The microbiota is the complex community of microorganisms that populate a particular environment in the human body, whereas the microbiome is defined by the entire habitat—microorganisms and their environment. The most abundant and, therefore, the most studied microbiome is that of the gastrointestinal tract. However, the microbiome of the female reproductive tract is an interesting research avenue, and this article explores its role in disease development. The vagina is the reproductive organ that hosts the largest number of bacteria, with a healthy profile represented mainly by Lactobacillus spp. On the other hand, the female upper reproductive tract (uterus, Fallopian tubes, ovaries) contains only a very small number of bacteria. Previously considered sterile, recent studies have shown the presence of a small microbiota here, but there are still debates on whether this is a physiologic or pathologic occurrence. Of particular note is that estrogen levels significantly influence the composition of the microbiota of the female reproductive tract. More and more studies show a link between the microbiome of the female reproductive tract and the development of gynecological cancers. This article reviews some of these findings.

Background: Vascular endothelial growth factor (VEGF) plays an important role in tumor progression in ovarian cancer, but the complex mechanism and interaction with oxidative stress are not fully understood. Methods: A prospective study included 52 patients with ovarian adenocarcinoma stage IIIA-IV. Serum VEGF and reactive oxygen species (ROS) such as malondialdehyde and ceruloplasmin were measured. Results: VEGF levels were elevated (mean 1014.7 ± 165 pg/mL), especially in patients with macroscopic residual disease (1058 vs. 810 pg/mL, p = 0.0001). Median progression-free survival (PFS) and overall survival (OS) were 6 and 40 months in patients with a very high VEGF (over 1200 pg/mL), 11 and 48 months in patients with VEGF between 1000–1200 pg/mL, 18 and 84 months in patients with VEGF between 800–1000 pg/mL, and not reached in patients with normal VEGF. Increased VEGF values were associated with a 2.6-fold increased risk of disease progression (HR = 2.60, 95% CI 1.69–3.99), and a 1.4-fold increased risk of death (HR = 1.4, 95% CI 1.15–1.91, p = 0.002). Receiver operator characteristic (ROC) curves were used to validate VEGF as a prognostic factor and the area under the curve (AUC) was 0.814, p = 0.036 for PFS and 0.729, p = 0.043, for OS. There was a positive correlation between VEGF and malondialdehyde, Pearson coefficient of 0.35, p = 0.0001. Conclusions: VEGF and malondialdehyde are important prognostic markers in ovarian cancer, especially in macroscopic residual disease, and there is a positive correlation between angiogenesis and oxidative stress.

Leptomeningeal metastases (LM) are a rare but rapidly fatal complication defined by the spread of tumor cells within the leptomeninges and the subarachnoid space, found in approximately 10% of patients with HER2-positive breast cancers. This pilot study evaluated the efficacy of local treatment with intrathecal Trastuzumab (IT) added to systemic treatment. The oncologic outcome of 14 patients with HER2-positive LM is reported. Seven received IT, and seven received standard of care (SOC). The mean number of IT cycles administered was 12.14 ± 4.00. The response rate to CNS after IT treatment + SOC was 71.4%, and three patients (42.8%) obtained durable responses lasting more than 12 months. The median progression-free survival (mPFS) after LM diagnosis was six months, and the median overall survival (mOS) was ten months. The mean values of the PFS in favor of IT therapy (10.6 mo vs. 6.6 mo) and OS (13.7 vs. 9.3 mo) suggest a non-negligible investigation direction in the sense of exploiting intrathecal administration as a possible treatment modality in these patients. Adverse events reported were local pain related to intrathecal administration and one case of arachnoiditis, hematoma, and CSF fistulae. Intrathecal administration of Trastuzumab, alongside systemic treatment and radiotherapy, might improve oncologic outcomes in LM HER2-positive breast cancer with manageable toxicity.

In 2021, the 5th edition of the WHO Classification of Tumors of the Central Nervous System (WHO-CNS5) was published as the sixth volume of the international standard for brain and spinal cord tumor classification. The most remarkable practical change in the current classification involves grading gliomas according to molecular characterization. IDH mutant (10%) and IDH wild-type tumors (90%) are two different entities that possess unique biological features and various clinical outcomes regarding treatment response and overall survival. This article presents two comparative cases that highlight the clinical importance of these new classification standards. The first clinical case aimed to provide a comprehensive argument for determining the IDH status in tumors initially appearing as low-grade astrocytoma upon histologic examination, thus underlining the importance of the WHO-CNS5. The second case showed the implications of the histologic overdiagnosis of glioblastoma using the previous classification system with a treatment span of 7 years that proceeded through full-dose re-irradiation up to metronomic therapy. The new WHO-CNS5 classification significantly impacted complex neurooncological cases, thus changing the initial approach to a more precise therapeutic management.

While GH may play a role in malignancy progression (enhancing promitogenic and antiapoptotic properties), it does not seem to induce malignancy (7). Complications of acromegaly, such as increased intestinal size or diabetes are other risk factors for malignancy (8). However, the risk of malignancies in acromegaly remains controversial. Epidemiological studies show diverging results. Up to 2016, a modestly increased cancer risk was reported, especially for colon and thyroid neoplasms (9)(10)(11)(12). Several studies have since then reported an increased cancer risk (10)(11)(12)(13)(14)(15)(16), while others have not (17) -see Table 1. A recent meta-analysis revealed an increased risk of gastric, breast, and urinary tract cancers (18). From an epidemiological perspective, conflicting data could be explained by study limitations such as the low number of patients, surveillance bias, the lack of adjustment of confounding variables, the heterogeneity of control groups (general population/other pituitary adenomas), and inaccuracies in comparison older and more recent studies due to timedepended changes in life expectancy, modifications in cancer.The current Frontiers in Endocrinology topic collection presents real-life data from several large cohorts of acromegaly patients. Advances in acromegaly treatment have led to a greater potential to achieve disease control by decreasing the GH and IGF-I burden and improving followup care which may reduce cancer risk (19). Furthermore, the overall increased awareness of acromegaly, with decreasing diagnostic delay, and increasing incidence rate of patients with a milder phenotype of acromegaly, possibly also affect the cancer risk (20)(21)(22).Data from the Danish nationwide AcroDEN cohort (739 patients treated since 1990) demonstrate improved diagnostics, with a continual increase in the likelihood of being diagnosed and treated for conditions such as diabetes, heart disease, sleep apnea, joint disease, and osteoporosis (23). Also, an increased proportion of patients achieving hormonal disease control was reported (69% to 88%). The risk of being diagnosed with cancer did in contrast not significantly change, with an overall cancer risk of 1.1 (10) and a mortality rate of 1.3, mainly attributed to cardiovascular mortality (9,10).Rolla M et al. assessed acromegaly's complications at a referral center in Poland. In a series of 179 patients (1976-2018), 40% were cured by surgery, and 31% were pharmacologically controlled. During 496 hospitalizations, 43 colonoscopies were performed, and 21 colonic polyps were discovered (11.7% of cases). Despite the frequent use of thyroid ultrasound (198/496 hospitalizations) and a high proportion of goiter (52%), only two cases of thyroid cancer were diagnosed (24). A similar low risk of thyroid cancer in acromegaly was reported from the AcroDEN cohort (10,24) The effect of modern treatment was further reported by Galoiu S et al. from a referral center in Romania, including 399 acromegaly (2001-2022). The surgical cure rate was 31% and the pharmacologically controlled was 22%. The standardized mortality rate (SMR) was 1.18, and decreased (from SMR=1.25) to a level comparable to the reference population (SMR=1.09) in patients diagnosed after 2008. Males had a lower mortality ratio (SMR=0.99), compared to females with acromegaly (SMR=1.63) (25). Several studies have reported a similar trend, with decreasing mortality and a shift in the causes of death resembling those of the reference population (21). In the AcroDEN cohort, the mortality was slightly increased (SIR=1.3), whereas cancer-specific mortality was not (10).The incidence of benign tumors is increased in acromegaly (SIR=2.4) (15). Guo et al. conducted a systematic review of 24 studies on the prevalence of meningiomas in patients with acromegaly or those exposed to exogenous GH therapy. Meningiomas occurred either synchronous or metachronous with acromegaly; no significant correlation was found between GH/IGF-1 levels and meningioma size; some patients with acromegaly and meningiomas were treated with radiotherapy, which is known to increase the risk of developing a second brain tumor (26) In four cases of acromegaly with meningiomas, without previous radiotherapy, there was a family history of pituitary adenomas and cancers. The authors suggest that hereditary cancer syndromes might play a role in the co-occurrence of acromegaly and meningiomas (27). Whereas skin cancer risk is not increased in acromegaly (18), skin lesions were more frequently observed in acromegaly compared to patients with non-functioning pituitary adenomas. There was an improvement of these skin lesions three months after surgery in younger patients and patients who presented with the highest GH levels (28).In summary, acromegaly is associated with an increased risk of certain types of cancers, although the specific evidence remains controversial. Early diagnosis and advances in the treatment of acromegaly improved disease control and decreased mortality rates. Current data do not justify extensive cancer screening beyond standard guidelines, although clinical attention is crucial[JD1], especially in elderly patients (13,29), in patients with a longer disease duration (14,30), and in acromegaly patients with diabetes mellitus [JD2][CV3][CV4](30) Large studies with long follow-up are needed to further understand the impact of GH excess on cancer risk and to refine screening protocols.