Dose-dependence of radiotherapy-induced changes in serum levels of choline-containing phospholipids; the importance of lower doses delivered to large volumes of normal tissues.

BACKGROUND: Conformal radiotherapy is a primary treatment in head and neck cancer, which putative adverse effects depend on relatively low doses of radiation delivered to increased volumes of normal tissues. Systemic effects of such treatment include radiation-induced changes in serum lipid profile, yet dose- and volume-dependence of these changes remain to be established. METHODS: Here we analyzed levels of choline-containing phospholipids in serum samples collected consecutively during the radiotherapy used as the only treatment modality. The liquid chromatography-mass spectrometry (LC-MS) approach applied in the study enabled the detection and quantitation of 151 phospholipids, including (lyso)phosphatidylcholines and sphingomyelins. RESULTS: No statistically significant differences were found in the pretreatment samples from patients with different locations and stages of cancer. To compensate for potential differences between schemes of radiotherapy, the biologically effective doses were calculated and used in the search of correlations with specific lipid levels. We found that the levels of several phospholipids depended on the maximum dose delivered to the gross tumor volume and total radiation energy absorbed by the patient's body. Increased doses correlated with increased levels of sphingomyelins and reduced levels of phosphatidylcholines. Furthermore, we observed several phospholipids whose serum levels correlated with the degree of acute radiation toxicity. CONCLUSION: Noteworthy, serum phospholipid levels were associated mainly with volumes of normal tissues irradiated with relatively low doses (i.e., total accumulated dose 20 Gy), which indicated the importance of such effects on the systemic response of the patient's organism to intensity-modulated radiotherapy (IMRT).

High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.

The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.

The application of 18F-FDG-PET/CT in gastric cancerstaging and factors affecting its sensitivity.

OBJECTIVE: To evaluate the accuracy offluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), to correctly determine initial tumor stage in treatment-naive gastric cancer patients and to analyze the factors influencing the risk of false negative results. SUBJECTS AND METHODS: The baseline 18F-FDG PET/CT scans of 111 previously untreated gastric cancer patients were retrospectively assessed. Sensitivity, specificity, positive (PPV) and negative prediction value (NPV) were evaluated. An array of clinical, pathological and metabolic variables was analyzed to identify factors contributing to the risk of a false positive (FP) and false negative (FN) PET/CT result in detecting primary and metastatic tumor sites. RESULTS: The sensitivity, specificity, PPV and NPV of PET/CT to visualize distant metastases were 76.4%; 86.7%; 83% and 81.2%, respectively. In 13 (11.7%) patients the PET/CT exam was able to identify metastatic sites not recognized in radiographic staging, significantly altering the initially planned management. Of 64 PET/CT studies negative for distant metastases, 12 (18.75%) were clinically confirmed to be false negative. The risk of acquiring a FN result for primary tumor was 10.8% (12/111) and the overall risk of any FN readout for either primary and metastatic sites was 18.9% (21/111). The factors that contributed to increased probability of a FN result for primary tumor detection were early primary tumor stage T1-T2 (+16.2%; χ2=5.0, P=0.025), female sex (+10.1%; χ2=5.71, P=0.017) and neutrophil count below 4.2k/µL (9.7%; χ2=6.1, P=0.014). Patients with non-intestinal Lauren histologic type (+18.7%; χ2=8.9, P=0.003) or signet-ring/mucinous carcinoma (+9.6%; χ2=7.7, P=0.005) had increased probability of PET/CT being unable to identify their distant metastases. Women and patients with low neutrophil count featured borderline insignificantly increased percentage of non-intestinal tumor histology (P=0.07 and P=0.057, respectively). CONCLUSION: Fluorine-18-FDG PET/CT is a valuable diagnostic method in gastric cancer patients which significantly contributes to determining the TNM stage and thus helps choose correct patient management. Histology and primary tumor stage as well as patient cohorts in which these factors may vary should be considered when evaluating results to decrease a chance of a false negative readout.

Cyclin-dependent kinase 4/6 inhibitors combined with stereotactic ablative radiotherapy in oligometastatic HR-positive/HER2-negative breast cancer patients.

OBJECTIVES: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved the survival of patients with hormone receptor-positive HER2-negative advanced breast cancer (ABC). Although stereotactic ablative radiotherapy (SABR) is used more often in routine clinical practice, data on the safety and efficacy of combining SABR with CDK4/6i are lacking. Herein, we present the results of SABR combined with CDK4/6i in ABC. METHODS: Patients with ABC who received CDK4/6i and SABR between 2018 and 2023 were analysed. RESULTS: Among 384 patients treated with CDK4/6i, 34 patients received 44 courses of SABR. Two-year progression-free survival (PFS) was 63.6% (95% CI, 45.8-88.3), and the median PFS was 32 months. Three-year overall survival (OS) was 88.9% (95% CI, 77.7-100). Two-year local control (LC) was 92.7% (95% CI, 83.4-100). Median OS and LC were not reached. The subgroup analysis showed the difference in survival between oligometastatic patients (OMD) and non-OMD subgroup. Two-year PFS was 69.2% (95% CI, 44.5-100) in OMD compared with 57.4% (95% CI, 36-91.7) in the non-OMD (P = .042). Three-year OS was 90% (95% CI, 73.2-100) in OMD compared with 86.2% (95% CI, 70-100) in the non-OMD (P = .67). Median PFS and OS in the non-OMD were 26 and 56 months, respectively, and were not reached in OMD. Fifteen patients required CDK4/6i dose reduction, and 2 discontinued treatment due to toxicity. No difference in high-grade toxicity was observed between the sequential and concurrent SABR. CONCLUSION: The addition of SABR to CDK4/6i seems to be safe and effective, especially in patients with oligometastatic disease. ADVANCES IN KNOWLEDGE: In advanced breast cancer patients treated with CDK4/6i, SABR provides a high local control and may provide additional benefit in an oligometastatic setting.

LUNA EMG as a Marker of Adherence to Prehabilitation Programs and Its Effect on Postoperative Outcomes among Patients Undergoing Cytoreductive Surgery for Ovarian Cancer and Suspected Ovarian Tumors.

BACKGROUND: Prehabilitation is a novel strategy in preoperative management. The aim of this study was to investigate the effect of prehabilitation programs on peri- and postoperative outcomes and to verify if LUNA EMG has the capacity to monitor compliance with prehabilitation programs. METHODS: A total of seventy patients with suspected ovarian cancer were recruited between April 2021 and September 2022 and were divided into a prehabilitation group (36 patients) or a control group (34 patients). A LUNA EMG device was utilized to monitor muscle strength and tension. RESULTS: Within the prehabilitation group, we observed a significant increase in the 6-Minute Walk Test distance by 17 m (median, IQR: 0-42.5, p < 0.001) and a significant increase in muscle strength measured with LUNA EMG. In comparison to the control group, the prehabilitation group showed fewer complications according to the Clavien-Dindo classification (47.2% vs. 20.6%, p = 0.02) and shorter postoperative hospital stays (median 5.0 days [IQR: 4.0-6.2] vs. 7.0 days [IQR: 6.0-10.0], p < 0.001). CONCLUSION: Prehabilitation has a positive effect on physical capacity and muscle strength and is associated with a reduction in the number of complications after surgery. LUNA EMG can be a useful tool for monitoring patients' adherence to prehabilitation programs.

Liquid biopsy utilizing miRNA in patients with advanced breast cancer treated with cyclin­dependent kinase 4/6 inhibitors.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are the mainstay of treatment of hormone receptor+/human epidermal growth factor receptor 2-patients with advanced breast cancer (ABC). Despite improvements in overall survival, most patients experience disease progression. Biomarkers derived from a liquid biopsy are appealing for their potential to detect resistance to treatment earlier than computed tomography imaging. However, clinical data concerning microRNAs (miRNAs/miRs) in the context of CDK4/6is are lacking. Thus, the present study assessed the use of miRNAs in patients with ABC treated with CDK4/6is. Patients treated for ABC with CDK4/6is between June and August 2022 were eligible. miRNA expression analyses were performed using a TaqMan™ low-density miRNA array. A total of 80 consecutive patients with ABC treated with CDK4/6is at Maria Sklodowska-Curie National Research Institute of Oncology (Gliwice, Poland) were assessed, with 14 patients diagnosed with progressive disease at the time of sampling, 55 patients exhibited clinical benefit from CDK4/6i treatment and 11 patients were at the beginning of CDK4/6i treatment. Patients with disease progression had significantly higher levels of miR-21 (P=0.027), miR-34a (P=0.011), miR-193b (P=0.032), miR-200a (P=0.027) and miR-200b (P=0.003) compared with patients who benefitted from CDK4/6i treatment. Significantly higher levels of miR-34a expression were observed in patients with progressive disease than in patients beginning treatment (P=0.031). The present study demonstrated the potential innovative role of circulating miRNAs during CDK4/6i treatment. Plasma-based expression of miR-21, -34a, -193b, -200a and -200b effectively distinguished patients with ABC who responded to CDK4/6i treatment from patients who were resistant. However, longitudinal studies are required to verify the predictive and prognostic potential of miRNA.

Safety and feasibility of CDK4/6 inhibitors treatment combined with radiotherapy in patients with HR-positive/HER2-negative breast cancer. A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-) breast cancer has led to practice-changing improvements in overall survival. However, there are conflicting data concerning the safety of CDK4/6i combination with radiotherapy, and no consensus guidelines exist to guide practice. We conducted a meta-analysis to assess the safety and feasibility of CDK4/6i treatment with radiotherapy. MATERIALS AND METHODS: A comprehensive search was performed in PubMed/MEDLINE, Web of Science, and Scopus, for studies in advanced/metastatic breast cancer receiving CDK4/6i and radiotherapy with the provided safety data on the occurrence of toxicity. The main outcomes were safety (grade 3-5 adverse events), CDK 4/6i dose reduction, and the discontinuation rate due to toxicity. RESULTS: Fifteen studies comprising 1133 patients with HR+/HER2- breast cancer patients were included. Among them, 617 pts received CDK4/6i and radiotherapy; the median follow-up was 17.0 months (IQR 9.2 - 18.0), and the median age was 58.8 years (IQR 55.5---62.5). The pooled prevalence of severe hematologic toxicity was 29.4% (95% CI 14.0% - 47.4%; I2 = 93%; τ2 = 0.084; p < 0.01 and severe non-hematologic toxicity was 2.8% (95% CI 1.1% - 4.8%; I2 = 0%; τ2 = 0.0; p = 0.67). The pooled prevalence of CDK4/6i dose reduction was 24.0% (95% CI 11.1% - 39.4%; I2 = 90%; τ2 = 0.052; p < 0.01) with no difference between CDK4/6i plus RT vs. CDK4/6i (odds ratio of 0.934; 95% CI 0.66 - 1.33; I2 = 0%; τ2 = 0.0; p = 0.56). The pooled prevalence of CDK4/6i discontinuation due to toxicity was 2.3% (95% CI 0.4% - 5.2%; I2 = 23%; τ2 = 0.002; p = 0.24). CONCLUSION: The findings of this study suggest that radiotherapy in addition to CDK4/6i treatment in breast cancer patients is generally safe and well tolerated and remains a viable treatment option.

Influence of nutritional counseling on treatment results in patients with head and neck cancers.

OBJECTIVES: Nutritional intervention, including nutritional counseling (NC), plays a significant role in the comprehensive management of patients with head and neck cancer (HNC). The aim of this study was to investigate the effects of NC combined with oral nutritional supplements during radical treatment on weight loss and survival outcomes in patients with HNC. METHODS: The study included 310 patients who received radical treatment for HNC. Among these patients, 119 underwent NC along with oral nutritional supplements (NCONS); 191 were supported with oral nutritional supplements only (ONS). The study aimed to investigate the effects of sex, disease stage, treatment modality, and tumor site on weight loss. Additionally, the Kaplan-Meier method assessed the influence of NC on overall survival and disease-free survival. RESULTS: The present study suggested that the NC independently prevented weight loss, regardless of sex and disease stage (female: -1.6%, P = 0.001; male: -2.3 %, P = 0.003; T stage (0-2): -1.7%, P = 0.008; T stage (3-4): -2.7%, P = 0.003; N stage (0-1): 2.5%, P = 0,027; N stage (3-4): 2.9%, P < 0.001). The protective effect was most significant in patients with oral cancer and oropharyngeal cancer and in patients treated with chemotherapy (oral: -1.7%, P = 0.03; oropharynx: -3.3%, P < 0.001; radiochemotherapy: -3%, P = 0.028; induction chemotherapy preceded radiochemotherapy: -6%, P < 0.001). Furthermore, the 3-year overall survival rates were 93.4% and 85.4% in the NC along with oral nutritional supplements (NCONS) and oral nutritional supplement (ONS) groups, respectively (P = 0.031). CONCLUSIONS: Patients with HNC who received NC during radical treatment experienced reduced weight loss. This effect was particularly pronounced in patients with oral cavity or oropharyngeal cancer and those undergoing chemotherapy. Additionally, NC was associated with improved overall survival in this patient cohort. Nevertheless, further studies are required to validate and support these findings.

Efficacy of CDK 4/6 Inhibitors and Radiotherapy in Breast Cancer Patients with Brain Metastases.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard of care for HR-positive/HER2-negative advanced breast cancer patients. However, their role in the treatment of brain metastases is currently unclear. We retrospectively evaluate the results of patients (pts) with advanced breast cancer treated at our institution with CDK4/6i and radiotherapy to the brain. The primary endpoint was progression-free survival (PFS). Secondary endpoints were local control (LC) and severe toxicity. Among 371 pts treated with CDK4/6i, 24 pts (6.5%) received radiotherapy to the brain before (11 pts), during (6 pts), or after (7 pts) CDK4/6i treatment. Sixteen pts received ribociclib, six received palbociclib, and two received abemaciclib. Six- and twelve-month PFS was 76.5% (95% CI: 60.3-96.9) and 49.7% (95% CI: 31.7-77.9), respectively, whereas six- and twelve-month LC was 80.2% (95% CI: 58.7-100) and 68.8% (95% CI: 44.5-100), respectively. With a median follow-up of 9.5 months, no unexpected toxicity was observed. We conclude that treatment with both CDK4/6i and brain radiotherapy is feasible and should not increase the toxicity compared to brain radiotherapy or CDK4/6i alone. However, the small number of individuals treated concurrently limits the conclusions about the combination of both modalities, and the results from ongoing prospective clinical trials are eagerly awaited to understand both the toxicity profile and the clinical response fully.

The Severity of Pain in Prostate Biopsy Depends on the Biopsy Sector.

BACKGROUND: The pain experienced by a patient during a prostate fusion biopsy is cumulative and can also be modulated by many factors. The aim of the study was to assess the association between the degree of pain intensity during prostate biopsy and the region of the biopted organ. MATERIALS AND METHODS: The study included a group of 143 patients who underwent prostate fusion biopsy under local analgesia followed by blockage of the periprostatic nerve. After a biopsy, the patients completed the original questionnaire about the pain experienced during the procedure. RESULTS: There was a statistically significant difference in pain score between cores taken in the apex (median 5 (IQR 2-5)), medium level (median 1 (IQR 1-2)), and prostate base (median 1 (IQR 1-3)) (p < 0.001). The malignancy scale ISUP ≥ 2 (p = 0.038) and lower PSA value (r = -0.17; p = 0.046) are associated with higher pain during procedure. Biopsy time was correlated with discomfort (r = 0.19; p = 0.04). Age (p = 0.65), lesion size (p = 0.29), PI-RADS score (p = 0.86), prostate volume (p = 0.22), and the number of cores (p = 0.56) did not correspond to the pain scale. CONCLUSIONS: The apex is the most sensitive sector of the prostate. ISUP ≥ 2 and patients with low PSA levels more often indicated higher values on the pain rating scale.

The influence of the operator's experience on the outcomes of fusion prostate biopsy.

Introduction: Magnetic resonance imgaing (MRI) targeted biopsy is the gold standard for prostate cancer (PCa) diagnosis. In this study, we examined the association between the operator's experience and the improvement in the precision of the MRI prostate biopsy procedure and the detection of PCa. Material and methods: We included consecutive patients who underwent prostate fusion biopsy. Data on biopsy duration, prostate-specific antigen (PSA) value, lesion size, number of samples taken, number of cores involved, and International Society of Urological Pathology (ISUP) grade were subjected to statistical analysis, with the study group divided into three consecutive time periods (tertiles). Results: There were statistically significant differences in biopsy duration between tertiles (p <0.001). The greatest difference in the involved/taken cores ratio occurred between the first and third tertile (p = 0.002). The difference between the first and second tertile was insignificant (p = 0.4), while the difference between the second and third tertile was statistically significant (p = 0.004). The differences between tertiles in Prostate Imaging and Reporting Data System v2.1 were also significant (p = 0.003). The PSA value (p = 0.036) was statistically significant, unlike prostate volume (p = 0.16), digital rectal examination (DRE) (p = 0.7), and ISUP grade (p = 0.7). There was no statistical difference between tested tertiles in the number of detected PCa ISUP ≥2 (Z = 0.191; p = 0.8). Conclusions: The abilities and precision of the operator increase with the increase in the number of procedures performed. The biopsy duration is shortened, and the detection of PCa during the procedure seems to improve with the operator's experience.

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.

Outcomes of Cytoreductive Radical Prostatectomy for Oligometastatic Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography: Results of a Multicenter European Study.

BACKGROUND: De novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown. OBJECTIVE: To analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET. DESIGN, SETTING, AND PARTICIPANTS: Overall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET. INTERVENTION: Cytoreductive radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Thirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed. RESULTS AND LIMITATIONS: Overall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5-93.7%) and 98.9% (95% CI 96.8-100%), respectively. The limitations include retrospective design and short-term follow-up. CONCLUSIONS: Cytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy. PATIENT SUMMARY: We found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications.

Heat shock factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells.

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from The Cancer Genome Atlas database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers an elevated HSF1 level is associated with metastatic disease.

About 70% of breast cancers rely on supplies of a hormone called estrogen ­ which is the main hormone responsible for female physical characteristics ­ to grow. Breast cancer cells that are sensitive to estrogen possess proteins known as estrogen receptors and are classified as estrogen-receptor positive. When estrogen interacts with its receptor in a cancer cell, it stimulates the cell to grow and migrate to other parts of the body. Therefore, therapies that decrease the amount of estrogen the body produces, or inhibit the receptor itself, are widely used to treat patients with estrogen receptor-positive breast cancers. When estrogen interacts with an estrogen receptor known as ERα it can also activate a protein called HSF1, which helps cells to survive under stress. In turn, HSF1 regulates several other proteins that are necessary for ERα and other estrogen receptors to work properly. Previous studies have suggested that high levels of HSF1 may worsen the outcomes for patients with estrogen receptor-positive breast cancers, but it remains unclear how HSF1 acts in breast cancer cells. Vydra, Janus, Kus et al. used genetics and bioinformatics approaches to study HSF1 in human breast cancer cells. The experiments revealed that breast cancer cells with lower levels of HSF1 also had lower levels of ERα and responded less well to estrogen than cells with higher levels of HSF1. Further experiments suggested that in the absence of estrogen, HSF1 helps to keep ERα inactive. However, when estrogen is present, HSF1 cooperates with ERα and enhances its activity to help cells grow and migrate. Vydra, Janus, Kus et al. also found that cells with higher levels of HSF1 were less sensitive to two drug therapies that are commonly used to treat estrogen receptor-positive breast cancers. These findings reveal that the effect HSF1 has on ERα activity depends on the presence of estrogen. Therefore, cancer therapies that decrease the amount of estrogen a patient produces may have a different effect on estrogen receptor-positive tumors with high HSF1 levels than tumors with low HSF1 levels.

A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype-Phenotype Correlations.

Introduction: Pancreatic neuroendocrine tumors (PNETs) in hereditary syndromes pose a significant challenge to clinicians. The rarity of these syndromes and PNETs itself make it difficult to directly compare them with sporadic PNETs. Despite research suggesting differences between these two entities, the same approach is used in hereditary and sporadic PNETs. Methods: We included 63 patients with hereditary PNET (GpNET) and 145 with sporadic PNET (SpNET) in a retrospective observational study. Clinical and genetic data were collected in two Polish endocrine departments from January 2004 to February 2020. Only patients with confirmed germline mutations were included in the GpNET cohort. We attempted to establish prognostic factors of metastases and overall survival in both groups and genotype-phenotype correlations in the GpNET group. Results: Patients with GpNET were younger and diagnosed earlier, whereas their tumors were smaller and more frequently multifocal compared with patients with SpNET. Metastases occurred more frequently in the SpNET group, and their appearance was associated with tumor size in both groups. GpNET patients had longer overall survival (OS). OS was affected by age, age at diagnosis, sex, grade, stage, tumor diameter, occurrence and localization of metastases, type of treatment, and comorbidities. In the MEN1 group, carriers of frameshift with STOP codon, splice site, and missense mutations tended to have less advanced disease, while patients with mutations in exon 2 tended to have metastases more frequently. Conclusions: Direct comparisons of GpNET and SpNET demonstrate significant differences in the clinical courses of both entities, which should force different approaches. A larger group of patients with GpNET should be assessed to confirm genotype-phenotype correlations.

High-Grade Gliomas in Children-A Multi-Institutional Polish Study.

Due to the rarity of high-grade gliomas (HGG) in children, data on this topic are scarce. The study aimed to investigate the long-term results of treatment of children with HGG and to identify factors related to better survival. We performed a retrospective analysis of patients treated for HGG who had the main tumor located outside the brainstem. The evaluation of factors that correlated with better survival was performed with the Cox proportional-hazard model. Survival was estimated with the Kaplan-Meier method. The study group consisted of 82 consecutive patients. All of them underwent surgery as primary treatment. Chemotherapy was applied in 93% of children with one third treated with temozolomide. After or during the systemic treatment, 79% of them received radiotherapy with a median dose of 54 Gy. Median follow-up was 122 months, and during that time, 59 patients died. One-, 2-, 5-, and 10-year overall survival was 78%, 48%, 30% and 17%, respectively. Patients with radical (R0) resection and temozolomide-based chemotherapy had better overall survival. Progression-free survival was better in patients after R0 resection and radical radiotherapy. The best outcome in HGG patients was observed in patients after R0 resection with immediate postoperative temozolomide-based chemotherapy and radical radiotherapy.

Reliability of Serial Prostate Magnetic Resonance Imaging to Detect Prostate Cancer Progression During Active Surveillance: A Systematic Review and Meta-analysis.

CONTEXT: Although magnetic resonance imaging (MRI) is broadly implemented into active surveillance (AS) protocols, data on the reliability of serial MRI in order to help guide follow-up biopsy are inconclusive. OBJECTIVE: To assess the diagnostic estimates of serial prostate MRI for prostate cancer (PCa) progression during AS. EVIDENCE ACQUISITION: We systematically searched PubMed, Scopus, and Web of Science databases to select studies analyzing the association between changes on serial prostate MRI and PCa progression during AS. We included studies that provided data for MRI progression, which allowed us to calculate diagnostic estimates. We compared Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) accuracy with institution-specific definitions. EVIDENCE SYNTHESIS: We included 15 studies with 2240 patients. Six used PRECISE criteria and nine institution-specific definitions of MRI progression. The pooled PCa progression rate, which included histological progression to Gleason grade ≥2, was 27%. The pooled sensitivity and specificity were 0.59 (95% confidence interval [CI] 0.44-0.73) and 0.75 (95% CI 0.66-0.84) respectively. There was significant heterogeneity between included studies. Depending on PCa progression prevalence, the pooled negative predictive value for serial prostate MRI ranged from 0.81 (95% CI 0.73-0.88) to 0.88 (95% CI 0.83-0.93) and the pooled positive predictive value ranged from 0.37 (95% CI 0.24-0.54) to 0.50 (95% CI 0.36-0.66). There were no significant differences in the pooled sensitivity (p = 0.37) and specificity (p = 0.74) of PRECISE and institution-specific schemes. CONCLUSIONS: Serial MRI still should not be considered a sole factor for excluding PCa progression during AS, and changes on MRI are not accurate enough to indicate PCa progression. There was a nonsignificant trend toward improved diagnostic estimates of PRECISE recommendations. These findings highlight the need to further define the optimal triggers and timing of biopsy during AS, as well as the need for optimizing the quality, interpretation, and reporting of serial prostate MRI. PATIENT SUMMARY: Our study suggests that serial prostate magnetic resonance imaging (MRI) alone in patients on active surveillance is not accurate enough to reliably rule out or rule in prostate cancer progression. Other clinical factors and biomarkers along with serial MRI are required to safely tailor the intensity of follow-up biopsies.

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis.

Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a-CD7- subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options.

Changing patterns of urologic emergency visits and admissions during the COVID-19 pandemic: a retrospective, multicenter, nationwide study.

INTRODUCTION: We aimed to examine the change in the number and severity of visits to the emergency departments (EDs) and subsequent admissions for urgent urologic conditions in the early stage of the coronavirus disease 2019 (COVID-19) pandemic in Poland. MATERIAL AND METHODS: We evaluated data from 13 urologic centers in Poland and compared the number of visits to the EDs and subsequent admissions before and after the advent of COVID-19 in 2020, and before and after the escalating national restrictions. Furthermore, data on types of urologic complaints, crucial laboratory parameters, and post-admission procedures were analyzed. RESULTS: In total 1,696 and 2,187 urologic visits (22.45% decrease) and 387 and 439 urologic urgent admissions (11.85% decrease) were reported in given periods in 2020 and 2019, respectively. The year-over-year difference in daily mean visits was clear (36.1 vs. 46.5; p < 0.001). Declines were seen in all complaints but device malfunction. In 2020 daily mean visits and admissions decreased from 40.9 and 9.6 before lockdowns to 30.9 (p < 0.001) and 6.9 (p = 0.001) after severe restrictions, respectively. There was a trend towards more negative laboratory parameter profiles in 2020, with patients who visited the EDs after severe restrictions having twice as high median levels of C-reactive protein (15.39 vs. 7.84, p = 0.03). CONCLUSIONS: The observed declines in ED visits and admissions were apparent with the significant effect of national lockdowns. Our results indicate that some of the patients requiring urgent medical help did not appear at the ED or came later than they would have done before the pandemic, presenting with more severe complaints.