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We investigate the prognostic role of pre-treatment ratio between Type 1 (M1) and Type 2 (M2) tumor-associated macrophages (TAMs) in locally advanced cervical cancer (LACC) patients treated with chemoradiation (CT/RT). 84 consecutive LACC patients treated with cisplatin-based CT/RT for a total dose of 50.0 Gy, followed by radical surgery were analysed. Double-staining immunohistochemistry of CD163/p-STAT, CD68/pSTAT1, CD163/c-MAF, and CD68/c-MAF was performed on tumor samples taken at the time of diagnosis. TAMs with CD163+pSTAT1+, or CD68+pSTAT1+ were defined M1; CD163+c-MAF+ or CD68+c-MAF+ defined the M2 phenotype. The number of M1 and M2 cells was counted at low magnification by evaluating for each case the same tumour area. The ratio between M1 and M2 (M1/M2) was finally calculated. At diagnosis, we observed a direct correlation between the number of circulating monocytes and of TAMs (p-value = 0.001). Patients with high M1/M2 experienced more frequently complete pathologic response (no residual tumor) to CT/RT, compared to cases with low M1/M2 (55.0% Vs 29.5%; p-value = 0.029). At multivariate analysis M1/M2 (OR = 2.067; p-value = 0.037) emerged as independent predictor of pathologic response to CT/RT. Women with high M1/M2 showed a longer 5-yrs Disease-free (67.2% Vs. 44.3%; p-value = 0.019), and 5-yrs Overall (69.3% Vs. 46.9%; p-value = 0.037) survival, compared to cases with low M1/M2. The presence of a high M1/M2 ratio was independently associated with an unfavourable survival outcome in multivariate analysis. Polarisation of TAMs toward a M2 phenotype, as reflected by a lower M1/M2 ratio, is an independent predictor of poor response to CT/RT, and shorter survival in LACC.

Objective To evaluate plasma phosphorylated neurofilament heavy chain (pNF‐H) as a biomarker in spinal muscular atrophy (SMA). Methods Levels of pNF‐H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease. Results Median pNF‐H plasma level was 167.0 pg/mL (7.46–7,030; n = 34) in children without SMA (aged 7 weeks–18 years) and was higher in those aged < 1 versus 1–18 years (P = 0.0002). In ENDEAR participants with infantile‐onset SMA, median baseline pNF‐H level (15,400 pg/mL; 2390–50,100; n = 117) was ~10‐fold higher than that of age‐matched infants without SMA (P < 0.0001) and ~90‐fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF‐H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF‐H levels: nusinersen‐treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control–treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. Interpretation Plasma pNF‐H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF‐H levels followed by relative stabilization. Together these data suggest plasma pNF‐H is a promising marker of disease activity/treatment response in infants with SMA.

Objective: The aim of this meta-analysis was to discuss evidence supporting the efficacy of adjuvant human papillomavirus (HPV) vaccination in reducing the risk of recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical treatment. Methods: A systematic literature search was performed for studies reporting the impact of HPV vaccination on reducing the risk of recurrence of CIN 2+ after surgical excision. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). Results: Eleven studies met the inclusion criteria and were selected for analysis. In total, 21,310 patients were included: 4039 (19%) received peri-operational adjuvant HPV vaccination while 17,271 (81%) received surgery alone. The recurrence of CIN 2+ after treatment was significantly lower in the vaccinated compared with the unvaccinated group (OR 0.35; 95% CI 0.21–0.56; p < 0.0001). The recurrence of CIN 1+ after treatment was significantly lower in the vaccinated compared with the unvaccinated group (OR 0.51; 95% CI 0.31–0.83; p = 0.006). A non-significant trend of reduction rate of HPV persistence was observed in the vaccinated compared with the unvaccinated cohorts (OR was 0.84; 95% CI 0.61–1.15; p = 0.28). Conclusions: HPV vaccination, in adjuvant setting, is associated with a reduced risk of recurrent CIN 1+ and CIN 2+ after surgical treatment.

Adipose-derived stem cells (ADSCs) are promising in regenerative medicine. Their proliferation, survival and activation are influenced by specific signals within their microenvironment, also known as niche. The stem cell niche is regulated by complex interactions between multiple cell types. When transplanted in a specific area, ADSCs can secrete several immunomodulatory factors. At the same time, a tumor microenvironment can influence stem cell behavior, modulating proliferation and their ability to differentiate into a specific phenotype. Whitin this context, we exposed ADSCs to plasma samples derived from human patients diagnosed with prostate cancer (PC), or precancerous lesions (PL), or benign prostatic hyperplasia (BPH) for 4, 7 or 10 days. We then analyzed the expression of main stemness-related markers and cell-cycle regulators. We also measured cytokine production and polyamine secretion in culture medium and evaluated cell morphology and collagen production by confocal microscopy. The results obtained from this study show significant changes in the morphology of ADSCs exposed to plasma samples, especially in the presence of prostate cancer plasma, suggesting important implications in the use of ADSCs for the development of new treatments and application in regenerative medicine.

Stem cell pluripotency gene Sox2 stimulates expression of proneural basic-helix-loop-helix transcription factor Atoh1 . Sox2 is necessary for the development of cochlear hair cells and binds to the Atoh1 3’ enhancer to stimulate Atoh1 expression. We show here that Sox2 deletion in late embryogenesis results in the formation of extra hair cells, in contrast to the absence of hair cell development obtained after Sox2 knockout early in gestation. Sox2 overexpression decreased the level of Atoh1 protein despite an increase in Atoh1 mRNA. Sox2 upregulated E3 ubiquitin ligase, Huwe1 , by direct binding to the Huwe1 gene. By upregulating its cognate E3 ligase, Sox2 disrupts the positive feedback loop through which Atoh1 protein increases the expression of Atoh1 . We conclude that Sox2 initiates expression, while also limiting continued activity of bHLH transcription factor, Atoh1, and this inhibition represents a new mechanism for regulating the activity of this powerful initiator of hair cell development.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Background A long-term prospective assessment of QoL in cervical cancer patients is still lacking. Here, we provide the first 2-years prospective, longitudinal study evaluating emotional distress and QoL in early stage (ECC) and locally advanced (LACC) cervical cancer patients who remained disease-free 2-years from diagnosis. Methods The questionnaires: Hospital Anxiety and Depression Scale (HADS), Global Health Status items of EORTC QLQ-C30 (GHS), and EORTC QLQ-CX24 (CX24) have been administered by a dedicated team of psycho-oncologists, administered at baseline, and after 3, 6, 12 and 24 months from surgery The Generalized Linear Model for repeated measure was used to analyze modifications of QoL measures over time. Results In both groups, an early reduction of the percentage of patients with anxiety levels ≥11 was observed at the 3-month evaluation (ECC: 25.7% at baseline Vs 14.7% after 3 months, p value=0.001; LACC: 22.2% at baseline Vs 15.4% after 3 months, p value=0.001). Despite this favorable trend, after 2 years from diagnosis, 11.9% of ECC and 15.6% of LACC patients still showed an anxiety score ≥11. No significant changes over time were observed in term of Depression levels. Focusing on QoL issues, mean GHS and Sexual Activity scores showed an improvement over time in both groups compared to baseline (GHS: 5.7% difference for ECC, p value=0.001, and 11.0% in LACC, p value=0.001; SXA: 13.9% difference for ECC, p value=0.001; and 6.1% in LACC, p value=0.008). On the other hand, Body Image mean scores were significantly impaired by chemoradiation administration in LACC patients, without long-term recovery (7.5% difference, p value=0.001). Finally, in both groups, lymphedema (LY) and menopausal symptoms (MS) showed an early worsening which persisted 2-year after surgery (LY: 19.5% difference for ECC, p value=0.014, and 27.3% in LACC, p value=0.001; MS: 14.4% difference for ECC, p value=0.004, and 16.0% in LACC, p value=0.002). Conclusions Despite a significant improvement over time, elevated anxiety levels are still detectable at 24 months after surgery in approximately 10% of cervical cancer patients. Much more attention should be focused on surgical/medical approaches able to minimize the negative impact of lymphedema and menopausal symptoms on QoL.

Background and Objectives: Ectopic pregnancy (EP) is a life-threatening medical and surgical condition. Tubal stump EPs and heterotopic pregnancies can occur after in vitro fertilization-embryo transfer (IVF-ET), even after salpingectomy. The purpose of this study is to investigate the risk factors, diagnosis, and treatment of tubal stump EPs after IVF-ET in patients with prior salpingectomy or adnexectomy. We also aim to evaluate the intrauterine pregnancy (IUP) outcome in cases of heterotopic pregnancy in this population. Materials and Methods: This systematic review (PROSPERO CRD42023352959) followed PRISMA guidelines. A literature search of MEDLINE®, Scopus, Web of Science, and clinicaltrials.gov was conducted on 30 April 2024. We included studies on tubal stump EP after IVF-ET in patients with previous salpingectomy or adnexectomy and created a qualitative summary. Results: We included 40 studies reporting on 57 patients (58 EP episodes). Most patients (69.0%) had prior bilateral salpingectomy. Tubal rupture occurred in 69.6% of cases, with 69.0% of these cases reporting hemoperitoneum. Abdominal pain was the most frequent symptom (71.7%). Heterotopic pregnancy occurred in 60.0% of cases (82.7% singletons). The IUP outcome was delivery in 81.9% of cases, with 95.5% of singletons delivering at term, compared with 40.0% of twins. The surgical approach (laparoscopy vs. laparotomy) did not change the IUP outcome. Tubal stump excision (74.1%) was the most common treatment. Overall, the certainty of the evidence was judged as moderate to very low according to the GRADE-CERQual approach, mainly due to small sample sizes, observational designs, and heterogeneity among studies. Conclusions: This review, the first on this topic, provides key data for counselling patients with a tubal stump heterotopic pregnancy. Despite its rarity, close follow-up until 8–10 weeks is recommended for IVF-ET patients with positive β-hCG, monitoring for abdominal pain. Successful management (expectant, medical, or surgical) should be guided by β-hCG levels and ultrasound findings (e.g., absence of heartbeat). Medical treatment shows encouraging obstetric outcomes and warrants further research.

Background This study investigated the feasibility and safety of laparoscopic splenectomy conducted in the contexts of both laparoscopic secondary surgery for isolated recurrence in the spleen and primary laparoscopic cytoreductive surgery for advanced ovarian cancer. Methods We performed a perspective observational study including all consecutive patients with ovarian cancer who underwent laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer or secondary surgery for isolated splenic recurrence between January 2016 and May 2020. Results We enrolled 13 consecutive patients, candidate to laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer (6 patients) or secondary surgery for isolated splenic recurrence of platinum-sensitive ovarian cancer (7 patients). Median operative time (509 min [range, 200–845]) for primary cytoreductive surgery varied according to surgical complexity depending on the extensiveness of the disease. Median operative time for secondary surgery for isolated splenic metastasis was 253 min (90–380). Only 1 patient with isolated splenic recurrence required conversion to an open approach. No intraoperative complication occurred, and no intraoperative blood transfusions were required. Median hospital stay was 3 days (range, 2–5) for isolated recurrence and 9 days (7–18) for primary cytoreductive surgery. Complete tumor resection was achieved in all patients. Median time from surgery to adjuvant chemotherapy was 16 days (7–24). All six patients who underwent laparoscopic splenectomy during primary cytoreductive surgery remain alive, four of whom exhibit no evidence of disease (median follow-up 25 months [4–36]). Among patients who underwent laparoscopic splenectomy during secondary surgery for isolated splenic relapse, all patients are alive and only one had a central diaphragmatic relapse 2 years after surgery (median follow-up 17 months ([5–48 months]). Conclusions The laparoscopic approach to splenectomy is feasible and safe both in patients undergoing primary cytoreductive surgery for advanced stage disease and those with isolated recurrence of ovarian cancer, without compromising survival and allowing early initiation of postoperative systemic chemotherapy.

The spiral ganglion neurons constitute the primary connection between auditory hair cells and the brain. The spiral ganglion afferent fibers and their synapse with hair cells do not regenerate to any significant degree in adult mammalian ears after damage. We have investigated gene expression changes after kainate-induced disruption of the synapses in a neonatal cochlear explant model in which peripheral fibers and the afferent synapse do regenerate. We compared gene expression early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration. These analyses revealed a total of 2.5% differentially regulated transcripts (588 out of 24,000) based on a threshold of p<0.005. Inflammatory response genes as well as genes involved in regeneration of neural circuits were upregulated in the spiral ganglion neurons and organ of Corti, where the hair cells reside. Prominent genes upregulated at several time points included genes with roles in neurogenesis (Elavl4 and Sox21), neural outgrowth (Ntrk3 and Ppp1r1c), axonal guidance (Rgmb and Sema7a), synaptogenesis (Nlgn2 and Psd2), and synaptic vesicular function (Syt8 and Syn1). Immunohistochemical and in situ hybridization analysis of genes that had not previously been described in the cochlea confirmed their cochlear expression. The time course of expression of these genes suggests that kainate treatment resulted in a two-phase response in spiral ganglion neurons: an acute response consistent with inflammation, followed by an upregulation of neural regeneration genes. Identification of the genes activated during regeneration of these fibers suggests candidates that could be targeted to enhance regeneration in adult ears.