An Update on Appendiceal Neuroendocrine Tumors

The mainstay of appendiceal neuroendocrine neoplasm (aNEN) treatment is surgery, based on simple appendectomy or right-sided hemicolectomy with lymphadenectomy (RHC). The majority of aNENs are adequately treated with appendectomy, but current guidelines have poor accuracy in terms of selecting patients requiring RHC, especially in aNENs 1–2 cm in size. Simple appendectomy is curative for appendiceal NETs (G1–G2) < 1 cm (if the resection status is R0), whereas RHC with lymph node dissection is recommended in tumors ≥ 2 cm in diameter, based on the high risk of nodal metastases in these cases. The clinical management of aNENs 1–2 cm in size is more controversial because lymph node or distant metastases are uncommon but possible. In our opinion, patients with tumor size > 15 mm or with grading G2 (according to WHO 2010) and/or lympho-vascular invasion should be referred for radicalization with RHC. However, decision-making in these cases should include discussion within a multidisciplinary tumor board at referral centers with the aim of offering each patient a tailored treatment, also considering that relatively young patients with long-life expectancy represent the majority of cases

Prognostic Factors of Survival for High-Grade Neuroendocrine Neoplasia of the Bladder: A SEER Database Analysis

Background: High-grade neuroendocrine carcinoma (NEC) is a rare and aggressive variant of bladder cancer. Considering its rarity, its therapeutic management is challenging and not standardized. Methods: We analyzed data extracted from the Surveillance, Epidemiology, and End Results (SEER) registry to evaluate prognostic factors for high-grade NEC of the bladder. Results: We extracted data on 1134 patients: 77.6% were small cell NEC, 14.6% were NEC, 5.5% were mixed neuro-endocrine non-neuroendocrine neoplasia, and 2.3% were large cell NEC. The stage at diagnosis was localized for 45% of patients, lymph nodal disease (N+M0) for 9.2% of patients, and metastatic disease for 26.1% of patients. The median overall survival (OS) was 12 months. Multivariate analysis detected that factors associated with worse OS were age being >72 years old (HR 1.94), lymph nodal involvement (HR 2.01), metastatic disease (HR 2.04), and the size of the primary tumor being >44.5 mm (HR 1.80). In the N0M0 populations, the size of the primary tumor being <44.5 mm, age being <72 years old, and major surgery were independently associated with a lower risk of death. In the N+M0 group, the size of the primary lesion was the only factor to retain an association with OS. Conclusions: Our SEER database analysis evidenced prognostic factors for high-grade NEC of the bladder that are of pivotal relevance to guide treatment and the decision-making process

Estudio comparativo de la síntesis de ADN en hígado y riñón de ratones lactantes y adultos

In previous papers we have observed that the proliferative activity of numerous cell populations of suckling and young mice was different than the observed in adults. In the present work we analized the DNA synthesis of suckling and adult mice, by immunohistochemistry (Bromodioxiuridine) in both hepatocytes and renocytes, at two different time points. The object of the present experiment was to establish the correlation in cellular proliferation between both groups. We used C3HS suckling male mice of 21 days old and adult mice of 90 days old. The results showed that DNA synthesis of renocytes and hepatocytes in suckling mice were significantly higher than the adults, and we didn't find statistically differences between the values of both analysed time points. We can conclude that in suckling mice we could observe maximum and minimum values but we coudn't find a circadian rhythm like those established in adults.En trabajos previos hemos observado que la actividad proliferativa de numerosas poblaciones celulares del ratón lactante y joven difiere de la encontrada en el adulto. En el presente trabajo experimental, se estudia la síntesis de ADN del ratón lactante y adulto, mediante el método inmunohistoquímico de la Brdu (Bromodeoxiuridina), en las poblaciones celulares de hepatocitos y renocitos, a las OO:O0 h y 16:00 h, con el objeto de establecer la correspondencia en la proliferación celular entre ambos grupos etarios. Para ello se utilizaron machos lactantes de 21 días de edad y adultos de 90 días, de la cepa C3H/S. Los resultados muestran que los valores de síntesisde ADN de los renocitos y hepatodtos en los ratones lactantes son significativamente mayores (p<O.001) a los observados en los adultos, no encontrándose diferencias estadísticamente significativas entre los valores de ambos puntos horarios en los órganos estudiados. Podemos concluir que estos hallazgos demuestran que, si bien en los ratones lactantes aparecen valores máximos y mínimos en la actividad proliferativa de distintas poblaciones celulares, estas aún no presentan la ritmicidad establecida para los adultos

Large Cell Neuroendocrine Carcinoma of the Lung: Current Understanding and Challenges

Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare and highly aggres-sive type of lung cancer, with a complex biology that shares similarities with both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). The prognosis of LCNEC is poor, with a median overall survival of 8–12 months. The diagnosis of LCNEC requires the identification of neuroendocrine morphology and the expression of at least one of the neuroendocrine markers (chromogranin A, synaptophysin or CD56). In the last few years, the introduction of next-generation sequencing allowed the identification of molecular subtypes of LCNEC, with prognostic and potential therapeutic implications: one subtype is similar to SCLC (SCLC-like), while the other is similar to NSCLC (NSCLC-like). Because of LCNEC rarity, most evidence comes from small retrospective studies and treatment strategies that are extrapolated from those adopted in patients with SCLC and NSCLC. Nevertheless, limited but promising data about targeted therapies and immune checkpoint inhibitors in patients with LCNEC are emerging. LCNEC clinical management is still controversial and standardized treatment strategies are currently lacking. The aim of this manuscript is to review clinical and molecular data about LCNEC to better understand the optimal management and the potential prognostic and therapeutic implications of molecular subtypes

Lymph node ratio predicts efficacy of postoperative radiation therapy in nonmetastatic Merkel cell carcinoma: A population-based analysis

Background: After radical resection of a nonmetastatic Merkel cell carcinoma (M0 MCC), postoperative radiation therapy (RT) is recommended as it improves survival. However, the role of RT in specific subgroups of M0 MCC is unclear. We sought to identify whether there is a differential survival benefit from RT in specific M0 MCC patient subgroups. Methods: M0 MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database registry were collected. The best prognostic age, tumor size, and lymph node ratio (LNR, ratio between positive lymph nodes and resected lymph nodes) cutoffs were calculated. The primary endpoint was overall survival (OS). Results: A total of 5644 M0 MCC patients (median age 77 years, 62% male) were included: 4022 (71%) node-negative (N0) and 1551 (28%) node-positive (N+). Overall,&nbsp;2682 patients (48%) received RT. Age &gt; 76.5 years, tumor size &gt;13.5 mm, and LNR &gt;0.215 were associated with worse OS. RT was associated with longer OS in the M0 MCC, N0, and N+ group and independently associated with a 25%, 27%, and 26% reduction in the risk for death, respectively. RT benefit on survival was increased in tumor size &gt;13.5 mm in the N0 group and LNR &gt;0.215 in the N+ group. No OS benefit from RT was observed in T4 tumors (N0 and N+ groups). Conclusions: RT was associated with improved survival in M0 MCC, irrespective of the nodal status. LNR &gt;0.215 is a useful prognostic factor for clinical decision-making and for stratification and interpretation of clinical trials

Efficient activation of telecom emitters in silicon upon ns pulsed laser annealing

The recent demonstration of optically active telecom emitters makes silicon a compelling candidate for solid state quantum photonic platforms. Particularly fabrication of the G center has been demonstrated in carbon-rich silicon upon conventional thermal annealing. However, the high-yield controlled fabrication of these emitters at the wafer-scale still requires the identification of a suitable thermodynamic pathway enabling its activation following ion implantation. Here we demonstrate the efficient activation of G centers in high-purity silicon substrates upon ns pulsed laser annealing. The proposed method enables the non-invasive, localized activation of G centers by the supply of short non-stationary pulses, thus overcoming the limitations of conventional rapid thermal annealing related to the structural metastability of the emitters. A finite-element analysis highlights the strong non-stationarity of the technique, offering radically different defect-engineering capabilities with respect to conventional longer thermal treatments, paving the way to the direct and controlled fabrication of emitters embedded in integrated photonic circuits and waveguides

Targeted Genomic Profiling and Chemotherapy Outcomes in Grade 3 Gastro-Entero-Pancreatic Neuroendocrine Tumors (G3 GEP-NET)

Background: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. Methods: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. Results: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p &lt; 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). Conclusions: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs