Cell Carcinoid Research Articles

Metastatic pituitary lesion

Metastatic lesion of pituitary is a rare condition and is diagnosed in 1.8-4% of cases. Monitoring and treatment of such patients is a complex task and requires increased attention from a multidisciplinary team of specialists. The authors represent three patients with metastatic pituitary lesion who underwent neurosurgical treatment at the National Research Center of the National Research Institute of Endocrinology with subsequent pathomorphological confirmation of the diagnosis. The primary tumors were breast cancer, lung carcinoid, and clear cell kidney cancer. Two patients had distant metastases other than the pituitary gland. The clinical manifestation consisted in the appearance of symptoms of panhypopituitarism, chiasmal syndrome and mass effect in all cases. The follow-up period after surgical treatment was 0.25-2.5 years. Progression of the underlying disease was noted in two patients. One of them carried out stereotactic radiosurgical treatment and stereotactic oriented irradiation. One patient has a stable condition.

Prognostic thresholds of fluorine-18 fluorodeoxyglucose-positron emission tomography mean and maximum standardized uptake values for survival and nodal involvement in lung neuroendocrine neoplasms.

The mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose-positron emission tomography are prognostic biomarkers for survival and nodal involvement in non-small-cell lung cancer but their prognostic value in lung neuroendocrine neoplasms (NENs) remains unexplored. In this study, we aimed to examine whether they are also prognostic biomarkers for survival and nodal involvement in lung NENs. We retrospectively studied patients with typical carcinoid, atypical carcinoid or large cell neuroendocrine carcinoma who had been radically resected at our institution between 2008 and 2020. We measured SUVmean and SUVmax on all primary tumours and lymph nodes that were clinically and/or pathologically involved. We dichotomized the patients into groups of high or low SUVmean and SUVmax of the primary tumour using time-dependent receiver operating characteristic curves and compared their overall survival using Kaplan-Meier curves and Cox models. Lastly, we predicted the patients' pathological nodal status with SUVmean and SUVmax of the lymph nodes using binomial logistic models. The study included 245 patients. Patients died earlier if their SUVmean of the primary tumour exceeded 3.9 [hazard ratio 1.97, 95% confidence interval (CI) 1.27-3.04, P = 0.002] or SUVmax exceeded 5.3 (hazard ratio 1.85, 95% CI 1.20-2.87, P = 0.006). Likewise, patients had a higher risk of pathological nodal involvement if their SUVmean of the lymph nodes exceeded 3.3 (odds ratio 10.00, 95% CI 2.59-51.01, P = 0.002) or SUVmax exceeded 4.2 (odds ratio 4.00, 95% CI 1.20-14.65, P = 0.028). The fluorine-18 fluorodeoxyglucose-positron emission tomography SUVmean and SUVmax are strong prognostic biomarkers for survival and nodal involvement in lung NENs and could be important guides for making treatment decisions.

Small Cell Lung Cancer and Pleural Effusion: An Analysis from a District General Hospital.

The incidence of malignant pleural effusion (MPE) in patients with small cell lung cancer (SCLC) in an American population is approximately 11%, and overall survival in that group is 3 months (compared to 7 months without an effusion. To our knowledge, no study has been done in the United Kindgom and we thus sought to determine the characteristics of the local population. All patients coded as having small cell lung cancer from Somerset register from January 2012-September 2021 were reviewed. We excluded those with indeterminate pathology reports, carcinoid or large cell neuroendocrine cancers. Basic demographics, presence of an MPE and any interventions and outcomes were collected for descriptive analysis. Continuous variables are presented as mean (±) range, median (± IQR) when outliers were present and categorical variables as percentages where appropriate. Caldicott reference C3905. Four hundred one patients with SCLC were identified (11% of all patients, median time to death from presentation 208days, IQR 304 [many outliers); 224 (55.9%) were female, 177 male [median age 75years, IQR 13]. One hundred seven (27%) presented with an effusion: 23 were sampled, 10 had positive cytology, all were exudates, 8 required chest drainage, the mean performance status (PS) was 2 (range 1-4) and the median time to death 142days, IQR 45. Of the 294 with no initial effusions, 70 (24%) developed a pleural effusion with progressive disease (mean PS 1, median age 71.5years, IQR 14, median to death 327days, IQR 395, 1 outlier); 224 patients never had a MPE with a median time to death of 212 days, IQR 305, multiple outliers and, when compared to those with a MPE at any point, median time to death was 211days, IQR 295.5 (multiple outliers). Meaningful analysis was difficult because of the presence of multiple outliers in values collected and not correcting for stage at presentation or treatment modalities and previous studies did not correct for those either. Those presenting with an MPE had a poorer prognosis, probably signifying advanced disease and the presence of MPE in our SCLC cohort seems higher. Large prospective databases for this are required.

Bacterial extracellular vesicles induced oxidative stress and mitophagy through mTOR pathways in colon cancer cells, HT-29: Implications for bioactivity

Bacterial-extracellular-vesicles (BEVs) derived from Escherichia coli, strain-A5922, were used as a therapeutic tool to treat colon cancer cells, HT-29. BEVs induced oxidative stress, and observed mitochondrial autophagy, known as mitophagy, were crucial in initiation of treatment. The mitophagy, induced by the BEVs in HT-29 cells, produced adenocarcinomic cytotoxicity, and stopped the cells growth. The trigger for mitophagy, and an increase in productions of reactive oxygen species led to cellular oxidative stress, that eventually led to cells death. A reduction in the mitochondrial membrane potential, and an increase in the PINK1 expressions confirmed the oxidative stress involvements. The BEVs triggered cytotoxicity, and mitophagy in the HT-29 carcinoid cells, channelized through the Akt/mTOR pathways connecting the cellular oxidative stress, effectively played its part to cause cells death. These findings substantiated the BEVs' potential as a plausible tool for treating, and possibly preventing the colorectal cancer.

Lung neuroendocrine neoplasms: a single centre surgical series and analysis of staging.

To review the outcomes of surgically resected lung neuroendocrine neoplasms (LNEN) at a tertiary referral centre and to validate a previously published LNEN-specific staging system (NETL). All patients who were identified on histopathology to have LNEN were included. Pre-, intra- and post-operative outcomes were collected, including long-term survival. Patients were staged by both the TNM (seventh and eighth edition) and NETL staging (seventh and eighth edition definitions). Kaplan-Meier (KM) survival analysis was performed according to histopathology and stage, along with uni- and multivariate analyses. A total of 132 patients were included in the study, with a median age of 65 years; 55% were female. Typical carcinoid (TC) was the most common pathology (53.4%) followed by large cell neuroendocrine carcinoma (LCNEC - 23.5%), atypical carcinoid (AC - 20.5%) and small cell carcinoma (3.0%). The most common operation performed was a lobectomy (55.3%). Overall survival at 5 years was 80% (100% TC, 78.2% AC, LCNEC 40.9%) and 5-year disease free survival was 76.8% (TC 94.3%, AC 56.8%, LCNEC 56.4%). KM curves showed a trend towards NETL performing better than TNM, however, in multivariate analysis only the histological subtype was found to be significant in our study. This is the largest known Australian series of LNEN to date, showing survival comparable to international outcomes. We have demonstrated large variations in outcome, driven by histological grade. The TNM system does not correlate with survival and we have not been able to show that currently proposed NETL staging is superior.

Abstract 5034: Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas

Abstract Introduction/Background: Atypical lung carcinoids and lung neuroendocrine carcinomas (NECs) are currently incurable. Most of these cancers express the C-X-C chemokine receptor 4 (CXCR4), making CXCR4 an attractive target for cancer diagnosis and treatment using radioligand therapy (RLT) with nuclides such as alpha emitter Pb212 conjugated to Pentixather (Pent). Alpha particles produce dense ionization tracks and damage cytosolic structures such as mitochondria, leading to the generation of reactive oxygen species such as superoxide (O2 ●−) and hydroperoxides (H2O2 and ROOH) in targeted cancer cells. The FDA approved thioredoxin reductase inhibitor, auranofin (Aur), inhibits peroxiredoxin-mediated hydroperoxide metabolism increasing cell killing in targeted cancer cells. Hypothesis: Inhibition of hydroperoxide metabolism using Aur can enhance therapeutic efficacy of alpha particle emitting 212Pb-Pent in preclinical models of lung carcinoids and NECs. Results: Clinically, IHC revealed greater than 75% of atypical carcinoids and NECs tested had moderate to high CXCR4. qRT-PCR, flow cytometry and immunohistochemistry performed on different lung carcinoid and NEC lung cell lines, determined that the majority moderately or highly express CXCR4. The minimal non-toxic dose of Aur that inhibits 50-70% of thioredoxin reductase activity was 4 mg/kg (intraperitoneal once a day) in DMS273 (small cell lung cancer) xenografts 212Pb-Pent given IV (1 and 3 µCu/g) was effective at increasing the survival of mice with DMS273 xenografts. Mice were then treated with 1.5, 3 or 6 µCu/g 212Pb-Pent w/wo Aur 4 mg/kg/day. A trend test showed that both increasing dose of 212Pb-Pent and the addition of Aur, caused a significant (p<0.01) delay in tumor growth. There were no significant changes in body weights, complete blood counts, and serum alanine aminotransferase indicating the combination treatments were well tolerated. Radiation dosimetry estimates using quantitative SPECT/CT imaging with Pb203-Pent demonstrated average absorbed doses of 0.133 Gy/µCi (liver), 0.098 Gy/µCi (kidneys), 0.013 Gy/µCi (H292 xenografts), 0.028 Gy/µCi (DMS53 xenografts), 0.057 Gy/µCi (DMS273 xenografts), and 0.096 Gy/µCi (H69AR xenografts). Xenograft absorbed dose levels were positively correlated with CXCR4 expression. Conclusion: The use of 212Pb-Pent therapy to target CXCR4 on NECs showed pre-clinical efficacy in a dose dependent manner that was enhanced by Aur without significant normal tissue toxicity supporting the hypothesis that CXCR4 can be successfully targeted with the radionuclide theragnostic pair, Pb212/Pb203-pentixather. Citation Format: Melissa A. Fath, Dijie Liu, Claudia Robles-Planells, Jordan T. Ewald, Keegan A. Christensen, Spenser S. Johnson, Stephen A. Graves, Douglas R. Spitz, Yusuf Menda, M. Sue O’Dorisio. Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5034.

Feasibility of shape-sensing robotic-assisted bronchoscopy for biomarker identification in patients with thoracic malignancies

ObjectiveMolecular diagnostic assays require samples with high nucleic acid content to generate reliable data. Similarly, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) requires samples with adequate tumor content. We investigated whether shape-sensing robotic-assisted bronchoscopy (ssRAB) provides adequate samples for molecular and predictive testing. MethodsWe retrospectively identified diagnostic samples from a prospectively collected database. Pathologic reports were reviewed to assess adequacy of samples for molecular testing and feasibility of PD-L1 IHC. Tumor cellularity was quantified by an independent pathologist using paraffin-embedded sections. Univariable and multivariable linear regression models were constructed to assess associations between lesion- and procedure-related variables and tumor cellularity. ResultsIn total, 128 samples were analyzed: 104 primary lung cancers and 24 metastatic lesions. On initial pathologic assessment, ssRAB samples were deemed to be adequate for molecular testing in 84% of cases; on independent review of cellular blocks, median tumor cellularity was 60% (interquartile range, 25%-80%). Hybrid capture-based next-generation sequencing was successful for 25 of 26 samples (96%), polymerase chain reaction-based molecular testing (Idylla; Biocartis) was successful for 49 of 52 samples (94%), and PD-L1 IHC was successful for 61 of 67 samples (91%). Carcinoid and small cell carcinoma histologic subtype and adequacy on rapid on-site evaluation were associated with higher tumor cellularity. ConclusionsThe ssRAB platform provided adequate tissue for next-generation sequencing, polymerase chain reaction-based molecular testing, and PD-L1 IHC in >80% of cases. Tumor histology and adequacy on intraoperative cytologic assessment might be associated with sample quality and suitability for downstream assays.

Pulmonary Tumourlets: Case Report and Review of Literature

We report a case of tumourlets of the lung associated with carcinoid and neuroendocrine cell hyperplasia, found incidentally in a 30-year-old woman, who underwent bullectomy for pneumothorax. These lesions are histologically similar to carcinoid, but differ in molecular pathogenesis about which little is known. Their nature and significance is debated. Here, we point out the importance of histological, clinical, and diagnostic aspects and follow-up to have evidence of eventual malignant evolution.

Neuroendocrine tumor G3 of bronchopulmonary origin and its classification.

Neuroendocrine tumors (NET) with high proliferative activity (Ki-67 index >20% and/or mitotic counts >2 mm2 ) are defined as NET G3 in the 2019 World Health Organization (WHO) classification of digestive system neuroendocrine neoplasms (NENs). NETs G3 occur mostly in the pancreas, colon, rectum, and stomach and only rarely in the small intestine and the appendix. In the bronchopulmonary system, similar tumors have also been recognized and were mostly classified as atypical carcinoid (AC) or large cell neuroendocrine carcinoma. Bronchopulmonary NENs that were classified as NETs G3 are characterized by histological and immunohistochemical similarities with carcinoids/NETs, and a clinical course that is more aggressive than with ACs and similar to that of neuroendocrine carcinomas. The morphomolecular and clinical features of bronchopulmonary neoplasms with a high proliferative activity were reviewed and a future classification system that is applicable for both digestive and bronchopulmonary NETs is proposed.

Particular endoscopic presentation of multiple gastric ECLomas

66-year-old woman with no significant pathological history is admitted for etiologic assessment of anemia. It is an iron deficiency microcytic anemia with hemoglobin at 9.8g/dL. An upper digestive endoscopy showed multiple fundic polypoid lesions of variable size measuring more than 10mm, including a subcardial lesion measuring 20mm (Figure 1&2). With the presence of other antrals centimetrics polypoids lesions. The anatomopathological examination of the lesions is in favor of ECL (enterochromaffin like) cell carcinoids. Fundic biopsy revealed fundic atrophy consistent with Biermer's disease. The biological assessment showed a collapsed vitamin B12 level with the presence of anti parietal cell antibodies. The treatment is based on injectable iron infusions, vitamin B12 injections and taking proton pump inhibitors. supracentimetric polypoid lesions were resected endoscopically with regular endoscopic control of other small lesions. Gastric neuroendocrine tumors form a heterogeneous group, very largely dominated by tumors derived from so-called enterochromaffin-like (ECL) cells, endocrine cells specialized in the secretion of histamine and located within the fundic mucosa, at the deep part of the glands [1]. The vast majority of ECL cell tumors occur in a context of hypergastrinemia. It is most often a hypergastrinemia secondary to achlorhydria induced by chronic atrophic gastritis affecting the fundic mucosa (especially in the context of Biermer's disease). Endoscopically, gastric neuroendocrine tumors appear as multiple small polypoid lesions of less than 1 cm in size. Therapeutically, simple monitoring is recommended for ECLomas < 1 cm in size. In case of size > 1 cm, an endoscopic mucosectomy is sufficient if the submucosa is undamaged. Otherwise, ECLomas are treated by local resection associated with antrectomy.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) compared to computed tomography (CT) for advanced renal cell carcinoma (RCC).

4540 Background: There is emerging role of the use of PSMA PET in RCC. Herein, we report our experience in use of PSMA PET in recurrent or metastatic RCC in Brisbane, Australia. Methods: Patients (pts) who underwent PSMA PET and conventional diagnostic CT for metastatic or recurrent RCC between 2015 and 2020 at three institutions were identified. Retrospective chart reviews were conducted using standardized collection template. The outcomes included percentage of patients who had a change in management secondary to PSMA PET findings, comparison of metastasis detection for PSMA PET vs. CT, and biopsy histology of PSMA avid sites. Results: 42 PSMA PET were performed in 40 patients. 10 pts (25%) and 30 pts (75%) had PSMA PET in the metastatic disease and recurrent disease setting, respectively. Table 1 highlights demographics. Overall, 12 pts (30%, n=3 metastatic, n=9 recurrent) had a change in management following PSMA PET. In the metastatic disease group, 2 pts (20%) underwent initial systemic therapy (after histological confirmation) due to higher burden of disease shown with PSMA PET than CT, while systemic therapy was changed for 1 pt (10%). In the recurrent disease group, PSMA improved delineation of suspected recurrence (compared to CT) resulting in resection rather than surveillance (n=4; 13%) or change in surgical approach for resection (n=1; 3%). PSMA PET distribution showed more metastatic sites than CT leading to systemic therapy rather than resection of recurrence (n=2; 7%), while absent PSMA activity for suspected recurrence on CT led to surveillance rather than resection (n=2; 7%). PSMA PET detected more sites of metastases compared with conventional scan in 6 pts (60%) with metastatic disease and in 9 pts (30%) with recurrent disease. 26 pts had biopsy of PSMA avid sites. Majority of pts had confirmed recurrence of clear cell renal carcinoma (n= 22; 85%). Other histology included sarcomatoid renal cell carcinoma (n=2; 8%), carcinoid (n=1; 4%), and urothelial cancer (n=1; 4%). In 2 instances, biopsy/resection was performed of a suspected recurrence on CT that was not PSMA avid, and neither showed malignancy. Conclusions: PSMA PET detected more accurately metastatic and recurrent disease, with high pathological concordance, to result in change in management for 30% of patients. Prospective study is warranted to further investigate the utility of PSMA PET scan in advanced RCC.[Table: see text]

Combined use of 177 Lu-DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well-differentiated neuroendocrine tumors: A preclinical study.

Peptide receptor radionuclide therapy (177 Lu-DOTATATE) causes DNA strand breaks and has been validated for well-differentiated neuroendocrine tumor treatment. Poly-(ADP-ribose)-polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly-(ADP-ribose)-polymerase inhibitor fluzoparib could enhance the anti-tumor effects of 177 Lu-DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI-H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177 Lu-DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77 Lu-DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI-H727 cells and tumor xenografts. 177 Lu-DOTATATE (22.20MBqmL-1 ) and fluzoparib (50µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177 Lu-DOTATATE (22.20MBqmL-1 , 4.4-fold) and fluzoparib (50µm, 2.1-fold). 177 Lu-DOTATATE caused cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to 177 Lu-DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with 177 Lu-DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti-tumor effect of 177 Lu-DOTATATE in NCI-H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings.

The single-cell transcriptional landscape of lung carcinoid tumors.

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown. To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFβ and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the noninflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.

Randomized, parallel arm, phase II study of telotristat (Xermelo) in combination with lutetium Lu 177 dotatate (Lutathera) in well-differentiated neuroendocrine tumors (NETs).

TPS516 Background: PRRT using Lutetium Lu 177 Dotatate, has been approved by the FDA for metastatic, progressive gastroenteropancreatic neuroendocrine tumors (GEPNETs). Despite an impressive progression-free survival noted in NETTER-1 study, most patients will eventually progress after PRRT treatment. Increased serotonin secretion is found in a number of slow-growing NETs of the diffuse neuroendocrine system. Serotonin stimulates proliferation in cell lines of a typical (NCI-H727), an atypical (NCI-H720) bronchopulmonary NET, a small intestinal NET (KRJ-I), and a functioning human pancreatic carcinoid cell line (BON). This stimulation of growth by serotonin can be performed in an autocrine manner. Telotristat ethyl is a novel oral inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. In 2017, results of placebo-controlled phase III study (Telestar) evaluating Telotristat ethyl confirmed that among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with Telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in bowel movement frequency and urinary 5- hydroxy indoleacetic acid (u5-HIAA). Based on results of the Telestar trial, FDA approved 250 mg PO TID dosage of Telotristat for control of carcinoid syndrome diarrhea. Of note, 500 mg TID arm showed increased decline in urinary 5-HIAA as compared to 250 mg TID arm. Study Hypotheses: We hypothesize that inhibition of serotonin production will lead to cytostatic effect on neuroendocrine tumors and will complement anti-tumor activity of lutetium 177 dotatate. We anticipate our proposed combination will result in improved treatment efficacy as reflected by improved 20-month PFS as compared to historical control (NETTER-1). Methods: This is a single center, open label, randomized, parallel arm, phase II study evaluating two dose levels of Telotristat (Xermelo; 250 mg vs 500 mg) in combination with Lutetium Lu 177 Dotatate (Lutathera) in 70 well-differentiated neuroendocrine tumor patients. Study is currently enrolling patients and is expected to complete accrual in 3 years. Clinical trial information: NCT04543955.

Surgery of primary tracheal tumors

To determine the main forms of primary tracheal cancer (PTC), to specify the indications for various surgeries in these patients depending on extent and localization of lesion. There were 263 PTC patients. Benign tumors were diagnosed in 68 (25.9%) patients, malignancies - in 195 (74.1%) cases. Tracheal cancer includes 3 basic morphological variants - adenocystic cancer (49.7%), carcinoid (18.7%) and squamous cell carcinoma (19.0%). Other forms of malignancies were much less common. We applied endoscopic intraluminal and open surgeries. In malignant PTC, open surgeries were performed in 165 (84.6%) out of 195 patients. Baseline palliative endoscopic treatment was performed in 30 patients. They underwent airway recanalization (with subsequent tracheal stenting in 19 patients). Endoscopic resection was preferred for benign tumors. Twenty (12.1%) patients died after open surgery, and 1 (3.3%) patient died after endoscopic procedure. Most lethal outcomes occurred in early years of development of tracheal surgery. The causes of mortality were tracheal anastomotic failure in 12 patients, pneumonia in 6 patients, and arterial bleeding in 2 patients. Severe postoperative period was observed in all 3 patients after tracheal replacement with a silicone prosthesis. Long-term treatment outcomes depended on morphological structure of PTC. Favorable results were observed in patients with neuroendocrine tumor (carcinoid), worse outcomes in adenocystic cancer and unfavorable results in squamous cell carcinoma (p<0.0013). Five-year survival rates were 75%, 65.6%, and 13.3%; 10-year survival rates were 75%, 56.2%, and 13.3%, respectively. These outcomes after combined treatment of primary tracheal cancer were significantly better compared to lung cancer (p<0.05 when compared to global data). Treatment of primary tracheal cancer should be based on classical principles of modern oncology (combined therapy, tumor resection with lymphadenectomy). Open and endoscopic interventions are justified. PTC is characterized by more favorable outcomes compared to lung cancer. It is difficult to analyze long-term results in tracheal cancer depending on various features of tumor process due to small number of observations. Accurate conclusions require multiple-center studies, preferably with international participation, which can convincingly prove certain concept.

Experience of tracheo-bronchoplastic surgery for lung cancer

Introduction. Currently, surgical treatment of lung cancer is impossible without the use of tracheobronchoplastic operations, which in advanced specialized clinics take up to 5-10% of all radical operations. Material and methods. We conducted a retrospective study including 21 patients with centrally located lung cancer who underwent 22 tracheobronchoplastic radical operations between 2000 and 2021. The operated patients included 18 men and 3 women aged 42 to 67 years (mean age 54.5 ± 12.5 years). The morphological structure of the tumors was represented by carcinoid (2) and squamous cell carcinoma (19). The pathological process was located in the right lung in 16 patients and in the left lung — in five patients. Comorbid status was present in 20 patients. Standard lateral thoracotomy was used in 18 cases, and video-assisted minithoracotomy — in three cases. Extended lymphodissection up to D2 was performed in all surgeries. Combined surgeries included resection of adjacent organs: pericardium (2), unpaired vein (2), superior vena cava (1), diaphragmatic and vagus nerves (1), pleura (1). Results. The average duration of operations was 242.3 minutes (125-345 minutes), the average blood loss was 283.2 ml (50–1000 ml). Complications developed in 5 (22.7%) patients. Mortality was observed in 2 (9.1%) cases. Conclusion. The use of tracheobronchoplastic operations significantly expands the possibilities of thoracic surgery in treatment of lung cancer both due to technical resectability of the tumor at the transition to the main bronchus and trachea and due to functional operability at low respiratory functions and impossibility to perform pneumonectomy.

Expression of Estrogen and Progesterone Receptors in a Tailgut Cyst with Carcinoid Tumor

Abstract Introduction/Objective Tailgut cysts (TC) are congenital lesions that arise in the presacral space. They originate from the embryonic hindgut and usually present between the ages of 30-60, with female predominance. TCs are usually asymptomatic or can present with lower back, perianal or pelvic pain. Malignant transformation of a TC is a rare complication, with adenocarcinoma being the most common, followed by carcinoid tumor. About thirty cases of carcinoid tumors arising in a TC have been reported in the literature so far with a slight female predominance (1.5:1). Methods/Case Report We describe a 40-year-old Hispanic woman with a 9-year history of cyclic pelvic pain related to her menstrual cycles. She was diagnosed with adenomyosis and underwent hysterectomy that did not completely resolve her symptoms. Follow-up serial imaging showed a growing complex-cystic presacral mass, which was eventually excised. Grossly, there was a 3.6×3.1×2.5 cm multiloculated cystic mass filled with mucoid material. Microscopically, there were multiple cystic spaces lined by benign squamous and mucinous columnar epithelium and surrounded by smooth muscle cells. A 6-mm carcinoid tumor was found within a cyst wall and confirmed by positive synaptophysin and chromogranin staining with a Ki-67 proliferation index of &amp;lt;2%. Estrogen and progesterone receptor immunostains were positive in the epithelial cyst linings and the stromal cells but not in the carcinoid tumor cells. Results (if a Case Study enter NA) NA Conclusion We conclude that the diagnosis of TC should be considered in the differential of gynecologic patients with unresolved cyclic pelvic pain and that estrogen and progesterone could have an important role in the pathogenesis of TCs. Furthermore, estrogen receptors can be a therapeutic target in patients with this entity.

Video-assisted thoracic surgery sleeve resection and bronchoplasty using 3D imaging system: its safety and efficacy

BackgroundVideo-assisted thoracic surgery sleeve resection with bronchial anastomosis or bronchoplasty is a technically demanding procedure. Three-dimensional endoscopic surgery has been reported to be helpful in decreasing operation time and improving spatial perception with less surgical errors, but there have been rare reports about relatively difficult thoracoscopic procedures utilizing 3D thoracoscope. We performed this study to evaluate early clinical outcomes of thoracoscopic sleeve resection and bronchoplasty utilizing 3D thoracoscope.MethodsData from a total of 36 patients who underwent thoracoscopic sleeve lobectomy or bronchoplasty at our institution from December 2015 to October 2017 were retrospectively reviewed. Three-port approach with one utility incision was used with a 10 mm, 30° three-dimensional thoracoscope. Twenty-three patients (81%) were male, and mean age was 65.9 ± 9.4 years. Fourteen patients (38.9%) underwent sleeve resection with bronchial anastomosis, 22 (61.1%) underwent wedge or simple bronchoplasty, and one patient received concomitant PA procedure. Bronchial anastomosis sites were not covered with viable tissue flaps.ResultsThere was no (0%) suture needle injury from spatial misperception during bronchoplasty or sleeve anastomosis. There was no (0%) operative mortality. The pathologic report revealed squamous cell carcinoma (63.9%), adenocarcinoma (19.4%), carcinoid (6.9%), adenosquamous carcinoma (3.4%), and sarcomatoid carcinoma (2.8%). One (2.8%) late mortality was due to systemic recurrence of sarcomatoid carcinoma. There was no (0.0%) anastomotic failure. The mean number of dissected lymph nodes were 27.4 ± 13.2, and mean operation time was 216.8 ± 60.0 min. Median postoperative 24-h drain amount was 315 mL. Median chest tube days and hospital days were 4 and 6, respectively. Two patients (5.6%) had complications greater than Clavien-Dindo grade II—one case of ARDS, and the other case of a delayed bronchopleural fistula.ConclusionsThoracoscopic sleeve resection and bronchoplasty utilizing HD 3D thoracoscope is a safe and effective procedure with excellent early clinical outcomes. Further investigation for long-term outcomes will be needed.

Diagnosis-to-surgery interval and survival for different histologies of stage I-IIA lung cancer.

BackgroundGuidelines on timeliness of lung cancer surgery are inconsistent. Lung cancer histologic subtypes have different prognosis and treatment. It is important to understand the consequences of delayed surgery for each lung cancer histologic subtype. This study aimed to examine the association between diagnosis-to-surgery time interval and survival for early stage lung cancer and selected histologic subtypes.MethodsPatients diagnosed with stage I–IIA lung cancer between 2004 and 2015 receiving definitive surgery and being followed up until Dec. 31, 2018, were identified from Surveillance, Epidemiology, and End Results database. Histologic subtypes included adenocarcinoma, squamous or epidermoid carcinoma, bronchioloalveolar carcinoma, large cell carcinoma, adenosquamous carcinoma, carcinoid carcinoma, and small cell carcinoma. Diagnosis-to-surgery interval was treated as multi-categorical variables (<1, 1–2, 2–3, and ≥3 months) and binary variables (≥1 vs. <1 month, ≥2 vs. <2 months, and ≥3 vs. <3 months). Outcomes included cancer-specific and overall survival. Covariates included age at diagnosis, sex, race, marital status, tumor size, grade, surgery type, chemotherapy, radiotherapy, and study period. Kaplan-Meier survival curves and Cox proportional hazards regression models were applied to examine the survival differences.ResultsWith a median follow-up time of 51 months, a total of 40,612 patients were analyzed, including 40.1% adenocarcinoma and 24.5% squamous or epidermoid carcinoma. The proportion of patients receiving surgery <1, 1–2, 2–3, and ≥3 months from diagnosis were 34.2%, 33.9%, 19.8%, and 12.1%, respectively. Delayed surgery was associated with worse cancer-specific and overall survival for all lung cancers, adenocarcinoma, squamous or epidermoid, bronchioloalveolar, and large cell carcinoma (20–40% increased risk). Dose-dependent effects (longer delay, worse survival) were observed in all lung cancers, adenocarcinoma, and squamous and epidermoid carcinoma. No significant association between surgery delay and survival was observed in adenosquamous, carcinoid, and small cell carcinoma.ConclusionsOur findings support the guidelines of undertaking surgery within 1 month from diagnosis in patients with stage I–IIA lung cancer. The observed dose-dependent effects emphasize the clinical importance of early surgery. Future studies with larger sample size of less frequent histologic subtypes are warranted to provide more evidence for histology-specific lung cancer treatment guidelines.

A miR-375/YAP axis regulates neuroendocrine differentiation and tumorigenesis in lung carcinoid cells

Lung carcinoids are variably aggressive and mechanistically understudied neuroendocrine neoplasms (NENs). Here, we identified and elucidated the function of a miR-375/yes-associated protein (YAP) axis in lung carcinoid (H727) cells. miR-375 and YAP are respectively high and low expressed in wild-type H727 cells. Following lentiviral CRISPR/Cas9-mediated miR-375 depletion, we identified distinct transcriptomic changes including dramatic YAP upregulation. We also observed a significant decrease in neuroendocrine differentiation and substantial reductions in cell proliferation, transformation, and tumor growth in cell culture and xenograft mouse disease models. Similarly, YAP overexpression resulted in distinct and partially overlapping transcriptomic changes, phenocopying the effects of miR-375 depletion in the same models as above. Transient YAP knockdown in miR-375-depleted cells reversed the effects of miR-375 on neuroendocrine differentiation and cell proliferation. Pathways analysis and confirmatory real-time PCR studies of shared dysregulated target genes indicate that this axis controls neuroendocrine related functions such as neural differentiation, exocytosis, and secretion. Taken together, we provide compelling evidence that a miR-375/YAP axis is a critical mediator of neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.