression and improved resectability. Although features of the tumor biology (e.g., molecular markers) may guide adjuvant therapy, biological alterations after neoadjuvant therapy remain largely unexplored. We performed mass spectrometry to characterize the proteomes of 67 PDAC resection specimens of patients who received either neoadjuvant chemo (NCT) or chemo-radiation (NCRT) therapy. We employed data-independent acquisition (DIA), yielding a proteome coverage in excess of 3500 proteins. Moreover, we successfully integrated two publicly available proteome datasets of treatment-naïve PDAC to unravel proteome alterations in response to neoadjuvant therapy, highlighting the feasibility of this approach. We found highly distinguishable proteome profiles. Treatment-naïve PDAC was characterized by enrichment of immunoglobulins, complement and extracellular matrix (ECM) proteins. Post-NCT and post-NCRT PDAC presented high abundance of ribosomal and metabolic proteins as compared to treatment-naïve PDAC. Further analyses on patient survival and protein expression identified treatment-specific prognostic candidates. We present the first proteomic characterization of the residual PDAC mass after NCT and NCRT, and potential protein candidate markers associated with overall survival. We conclude that residual PDAC exhibits fundamentally different proteome profiles as compared to treatment-naïve PDAC, influenced by the type of neoadjuvant treatment. These findings may impact adjuvant or targeted therapy options.

In Situ Immunofluorescence Imaging of Vital Human Pancreatic Tissue Using Fiber-Optic Microscopy.

Surgical resection is the only curative option for pancreatic carcinoma, but disease-free and overall survival times after surgery are limited due to early tumor recurrence, most often originating from local microscopic tumor residues (R1 resection). The intraoperative identification of microscopic tumor residues within the resection margin in situ could improve surgical performance. The aim of this study was to evaluate the effectiveness of fiber-optic microscopy for detecting microscopic residues in vital pancreatic cancer tissues. Experimental Design. Fresh whole-mount human pancreatic tissues, histological tissue slides, cell culture, and chorioallantoic membrane xenografts were analyzed. Specimens were stained with selected fluorophore-conjugated antibodies and studied using conventional wide-field and self-designed multicolor fiber-optic fluorescence microscopy instruments. Whole-mount vital human tissues and xenografts were stained and imaged using an in situ immunofluorescence protocol. Fiber-optic microscopy enabled the detection of epitope-based fluorescence in vital whole-mount tissue using fluorophore-conjugated antibodies and enabled visualization of microvascular, epithelial, and malignant tumor cells. Among the selected antigen-antibody pairs, antibody clones WM59, AY13, and 9C4 were the most promising for fiber-optic imaging in human tissue samples and for endothelial, tumor and epithelial cell detection. Fresh dissected whole-mount tissue can be stained using direct exposure to selected antibody clones. Several antibody clones were identified that provided excellent immunofluorescence imaging of labeled structures, such as endothelial, epithelial, or EGFR-expressing cells. The combination of in situ immunofluorescence staining and fiber-optic microscopy visualizes structures in vital tissues and could be proposed as an useful tool for the in situ identification of residual tumor mass in patients with a high operative risk for incomplete resection.

Hydrogel design to overcome thermal resistance and ROS detoxification in photothermal and photodynamic therapy of cancer

Responsive heat resistance (by heat shock protein upregulation) and spontaneous reactive oxygen species (ROS) detoxification have been regarded as the major obstacles for photothermal/photodynamic therapy of cancer. To overcome the thermal resistance and improve ROS susceptibility in breast cancer therapy, Au ion-crosslinked hydrogels including indocyanine green (ICG) and polyphenol are devised. Au ion has been introduced for gel crosslinking (by catechol-Au3+ coordination), cellular glutathione depletion, and O2 production from cellular H2O2. ICG can generate singlet oxygen from O2 (for photodynamic therapy) and induce hyperthermia (for photothermal therapy) under the near-infrared laser exposure. (−)-Epigallocatechin gallate downregulates heat shock protein to overcome heat resistance during hyperthermia and exerts multiple anticancer functions in spite of its ironical antioxidant features. Those molecules are concinnously engaged in the hydrogel structure to offer fast gel transformation, syringe injection, self-restoration, and rheological tuning for augmented photo/chemotherapy of cancer. Intratumoral injection of multifunctional hydrogel efficiently suppressed the growth of primary breast cancer and completely eliminated the residual tumor mass. Proposed hydrogel system can be applied to tumor size reduction prior to surgery of breast cancer and the complete remission after its surgery.

Optimisation of Organ Preservation treatment strategies in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy: Additional contact X-ray brachytherapy versus eXtending the observation period and local excision (OPAXX) — protocol for two multicentre, parallel, single-arm, phase II studies

IntroductionStandard treatment for patients with intermediate or locally advanced rectal cancer is (chemo)radiotherapy followed by total mesorectal excision (TME) surgery. In recent years, organ preservation aiming at improving quality of...

Pituitary apoplexy associated with gram-negative meningitis following transsphenoidal surgery

BackgroundPituitary apoplexy (PA) is a rare but potentially life-threatening condition. While it is uncommon, it can present with findings that are clinically indistinguishable from acute bacterial meningitis. We report an unusual case of simultaneous coexistence of bacterial meningoencephalitis and pituitary apoplexy following transsphenoidal surgery (TSS) for pituitary macroadenoma, emphasizing the possibility of coexistence of the two entities.Case presentationA 62-year-old man was admitted with a moderate headache, gait disturbance, and progressively decreasing vision. Sellar magnetic resonance imaging showed a giant pituitary tumor of 4 × 5 cm with invasion of the cavernous sinus bilaterally, and a mass effect on the optic chiasm. The patient underwent a TSS and partial resection of a giant pituitary tumor. On postoperative day 11, he presented with an acute, severe headache and altered sensorium. An urgent computed tomography (CT) scan revealed hemorrhagic swelling of the residual. A complete analysis of the anterior pituitary hormones revealed panhypopituitarism. Administering steroid ameliorated the clinical features, but after decreasing the dose, the patient continued to deteriorate in his neurological status, a high fever, and marked stiffness were noted on postoperative day 14. Given the neck stiffness, leukocytosis, and high C-reactive protein level, acute meningitis was suspected, and the cerebrospinal fluid (CSF) was tested, which was consistent with acute bacterial meningitis. In the results of the bacterial cultures of the CSF, E. coli was identified and switched to ceftriaxone. The patient's neurological status and body temperature improved gradually. CSF test results returned to normal levels, and ceftriaxone was discontinued on day 10.ConclusionsThis is a report on a case of a giant pituitary tumor that developed late postoperative PA after having undergone a partial tumor resection. A postoperative CT scan showed hemorrhagic expansion of the residual tumor mass. Further, the patient exhibited typical symptoms of acute meningoencephalitis, the result of the cultures of the CSF was positive, and the patient's general condition deteriorated. In addition, laboratory findings indicated leukocytosis, an elevated C-reactive protein level, and neutrophilic pleocytosis. We highlighted diagnostic challenges and therapeutic delays arising as a result of rare concomitance.

Immunosuppressive M2 TAMs represent a promising target population to enhance phagocytosis of ovarian cancer cells in vitro.

Tumor-associated macrophages (TAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype and function of these cells. The present study aims to characterize macrophages in high-grade serous ovarian cancer (HGSOC). Phenotype and expression of co-regulatory markers were assessed on TAMs derived from malignant ascites (MA) or peripheral blood (PB) by multiparametric flow cytometry. Samples were obtained from HGSOC patients (n=29) and healthy donors (HDs, n=16). Additional expression analysis was performed by RNAseq (n=192). Correlation with clinically relevant parameters was conducted and validated by a second patient cohort (n=517). Finally, the role of TIGIT in repolarization and phagocytosis was investigated in vitro. Expression of the M2-associated receptors CD163, CD204, and CD206, as well as of the co-regulatory receptors TIGIT, CD226, TIM-3, and LAG-3 was significantly more frequent on macrophages in HGSOC than in HDs. CD39 and CD73 were broadly expressed on (mainly M2) macrophages, but without a clear clustering in HGSOC. CD163 mRNA levels were higher in TAMs from patients with residual tumor mass after surgery and associated with a shorter overall survival. In addition, TIGIT expression was associated with a higher tumor grading, indicating a prognostic relevance of M2 infiltration in HGSOC. TIGIT blockade significantly reduced the frequency of M2 macrophages. Moreover, combined blockade of TIGIT and CD47 significantly increased phagocytosis of ovarian cancer cells by TAMs in comparison to a single blockade of CD47. Combined blockade of TIGIT and CD47 represents a promising approach to enhance anti-CD47-facilitated phagocytosis.

Origin of Residual Tumor Masses in BRCA1/2-Driven Ovarian Carcinomas Treated by Neoadjuvant Chemotherapy: Selection of Preexisting BRCA1/2-Proficient Tumor Cells but Not the Gain of Second ORF-Restoring Mutation

Introduction: Tubo-ovarian carcinomas (OCs) are highly sensitive to platinum-based neoadjuvant chemotherapy (NACT) but almost never demonstrate complete pathologic response. Methods: We analyzed paired primary and residual tumor tissues from 30 patients with hereditary BRCA1/2-driven OCs (BRCA1: 17; BRCA2: 13), who were treated by carboplatin/paclitaxel NACT (median number of cycles: 3, range: 3–6). BRCA1/2 and TP53 genes were analyzed by the next-generation sequencing. The ratio between TP53 mutation-specific versus wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample, and the ratio between BRCA1/2-mutated and wild-type reads was used to estimate the presence of cells with the loss or retention of heterozygosity (LOH or ROH, respectively). Results: All 30 OCs had BRCA1/2 LOH in primary tumor and carried somatic TP53 mutation. Twenty-eight OCs had sufficient tumor cell cellularity in the post-NACT tissue to evaluate the ratio between mutated and wild-type BRCA1/2 alleles. Five (18%) out of 28 informative tumor pairs showed transition from LOH to ROH during NACT presumably affecting all or the vast majority of residual tumor cells. There were no signals of the emergence of a second open reading frame-restoring BRCA1/2 mutation. Conclusion: Chemonaive BRCA1/2-driven carcinomas may contain a fraction of tumor cells with preserved BRCA1/2 heterozygosity. NACT can cause a selection of pre-existing BRCA1/2-proficient tumor cells, without gaining secondary reversal BRCA1/2 mutations.

First trial of chemotherapy de-escalation in ovarian cancer (OC): A phase III randomized, open label study of niraparib maintenance after carboplatin and paclitaxel in patients with optimally debulked advanced (homologous recombination deficient) HRD high-grade ovarian cancer in first line therapy (N-PLUS/NOGGO-ov53/ENGOT-ov62).

TPS5620 Background: OC is the fifth most common cause of death from cancer in women. More than 70% of the patients are diagnosed with advanced disease and less than 40% of women with OC are cured. Currently, the standard therapy in HRD OC is surgical debulking followed by 6 cycles of chemotherapy with subsequent maintenance treatment with poly ADP ribose polymerase (PARP) inhibitors. Within the last decades, no focus was set on the benefits of fewer cycles of chemotherapy, even though there is evidence for comparable efficacy and less toxicity in comparison to more cycles. Chemotherapies are usually associated with side effects, which can be severe and even lead to therapy discontinuation. The data available about the needed number of chemotherapy cycles is weak, especially in the context of PARP inhibition. Furthermore, patients with stage III/IV with optimal cytoreduction are underrepresented in previous studies. In the N-PLUS trial, we hypothesize that recurrence-free survival (RFS) in patients receiving 3 cycles of chemotherapy followed by maintenance with niraparib is not inferior to 6 cycles of chemotherapy followed by niraparib in advanced HRD high-grade OC patients with no visible disease following primary tumor debulking. Methods: In this multicenter, randomized, open-label study 650 patients with advanced HRD high-grade OC with no residual tumor mass following primary tumor debulking will be enrolled. Patients will be randomized 1:1 to receive either 3 cycles carboplatin + paclitaxel and maintenance therapy with niraparib (Arm A) or 6 cycles carboplatin + paclitaxel and maintenance therapy with niraparib (Arm B) for a maximum of 36 months. Randomization will be performed according to the results of the NGS analysis and stratified either to BRCAm/LOH-independent or BRCAwt/LOHhigh, FIGO stage III vs. IV, and participating countries. The primary endpoint will be RFS, secondary endpoints will be OS, TFST, TWIST, PFS2, Quality of Life and safety assessments. Clinical trial information: NCT05460000 .

Validation of AGR2 and KRT19 as specific proteins being significantly and differentially expressed in teratoma compared to necrosis in retroperitoneal lymph node resections after chemotherapy (pcRPLND).

412 Background: Metastatic non-seminomatous testicular tumor patients with residual retroperitoneal tumor masses > 1cm after chemotherapy are treated with pcRPLND. The goal of pcRPLND is to remove viable tumors (V) and teratoma (T), which are present in approximately 10% and 40% of cases, respectively. However, histopathologically, only scar/necrosis (N) is identified in the remaining 50% of patients. In those patients, surgical therapy is not necessary, resulting in a relevant overtreatment. So far, no adequate distinction between the histologies exists preoperatively. Recently, the first biomarker was described with miR371a-3p in serum, which is highly specific for V, but not for T. In 2022 we reported AGR2 and KRT19 to be significantly and differentially expressed in teratoma compared to necrosis in pcRPLND tissue on protein and mRNA level. The aim of this study was to validate these proteins on an independent cohort. Methods: All consecutive pcRPLND patients from 2021 who were treated in the University Hospital of Cologne, Germany, were selected (n=66). All patients had residual masses > 1 cm and normalized or plateaued tumor markers. For immunohistochemistry, the monoclonal antibodies KRT19 and AGR2 were applied to representative Formalin-Fixed Paraffin-Embedded tissue. To quantify the results, the H-score was used. The investigators were blinded to the final pathohistological results. Results: The cohort was composed of 66 patients, 23 patients with T, 24 patients with V and 19 patients with N. Significantly higher H-scores were shown for AGR2 and KRT19 when comparing T vs. N and T vs. V (both p < 0.0001). The discriminatory ability of the two proteins AGR2 and KRT19 was calculated by AUCs for T vs. N and was 1.0 in each case with a corresponding sensitivity and specificity for T of 100%. Conclusions: With AGR2 and KRT19, we could validate the two proteins that are significantly and differentially expressed in the pcRPLND specimen in the clinically relevant groups T vs. N. In perspective, these proteins could be targeted by radiolabeled ligands as a tracer in order to reliably distinguish patients with teratoma from those with necrosis by means of functional imaging. Thus, overtreatment with pcRPLND of patients with N could be safely reduced.

Intratumoral heterogeneity affects tumor regression and Ki67 proliferation index in perioperatively treated gastric carcinoma

BackgroundIntratumoral heterogeneity (ITH) is a major problem in gastric cancer (GC). We tested Ki67 and tumor regression for ITH after neoadjuvant/perioperative chemotherapy.Methods429 paraffin blocks were obtained from 106 neoadjuvantly/perioperatively treated GCs (one to five blocks per case). Serial sections were stained with Masson’s trichrome, antibodies directed against cytokeratin and Ki67, and finally digitalized. Tumor regression and three different Ki67 proliferation indices (PI), i.e., maximum PI (KiH), minimum PI (KiL), and the difference between KiH/KiL (KiD) were obtained per block. Statistics were performed in a block-wise (all blocks irrespective of their case-origin) and case-wise manner.ResultsKi67 and tumor regression showed extensive ITH in our series (maximum ITH within a case: 31% to 85% for KiH; 4.5% to 95.6% for tumor regression). In addition, Ki67 was significantly associated with tumor regression (p < 0.001). Responders (<10% residual tumor, p = 0.016) exhibited prolonged survival. However, there was no significant survival benefit after cut-off values were increased ≥20% residual tumor mass. Ki67 remained without prognostic value.ConclusionsDigital image analysis in tumor regression evaluation might help overcome inter- and intraobserver variability and validate classification systems. Ki67 may serve as a sensitivity predictor for chemotherapy and an indicator of ITH.

A Pair of Prognostic Biomarkers in Triple-Negative Breast Cancer: KLK10 and KLK11 mRNA Expression

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor patient prognosis and limited therapeutic options. A lack of prognostic biomarkers and therapeutic targets fuels the need for new approaches to tackle this severe disease. Extracellular matrix degradation, release, and modulation of the activity of growth factors/cytokines/chemokines, and the initiation of signaling pathways by extracellular proteolytic networks, have been identified as major processes in the carcinogenesis of breast cancer. Members of the kallikrein-related peptidase (KLK) family contribute to these tumor-relevant processes, and are associated with breast cancer progression and metastasis. In this study, the clinical relevance of mRNA expression of two members of this family, KLK10 and KLK11, has been evaluated in TNBC. For this, their expression levels were quantified in tumor tissue of a large, well-characterized patient cohort (n = 123) via qPCR. Although, in general, the overall expression of both factors are lower in tumor tissue of breast cancer patients (encompassing all subtypes) compared to normal tissue of healthy donors, in the TNBC subtype, expression is even increased. In our cohort, a significant, positive correlation between the expression levels of both KLKs was detected, indicating a coordinate expression mode of these proteases. Elevated KLK10 and KLK11 mRNA levels were associated with poor patient prognosis. Moreover, both factors were found to be independent of other established clinical factors such as age, lymph node status, or residual tumor mass, as determined by multivariable Cox regression analysis. Thus, both proteases, KLK10 and KLK11, may represent unfavorable prognostic factors for TNBC patients and, furthermore, appear as promising potential targets for therapy in TNBC.

Analysis of the Equilibrium Phase in Immune-Controlled Tumors Provides Hints for Designing Better Strategies for Cancer Treatment.

When it comes to improving cancer therapies, one challenge is to identify key biological parameters that prevent immune escape and maintain an equilibrium state characterized by a stable subclinical tumor mass, controlled by the immune cells. Based on a space and size structured partial differential equation model, we developed numerical methods that allow us to predict the shape of the equilibrium at low cost, without running simulations of the initial-boundary value problem. In turn, the computation of the equilibrium state allowed us to apply global sensitivity analysis methods that assess which and how parameters influence the residual tumor mass. This analysis reveals that the elimination rate of tumor cells by immune cells far exceeds the influence of the other parameters on the equilibrium size of the tumor. Moreover, combining parameters that sustain and strengthen the antitumor immune response also proves more efficient at maintaining the tumor in a long-lasting equilibrium state. Applied to the biological parameters that define each type of cancer, such numerical investigations can provide hints for the design and optimization of cancer treatments.

Predictive biomarker for surgical outcome in patients with advanced primary high-grade serous ovarian cancer. Are we there yet? An analysis of the prospective biobank for ovarian cancer

BackgroundHigh-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is associated with high mortality rates. Surgical outcome is one of the most important prognostic factors. There are no valid biomarkers to identify which patients may benefit from a primary debulking approach. ObjectiveOur study aimed to discover and validate a predictive panel for surgical outcome of residual tumor mass after first-line debulking surgery. Study designFirstly, “In silico” analysis of publicly available datasets identified 200 genes as predictors for surgical outcome. The top selected genes were then validated using the novel Nanostring method, which was applied for the first time for this particular research objective. 225 primary ovarian cancer patients with well annotated clinical data and a complete debulking rate of 60% were compiled for a clinical cohort. The 14 best rated genes were then validated through the cohort, using immunohistochemistry testing.Lastly, we used our biomarker expression data to predict the presence of miliary carcinomatosis patterns. ResultsThe Nanostring analysis identified 37 genes differentially expressed between optimal and suboptimal debulked patients (p < 0.05). The immunohistochemistry validated the top 14 genes, reaching an AUC Ø0.650. The analysis for the prediction of miliary carcinomatosis patterns reached an AUC of Ø0.797. ConclusionThe tissue-based biomarkers in our analysis could not reliably predict post-operative residual tumor. Patient and non-patient-associated co-factors, surgical skills, and center experience remain the main determining factors when considering the surgical outcome at primary debulking in high-grade serous ovarian cancer patients.

Structure of residual metastases in patients with advanced testicular non-seminomatous germ cell tumors and incomplete serological and radiological response to chemotherapy

Objective: to analyze histological structure and identify predictors of detecting malignant non-seminoma in residual tumor masses obtained from patients with testicular non-seminomatous germ cell tumors (TNSGCTs) who had not achieved complete serological and radiological response to chemotherapy (CT).Materials and methods. This study included 96 out of 703 patients with TNSGCTs (13.7 %) operated on in N.N. Blokhin National Medical Research Center of Oncology. The inclusion criteria were as follows: verified advanced TNSGCT, elevated levels of alpha-fetoprotein and/or chorionic gonadotropin at the moment of CT initiation, at least 3 completed courses of first-line or second-line platinum-based CT, residual tumor foci after CT visualized with radiological methods, alpha-fetoprotein &gt;7.29 IU/mL or chorionic gonadotropin &gt;5 mIU/mL 3 weeks after the initiation of the last CT course, and surgery after CT. Histological examination of the primary tumors demonstrated that they contained elements of seminoma (n = 14; 14.6 %), teratoma (n = 29; 30.2 %), choriocarcinoma in (n = 23; 23.9 %), embryonal carcinoma (n = 45; 46.9 %), and yolk sac (n = 18; 18.8 %). All study participants received first-line CT; 58 of them (60.4 %) also received second-line CT. All patients underwent surgery after CT, including retroperitoneal lymph node dissection (RPLND) (n = 96; 100 %) and excision of extra-retroperitoneal lesions (n = 8; 8.3 %).Results. Histological examination of excised retroperitoneal masses showed that they contained areas of necrosis and fibrosis (n = 25; 26.0 %), teratoma (n = 29; 30.2 %), and viable malignant non-seminoma (n = 42; 43.8 %). There was a strong positive correlation between the existence of residual malignant non-seminomatous components in retroperitoneal masses and presence of choriocarcinoma (r = 0.300; р = 0.004), as well as the absence of embryonal carcinoma in the primary tumor (r = –0.300; р = 0.004), invasion of retroperitoneal metastases into major vessels and/or adjacent organs (r = 0.243; р = 0.017), and second-line CT prior to RPLND (r = 0.413; р &lt;0.0001). Patients having ≥3 risk factors were significantly more likely to have residual malignant non-seminoma in retroperitoneal masses than patients who had 0–2 risk factors (73.5 % vs 27.3 %; р &lt;0.0001). Excised residual extra-retroperitoneal masses contained areas of necrosis and fibrosis (n = 3; 37.5 %), teratoma (n = 1; 12.5 %), and malignant non-seminoma (n = 4; 62.5 %). Concordant structure of retroperitoneal and extra-retroperitoneal lesions was observed in 4 patients (50.0 %).Conclusion. Malignant non-seminomas were detected in 43.8 % of retroperitoneal and 62.5 % of extra-retroperitoneal residual tumorsremoved after CT in patients with advanced TNSGCTs and incomplete serological and radiological response. Discordant structure of metastases at different locations was observed in 50 % of patients. Our finding can be used to select candidates for surgical excision of residual tumors among these patients.

Successful surgical resection plus surgical cryoablation for the treatment of a large left ventricular fibroma

Residual tumor mass after large cardiac fibroma resection carries long-term risk, but cryoablation is useful during surgery to remove such tissue. Here, we present a case of a large cardiac fibroma of the posterior wall of the left ventricle, discovered during long-term, episodic ventricular tachycardia. Resection with cryoablation completely removed the tumor, eliminating postoperative, distant ventricular arrhythmias.

Differentially expressed mRNA/proteins can distinguish viable germ cell tumors and teratomas from necrosis in retroperitoneal lymph node resections after chemotherapy (pcRPLND).

408 Background: Metastatic non-seminomatous testicular tumor patients with residual retroperitoneal tumor masses &gt; 1cm after chemotherapy are treated with pcRPLND. The goal of pcRPLND is to remove viable tumors (V) and teratoma (T), which are present in approximately 10% and 40% of cases, respectively. However, histopathologically, only scar/necrosis (N) is identified in the remaining 50% of patients. In those patients, surgical therapy is not necessary, resulting in a relevant overtreatment. So far, no adequate distinction between the histologies exists preoperatively. Recently, the first biomarker was described with miR371a-3p in serum, which is highly specific for V, but not for T. Therefore, our goal was to identify mRNAs and proteins that are differentially expressed between V/T vs N, in particular between T and N, in pcRPLND resected cells. Methods: Forty-eight patients were identified, n = 16 each with T/V/N. Representative regions of T/V/N were microdissected and subsequently mRNA was extracted. Initially, 770 genes were analyzed using the nCounter PanCancer Progression Panel (Nanostring). For each group comparison, genes with a fold change of &lt; -2/ &gt; 2 and a p-value of &lt; 0.05 were identified. Hereafter, quantitative protein analysis (proteomics) was performed on the same samples. Finally, the proteins of the 5 mRNAs with the most different and significant expression levels between T vs. N were validated by immunohistochemistry and H-score calculation. Results: By Nanostring, we identified 84 significantly differentially expressed mRNAs for the group comparisons of T vs. N, 63 for V vs. N, and 189 for T vs. V. Quantitative protein analysis revealed 25 significantly differentially expressed proteins in T vs. N, 254 in V vs. N, and 134 between T vs. V. By immunohistochemistry, all 5 antibodies showed significantly increased H scores when comparing T vs. N and T vs. V. In accordance with the objective, we found two proteins, AGR2 and KRT19, with their corresponding genes that showed significantly differential expressions for the comparison of T vs. N in both, quantitative protein analysis and Nanostring mRNA analysis, and were successfully validated by immunohistochemistry. Conclusions: With AGR2 and KRT19, we have identified two proteins with their corresponding genes that are significantly and differentially expressed in the pcRPLND specimen in the clinically relevant groups T vs. N. Both were successfully validated by immunohistochemistry. In addition, further group differences (T vs. V/ V vs. N) were revealed depending on the analytical method. In perspective, these proteins could be targeted by radiolabeled ligands as a tracer in order to reliably distinguish patients with teratoma from those with necrosis by means of functional imaging. Thus, overtreatment with pcRPLND of patients with N could be safely reduced.

Diagnosis Issues and Management of Nasopharyngeal Non-Hodgkin Lymphomas

Background: Non-Hodgkin lymphomas (NHL) comprise a variety of lymphoproliferative malignancies with certain differences related to the morphological, clinical, immunohistochemical and hematological patterns, as well as the results of treatment. The patients with generalized and relapsed nasopharyngeal NHL experience marked disease burden and unfavorable impact on their life quality and working capacity.Objective: The aim of the study was to characterize the diagnosis issues of NHL with primary involvement of the nasopharynx and evaluate the short- and long-term results of management options.Materials and methods: This analytical and cohort study included 66 patients with different stages of nasopharyngeal NHL, who were managed at the Institute of Oncology from Moldova between 2014-2021. The diagnosis was confirmed by cytological, histopathological and immunohistochemical examinations. The histological types of NHL were verified and distinguished according to the 2017 Revision of WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. The patients treatment, follow-up and researches were realized at the comprehensive cancer center. The study was related to the hospitalized care. The patients age ranged between 19-85 years (average age - 58.4±2,14 years). Males were 28 (42%), females - 38 (58%). Stage I NHL was diagnosed in 10 (15.2%) cases, stage II - in 36 (54.5%), stage III - in 8 (12.1%) and stage IV - in 12 (18.2%). The eligible NHL patients underwent combined chemotherapy (CChT) regimens (CVChlP, R-CVChlP, CHOP and R-CHOP), associated with radiotherapy locoregional treatment in cases of bulky disease or residual tumor masses. The ECOG-WHO score and complete response (CR) rate assessed the short-term results. The long-term results were asserted by the overall one- and 5-year survival.Results: Primary nasopharyngeal NHL occurred commonly in females (58%) and in patients over 60 years (42.4%). The ECOG-WHO score accounted 1-3 at diagnosis. The aggressive NHL were diagnosed mostly (76.1%) in stage I and II due to the earlier developed disease burden. The primary tumor site was localized in the palatine tonsils in 22 (33.3%) patients, in 33 (50%) patients in the pharyngeal tonsil, in 2 (3%) patients in the lingual tonsil. The palatine and pharyngeal tonsils were concomitantly involved in 9 (13.7%) patients. Palatine tonsil involvement occurred mostly in patients over 60 years old, and pharyngeal tonsil involvement - in patients of 40-59 years. CR was achieved in 10 (100%) cases with stage I after combined chemotherapy (CChT) and radiotherapy locoregional treatment. CR occurred in 21 (67.7%), partial response (PR) - in 7 (22.6%) and response failure (RF) - in 3 (9.7%) in stage II NHL after CChT and radiotherapy locoregional treatment. In stage II NHL treated with CChT along, CR was achieved in 1 (25%), PR - in 2 (50%) and RF in 1 (25%). In stage III treated with CChT and radiotherapy locoregional treatment, CR was registered in 1 (20%), PR - in 2 (40%) and RF - in 2 (40%). PR occurred in 2 (66.7%), RF - in 1 (33.3%) in stage III managed with CChT alone. In stage IV NHL, CR was obtained 1 (11.1%) case, PR - in 5 (55.6%), RF - in 3 (33.3%) after CChT and radiotherapy locoregional treatment. PR occurred in 1 (33.3%), RF - in 2 (66.7%) cases in stage IV patients managed with CChT alone. No significant differences of CR rate were found in stage III (12,5%) and stage IV (8.3%) NHL (P>0.05). Irrespective of the stage, the highest CR rate was registered after CChT and radiotherapy locoregional treatment (97.1% of all cases), as compared to CChT alone (2.9% of all cases). The ECOG-WHO score reached 0-1 under the management with CChT and radiotherapy locoregional treatment in all cases with CR and PR. The overall survival was 79.9% at one year and 34.5% at 5 years. One- and 5-year survival proved to be significantly higher în stage I and II NHL - 96.1% and 64.2% respectively. One- and 5-year survival was 79.9% and 34.5% in stage III and IV NHL.Conclusions: Primary nasopharyngeal NHL were outlined by the predominant involvement of females, patients over 60 years and frequent site in the pharyngeal tonsil. The aggressive NHL were revealed commonly in stage I and II due to the progressive disease burden. The rates of the indolent and aggressive NHL turned out to be statistically equal in stage III and IV. The response and overall survival rates proved to be superior after R-CHOP regimen followed by the radiotherapy locoregional treatment. DisclosuresNo relevant conflicts of interest to declare.

Assessment of radiation sensitivity of unresectable intrahepatic cholangiocarcinoma in a series of patients submitted to radioembolization with yttrium-90 resin microspheres

Radioembolization is a valuable therapeutic option in patients with unresectable intrahepatic cholangiocarcinoma. The essential implementation of the absorbed dose calculation methods should take into account also the specific tumor radiosensitivity, expressed by the α parameter. Purpose of this study was to retrospectively calculate it in a series of patients with unresectable intrahepatic cholangiocarcinoma submitted to radioembolization. Twenty-one therapeutic procedures in 15 patients were analysed. Tumor absorbed doses were calculated processing the post-therapeutic 90Y-PET/CT images and the pre-treatment contrast-enhanced CT scans. Tumor absorbed dose and pre- and post-treatment tumor volumes were used to calculate α and α3D parameters (dividing targeted liver in n voxels of the same volume with specific voxel absorbed dose). A tumor volume reduction was observed after treatment. The median of tumor average absorbed dose was 93 Gy (95% CI 81–119) and its correlation with the residual tumor mass was statistically significant. The median of α and α3D parameters was 0.005 Gy−1 (95% CI 0.004–0.008) and 0.007 Gy−1 (95% CI 0.005–0.015), respectively. Multivariate analysis showed tumor volume and tumor absorbed dose as significant predictors of the time to tumor progression. The knowledge of radiobiological parameters gives the possibility to decide the administered activity in order to improve the outcome of the treatment.

The Role of Delayed Radiotherapy Initiation in Patients with Newly Diagnosed Glioblastoma with Residual Tumor Mass.

Treatment for newly diagnosed isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) includes maximum safe resection, followed by adjuvant radio(chemo)therapy (RCx) with temozolomide. There is evidence that it is safe for GBM patients to prolong time to irradiation over 4 weeks after surgery. This study aimed at evaluating whether this applies to GBM patients with different levels of residual tumor volume (RV). Medical records of all patients with newly diagnosed GBM at our department between 2014 and 2018 were reviewed. Patients who received adjuvant radio (chemo) therapy, aged older than 18 years, and with adequate perioperative imaging were included. Initial and residual tumor volumes were determined. Time to irradiation was dichotomized into two groups (≤28 and >28 days). Univariate analysis with Kaplan-Meier estimate and log-rank test was performed. Survival prediction and multivariate analysis were performed employing Cox proportional hazard regression. One hundred and twelve patients were included. Adjuvant treatment regimen, extent of resection, residual tumor volume, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation were statistically significant factors for overall survival (OS). Time to irradiation had no impact on progression-free survival (p = 0.946) or OS (p = 0.757). When stratified for different thresholds of residual tumor volume, survival predication via Cox regression favored time to irradiation below 28 days for patients with residual tumor volume above 2 mL, but statistical significance was not reached. Time to irradiation had no significant influence on OS of the entire cohort. Nevertheless, a statistically nonsignificant survival prolongation could be observed in patients with residual tumor volume > 2 mL when admitted to radiotherapy within 28 days after surgery.