The risk of second malignancies following prostate cancer radiotherapy in the era of conformal radiotherapy: a statement of the Prostate Cancer Working Group of the German Society of Radiation Oncology (DEGRO).

A significant number of prostate cancer patients are long-term survivors after primary definitive therapy, and the occurrence of late side effects, such as second primary cancers, has gained interest. The aim of this editorial is to discuss the most current evidence on second primary cancers based on six retrospective studies published in 2021-2024 using large data repositories not accounting for all possible confounding factors, such as smoking or pre-existing comorbidities. Overall, prostate cancer patients treated with curative radiotherapy have an increased risk (0.7-1%) of the development of second primary cancers compared to patients treated with surgery up to 25 years after treatment. However, current evidence suggests that the implementation of intensity modulated radiation therapy is not increasing the risk of second primary cancers compared to conformal 3D-planned radiotherapy. Furthermore, increasing evidence indicates that highly conformal radiotherapy techniques may not increase the probability of second primary cancers compared to radical prostatectomy. Consequently, future studies should consider the radiotherapy technique and other confounding factors to provide a more accurate estimation of the occurrence of second primary cancers.

Prostate cancer and elective nodal radiation therapy for cN0 and pN0-a never ending story? : Recommendations from the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO).

For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of randomized controlled trials, the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO) aimed to discuss and summarize the current literature. Modern trials have been recently published for both treatment-naïve patients (POP-RT trial) and patients after surgery (SPPORT trial). Although there are more reliable data to date, we identified several limitations currently complicating the definitions of general recommendations. For patients with cN0 (conventional or PSMA-PET staging) undergoing definitive radiotherapy, only men with high-risk factors for nodal involvement (e.g., cT3a, GS ≥ 8, PSA ≥ 20 ng/ml) seem to benefit from ENI. For biochemical relapse in the postoperative situation (pN0) and no PSMA imaging, ENI may be added to patients with risk factors according to the SPPORT trial (e.g., GS ≥ 8; PSA > 0.7 ng/ml). If PSMA-PET/CT is negative, ENI may be offered for selected men with high-risk factors as an individual treatment approach.

Correction to: Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma.

Following publication of the article, the author named as "B Dey", wished to point out that his full name is "Bijan K. Dey". This was not reflected in the typesetting of the article, and as a consequence the article is not visible on Pub Med when a search is conducted on his full name.

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma.

Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B.

Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells.

The androgen receptor (AR) stimulates and represses gene expression to promote the initiation and progression of prostate cancer. Here, we report that androgen represses the miR-99a/let7c/125b-2 cluster through AR and anti-androgen drugs block the androgen-repression of the miRNA cluster. AR directly binds to the host gene of the miR-99a/let7c/125b-2 cluster, LINC00478. Expression of the cluster is repressed or activated by chromatin remodelers EZH2 or JMJD3 in the presence or absence of androgen, respectively. Bioinformatics analysis reveals a significant enrichment of targets of miR-99a, let-7c and miR-125b in androgen-induced gene sets, suggesting that downregulation of the miR-99a/let7c/125b-2 cluster by androgen protects many of their target mRNAs from degradation and indirectly assists in the gene induction. We validated the hypothesis with 12 potential targets of the miR-99a/let7c/125b-2 cluster induced by androgen: 9 out of the 12 mRNAs are downregulated by the microRNA cluster. To ascertain the biological significance of this hypothesis, we focused on IGF1R, a known prostate cancer growth factor that is induced by androgen and directly targeted by the miR-99a/let7c/125b-2 cluster. The androgen-induced cell proliferation is ameliorated to a similar extent as anti-androgen drugs by preventing the repression of the microRNAs or induction of IGF1R in androgen-dependent prostate cancer cells. Expression of a microRNA-resistant form of IGF1R protects these cells from inhibition by the miR-99a/let7c/125b-2 cluster. These results indicate that a thorough understanding of how androgen stimulates prostate cancer growth requires not only an understanding of genes directly induced/repressed by AR, but also of genes indirectly induced by AR through the repression of key microRNAs.

The miR-99 family regulates the DNA damage response through its target SNF2H.

Chromatin remodeling factors are becoming known as crucial facilitators of recruitment of repair proteins to sites of DNA damage. Multiple chromatin remodeling protein complexes are now known to be required for efficient double strand break repair. In a screen for microRNAs (miRNAs) that modulate the DNA damage response, we discovered that expression of the miR-99 family of miRNAs correlates with radiation sensitivity. These miRNAs were also transiently induced following radiation. The miRNAs target the SWI/SNF chromatin remodeling factor SNF2H/SMARCA5, a component of the ACF1 complex. We found that by reducing levels of SNF2H, miR-99a and miR-100 reduced BRCA1 localization to sites of DNA damage. Introduction of the miR-99 family of miRNAs into cells reduced the rate and overall efficiency of repair by both homologous recombination and non-homologous end joining. Finally, induction of the miR-99 family following radiation prevents an increase in SNF2H expression and reduces the recruitment of BRCA1 to the sites of DNA damage following a second dose of radiation, reducing the efficiency of repair after multiple rounds of radiation, as used in fractionated radiotherapy.

The additional loss of Bak and not the lack of the protein tyrosine kinase p56/Lck in one JCaM1.6 subclone caused pronounced apoptosis resistance in response to stimuli of the intrinsic pathway.

Ionising radiation, hypoxia, and the cyclooxygenase-2 inhibitor Celecoxib are known agonists of the intrinsic apoptosis pathway that involves mitochondrial damage upstream of caspase activation. Mitochondrial integrity is regulated by the pro-apoptotic Bcl-2 protein family members Bak and Bax. Upstream of the mitochondria, many kinases and phosphatases control the apoptotic response. However, the role of the non-receptor tyrosine kinase p56/Lck during apoptosis is controversial. The present investigation demonstrate the existence of two JCaM1.6 subclones, one expressing and one deficient for Bak. The lack of p56/Lck expression in JCaM1.6 cells per se did hardly affect apoptosis induced by ionising radiation, hypoxia, or Celecoxib. Only the additional loss of Bak expression, as observed in one JCaM1.6 subclone, rendered the cells resistant. siRNA-mediated downregulation of Bak and p56/Lck mimicked the observed effects in the subclones. Earlier experiments performed with the Bak-negative clone might have lead to the wrong assumption that lack of p56/Lck alone, and not the additonal loss of Bak, was responsible for reduced sensitivity towards stimuli of the intrinsic apoptosis pathway.

Cerebral blood flow in preterm infants affected by sex, mechanical ventilation, and intrauterine growth.

Sex differences in cerebral blood flow (CBF) values have been demonstrated in adults but not in newborns. This study evaluated the influence of sex, intrauterine growth, and need of mechanical ventilation on resting cerebral blood flow in preterm neonates. Sixty-eight preterm infants with gestational ages of less than 34 weeks and birth weights of less than 1,500 gm were enrolled into the study. Cerebral blood flow was measured by the noninvasive intravenous xenon 133 method 3 times. Measurements were classified into 3 groups: group 1: measurement at 2-36 hours (n = 46); group 2: measurement at 36-108 hours (n = 39); and group 3: measurement at 108-240 hours (n = 41). In all 3 groups, the CBF in girls was significantly lower than in boys (group 1: 11.5 +/- 2.8 ml/100 gm/min vs 14.0 +/- 4.1 ml/100 gm/min; group 2: 13.4 +/- 2.9 ml/100 gm/min vs 16.3 +/- 4.3 ml/100 gm/min; group 3: 12.9 +/- 3.2 ml/100 gm/min vs 15.3 +/- 3.1 ml/100 gm/min). In group 1, the CBF in neonates requiring mechanical ventilation was significantly lower (P < .05) than in patients who were spontaneously breathing (11.5 +/- 3.7 ml/100 gm/min vs 14.2 +/- 3.1 ml/100 gm/min), and the CBF in neonates who were too small for gestational age was significantly higher (P < .005) than in children with appropriate intrauterine growth (16.1 +/- 4.1 ml/100 gm/min vs 11.5 +/- 2.6 ml/100 gm/min). It is concluded that in preterm neonates CBF is substantially affected by sex, intrauterine growth retardation, and the need of mechanical ventilation.