Adverse effects of long-term drain placement and the importance of direct aspiration: a retrospective cohort study.

BACKGROUND: Long-term placement of prophylactic drains may result in retrograde infections. AIM: To investigate the association between the timing of drain removal and clinical outcomes. METHODS: This retrospective, single-centre cohort study evaluated 110 patients who underwent elective gastrointestinal or hepatopancreatobiliary surgery and developed subsequent organ/space surgical site infection (SSI) between 2016 and 2020. The difference between the culture-positive species of prophylactic drains and direct aspiration was evaluated; whether the prophylactic drains functioned effectively at the time of SSI diagnosis; and whether the empirical antibiotics administered before drainage were effective against all the detected bacteria. Finally, clinical outcomes were compared between early (i.e. cases wherein the prophylactic drain had already been removed or replaced at the time of SSI diagnosis) and late (removal after diagnosis) drain removal. FINDINGS: The prophylactic drains functioned effectively in only 27 (25%) patients at the time of SSI diagnosis. Due to the results of direct aspiration cultures, 43% of patients required antibiotic escalation. The median time to drain removal or first replacement was seven postoperative days. The early removal group included 43 patients (39%). Compared with early removal, late removal resulted in a higher frequency of vancomycin use (7.0% vs 22.4%; P = 0.037). CONCLUSION: Prolonged prophylactic drain placement is associated with complicated infections requiring vancomycin; therefore, the drains should be removed as soon as possible. Additionally, obtaining the cultures of direct aspiration should be actively considered, as escalation of antimicrobial therapy is often performed based on culture results.

Automatic surgical phase recognition in laparoscopic inguinal hernia repair with artificial intelligence.

BACKGROUND: Because of the complexity of the intra-abdominal anatomy in the posterior approach, a longer learning curve has been observed in laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair. Consequently, automatic tools using artificial intelligence (AI) to monitor TAPP procedures and assess learning curves are required. The primary objective of this study was to establish a deep learning-based automated surgical phase recognition system for TAPP. A secondary objective was to investigate the relationship between surgical skills and phase duration. METHODS: This study enrolled 119 patients who underwent the TAPP procedure. The surgical videos were annotated (delineated in time) and split into seven surgical phases (preparation, peritoneal flap incision, peritoneal flap dissection, hernia dissection, mesh deployment, mesh fixation, peritoneal flap closure, and additional closure). An AI model was trained to automatically recognize surgical phases from videos. The relationship between phase duration and surgical skills were also evaluated. RESULTS: A fourfold cross-validation was used to assess the performance of the AI model. The accuracy was 88.81 and 85.82%, in unilateral and bilateral cases, respectively. In unilateral hernia cases, the duration of peritoneal incision (p = 0.003) and hernia dissection (p = 0.014) detected via AI were significantly shorter for experts than for trainees. CONCLUSION: An automated surgical phase recognition system was established for TAPP using deep learning with a high accuracy. Our AI-based system can be useful for the automatic monitoring of surgery progress, improving OR efficiency, evaluating surgical skills and video-based surgical education. Specific phase durations detected via the AI model were significantly associated with the surgeons' learning curve.

A proposal for uniformity in classification of lymph node stations in esophageal cancer.

The 11th edition of the "Japanese Classification of Esophageal Cancer" by the Japan Esophageal Society (JES) and the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) "Cancer Staging Manual" are two separate classification systems both widely used for the clinical and pathological staging of esophageal cancer. Furthermore, the lymph node stations from these classification systems are combined for research purposes in the multinational TIGER study, which investigates the distribution pattern of lymph node metastases. The existing classification systems greatly differ with regard to number, location and anatomical boundaries of locoregional lymph node stations. The differences in these classifications cause significant heterogeneity in studies on lymph node metastases in esophageal cancer. This makes data interpretation difficult and comparison of studies challenging. In this article, we propose a match for these two commonly used classification systems and additionally for the TIGER study classification, in order to be able to compare results of studies and exchange knowledge and to make steps towards one global uniform classification system for all patients with esophageal cancer.

Gastrectomy with or without omentectomy for cT3-4 gastric cancer: a multicentre cohort study.

BACKGROUND: Omentectomy is performed widely for locally advanced gastric cancer to prevent disease recurrence. However, its clinical benefit is unknown. METHODS: This retrospective cohort study compared the outcome of gastrectomy with preservation of the omentum (GPO) and gastrectomy with resection of the omentum (GRO) among patients with cT3-T4 gastric cancer who underwent gastrectomy between 2006 and 2012 in one of five participating institutions. A consensus conference identified 28 variables potentially associated with outcome after gastrectomy for the estimation of propensity scores, and propensity score matching (PSM) was undertaken to control for possible confounders. Postoperative surgical outcomes, overall survival and disease recurrence were compared between GPO and GRO. RESULTS: A total of 1758 patients were identified, of whom 526 remained after PSM, 263 in each group. Median follow-up was 4·9 (i.q.r. 3·1-5·9) years in the GRO group and 5·0 (2·5-6·8) years in the GPO group. The incidence of postoperative complications of Clavien-Dindo grade III or more was significantly higher in the GRO group (17·5 versus 10·3 per cent; P = 0·016). Five-year overall survival rates were 77·1 per cent in the GRO group and 79·4 per cent in the GPO group (P = 0·749). There were no significant differences in recurrence rate or pattern of recurrence between the groups. CONCLUSION: Overall survival and disease recurrence were comparable in patients with cT3-4 gastric cancer who underwent GPO or GRO.

ANTECEDENTES: La omentectomía se realiza ampliamente en el cáncer gástrico localmente avanzado para prevenir la recidiva de la enfermedad. Sin embargo, se desconoce su beneficio clínico. MÉTODOS: Este estudio retrospectivo comparó el resultado de la gastrectomía con preservación del omento (gastrectomy with preservation of the omentum, GPO) con la gastrectomía con resección del omento (gastrectomy with resection of the omentum, GRO) para el cáncer gástrico con estadio clínico T3/T4. Se incluyeron pacientes sometidos a gastrectomía por cáncer gástrico clínico T3/T4 (2006-2012) y se recogieron datos relevantes de 5 hospitales participantes. A través de una conferencia de consenso se identificaron 28 variables potencialmente asociadas con el resultado tras la gastrectomía, mediante las cuales se estimaron las puntuaciones de propensión, utilizándose el emparejamiento por puntuación de propensión (propensity score matching, PSM) para el control de posibles factores de confusión. Los resultados quirúrgicos postoperatorios, la supervivencia global y la recidiva de la enfermedad se compararon entre las gastrectomías con GPO y GRO. RESULTADOS: En total, se identificaron 1.758 pacientes, seleccionándose 526 (263 GRO y 263 GPO) tras el PSM. La mediana (rango intercuartílico) de seguimiento fue de 4,9 años (3,1-5,9) en el grupo GRO y de 5,0 años (2,5-6,8) en el grupo GPO. La incidencia de complicaciones postoperatorias de Clavien-Dindo grado III o más alto fue significativamente más elevada en el grupo GRO que en el grupo GPO (17,1% versus 9,1%; P = 0,010). La supervivencia global a los 5 años fue del 77,1% para el grupo GRO y del 79,4% para el grupo GPO (P = 0,749). No hubo diferencias estadísticamente significativas en la tasa de recidiva o patrón de recidiva entre ambos grupos. CONCLUSIÓN: La supervivencia global y la recidiva de la enfermedad son comparables en pacientes con cáncer gástrico estadio clínico T3-4 sometidos a GPO o GRO.

Minimally invasive oesophagectomy with extended lymph node dissection and thoracic duct resection for early-stage oesophageal squamous cell carcinoma.

BACKGROUND: Oesophageal squamous cell carcinoma is an aggressive disease owing to early and widespread lymph node metastases. Multimodal therapy and radical surgery may improve prognosis. Few studies have investigated the efficacy of radical lymph node and thoracic duct resection. METHODS: Patients with oesophageal squamous cell carcinoma who underwent transthoracic minimally invasive oesophagectomy (TMIE) for cancer at Keio University Hospital between January 2004 and December 2016 were selected. Between 2004 and 2008, TMIE was performed in the lateral decubitus position without thoracic duct resection (standard TMIE). From 2009 onwards, TMIE with extended lymph node and thoracic duct resection was introduced (extended TMIE). Demographics, co-morbidity, number of retrieved lymph nodes, pathology, postoperative complications and recurrence-free survival (RFS) were compared between groups. RESULTS: Forty-four patients underwent standard TMIE and 191 extended TMIE. There were no significant differences in clinical and pathological tumour stage or postoperative complications. The extended-TMIE group had more lymph nodes removed at nodal stations 106recL and 112. Among patients with cT1 N0 disease, RFS was better in the extended-TMIE group (P < 0·001), whereas there was no difference in RFS between groups in patients with advanced disease. CONCLUSION: Extended TMIE including thoracic duct resection increased the number of lymph nodes retrieved and was associated with improved survival in patients with cT1 N0 oesophageal squamous cell carcinoma.

Meta-analysis of the impact of postoperative complications on survival after oesophagectomy for cancer.

BACKGROUND: Oesophagectomy has a high risk of postoperative morbidity. The impact of postoperative complications on overall survival of oesophageal cancer remains unclear. This meta-analysis addressed the impact of complications on long-term survival following oesophagectomy. METHODS: A search of PubMed and Cochrane Library databases was undertaken for systematic review of papers published between January 1995 and August 2016 that analysed the relation between postoperative complications and long-term survival. In the meta-analysis, data were pooled. The main outcome was overall survival (OS). Secondary endpoints included disease-free (DFS) and cancer-specific (CSS) survival. RESULTS: A total of 357 citations was reviewed; 21 studies comprising 11 368 patients were included in the analyses. Overall, postoperative complications were associated with significantly decreased 5-year OS (hazard ratio (HR) 1·16, 95 per cent c.i. 1·06 to 1·26; P = 0·001) and 5-year CSS (HR 1·27, 1·09 to 1·47; P = 0·002). Pulmonary complications were associated with decreased 5-year OS (HR 1·37, 1·16 to 1·62; P < 0·001), CSS (HR 1·60, 1·35 to 1·89; P < 0·001) and 5-year DFS (HR 1·16, 1·00 to 1·33; P = 0·05). Patients with anastomotic leakage had significantly decreased 5-year OS (HR 1·20, 1·10 to 1·30; P < 0·001), 5-year CSS (HR 1·81, 1·11 to 2·95; P = 0·02) and 5-year DFS (HR 1·13, 1·02 to 1·25; P = 0·01). CONCLUSION: Postoperative complications after oesophagectomy, including pulmonary complications and anastomotic leakage, decreased long-term survival.

Size of recurrent laryngeal nerve as a new risk factor for postoperative vocal cord paralysis.

Recurrent laryngeal nerve paralysis (RLNP) is a frequent and serious complication following esophageal cancer surgery. Therefore, this study aims to evaluate the correlation between recurrent laryngeal nerve (RLN) size and RLNP. This was a retrospective study of esophageal cancer patients who underwent thoracoscopic esophagectomy from January 2012 to December 2014. Eighty-four patients were included in the primary analysis. Diameter of the RLN was measured using the digital video recording of surgical procedures by the ratio between scissor and RLN. For evaluation of vocal cord paralysis or paresis, indirect laryngoscopy was performed. Because RLNP more frequently occurs on the left side than the right, we evaluated the correlation between size of the left RLN and left RLNP. The median size of the left RLN was 1.51 mm. We found that the incidence of postoperative left RLNP (Clavien-Dindo classification ≥1) was significantly higher (71% vs. 24%; P < 0.001) in thin RLNs (≤1.5 mm) than in thick RLNs (>1.5 mm). Thin RLN (P < 0.001), female sex (P = 0.025), and being overweight (P = 0.034) were identified as significant independent risk factors for postoperative RLNP. RLNP more easily occurred when the RLN was thin. It is difficult to confirm occurrence of postoperative RLNP before and at extubation. Therefore, it is helpful to know its risk factors including size of RLN.

Clinical significance of plasma fibrinogen level as a predictive marker for postoperative recurrence of esophageal squamous cell carcinoma in patients receiving neoadjuvant treatment.

Among multidisciplinary therapies developed for advanced esophageal cancer, neoadjuvant chemotherapy and chemoradiotherapy have been established as standard treatments. To deliver cautious follow up and intense treatment for high-risk patients, a simple and instructive biomarker for the postoperative recurrence needs to be identified. Fibrinogen, a common component of hemostasis, has been suggested to not only play an important role in cancer metastasis, but also correlate with tumor recurrence. We aim to clarify the validity of plasma fibrinogen as a marker for predicting the postoperative recurrence of esophageal squamous cell carcinoma patients who received neoadjuvant treatment. We reviewed 72 consecutive patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy or chemoradiotherapy, followed by esophagectomy at the Keio University Hospital from 2001 to 2010. Of them, we retrospectively examined 68 patients who underwent plasma fibrinogen examination before and after neoadjuvant treatment and underwent transthoracic radical esophagectomy. We investigated patient characteristics, clinicopathological factors, neoadjuvant treatment effects, postoperative course, and plasma fibrinogen levels. We investigated pretreatment and preoperative (postneoadjuvant treatment) plasma fibrinogen levels, as well as changes in fibrinogen levels before and after neoadjuvant treatment. Patients with preoperative hyperfibrinogenemia (>350 mg/dL) and patients with increased plasma fibrinogen levels during neoadjuvant treatment showed significantly shorter postoperative disease-free survival (DFS) (P = 0.002 and P = 0.037, respectively). Moreover, we classified these patients into three classes on the basis of their preoperative fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment. Patients who had both high preoperative plasma fibrinogen and increased fibrinogen levels showed significantly shorter DFS than others. In contrast, patients who had normal preoperative plasma fibrinogen and decreased fibrinogen levels showed significantly longer DFS. Based on this fibrinogen classification, we could differentiate between significantly favorable and poor prognosis patients group. Overall, this classification (hazard ratio = 1.812, P = 0.013) and the response to neoadjuvant treatment (hazard ratio = 0.350, P = 0.007) were found to be significant determining factors for postoperative DFS. With the validity of preoperative plasma fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment, the plasma fibrinogen level was found to be a possible biomarker for postoperative recurrence in advanced esophageal cancer patients who received neoadjuvant treatment. Moreover, plasma fibrinogen classification could be a simple and valuable predictive marker for postoperative follow up.

Clinical utility of preoperative evaluation of bronchial arteries by three-dimensional computed tomographic angiography for esophageal cancer surgery.

An identification of bronchial arteries (BAs) is critical in esophageal cancer surgery to avoid tracheobronchial ischemia and unexpected massive bleeding during surgical procedure particularly in thoracoscopic video-assisted esophagectomy. We describe the efficacy of three-dimensional computed tomographic angiography (3D-CTA) of BAs for preoperative evaluation in esophageal cancer surgery. Sixty-four patients with esophageal cancer who preoperatively underwent multidetector computed tomography examination were included in this study. We evaluated the number, origin, and intraoperative preservation rate of BAs, and we compared the number of thoracic paratracheal lymph nodes harvested between two groups comprising patients who either underwent preoperative 3D-CTA of BAs (3D-CTA group) or did not (non-3D-CTA group). The right and left BAs were preoperatively identified in 62 patients (97%) and 55 patients (86%), respectively, using 3D-CTA. In 34 patients (53%), the right BA originated as a common trunk with the right intercostal artery. In 48 patients (75%), the left BA originated from the descending aorta as a single or double branch. Some anomalies such as the right BA originated from the left subclavian artery were observed. In all patients, either the right or the left BA was preserved. The number of harvested lymph nodes in left side of paratrachea was significantly increased in 3D-CTA group, than those in non-3D-CTA group. 3D-CTA clearly revealed BA anatomy, contributing to BA preservation and safe and precise lymphadenectomy in esophageal cancer surgery. 3D-CTA of BAs is useful for preoperative evaluation in esophageal cancer surgery.

Alterations of p53, cyclin D1 and pRB expression in the carcinogenesis of esophageal squamous cell carcinoma.

Many molecular alterations occur in esophageal carcinogenesis; however, little is known about the molecular genetic events responsible for the development of carcinoma. We investigated the expression of ki67, p53, cyclin D1 and pRB in 105 biopsy specimens using immunohistochemistry from iodine unstained lesions as indicators of carcinogenesis of the esophagus. Also, the genetic alternation of esophageal dysplasia from patients with accompanying esophageal squamous cell carcinoma (ESCC) was examined to study the evidence for field carcinogenesis in the esophagus. The expression of p53, cyclin D1 and pRB was detected in 31, 0 and 51.7% respectively of mild dysplasia; 40, 0 and 70% of moderate dysplasia; 40, 20 and 70% of severe dysplasia; and 48, 32 and 80% of carcinoma specimens. p53 expression was significantly increased in mild dysplasia, whereas cyclin D1 and pRB expression were significantly increased in carcinoma as compared to both normal epithelium and esophagitis. The ki67 LI and the rate of p53 expression were significantly higher in dysplasia with ESCC than in dysplasia without ESCC. Ki67, p53, cyclin D1 and pRB expression may be useful biomarkers for assessing the risk of developing esophageal cancer. Dysplasia observed at screening for secondary lesions has a highly malignant potential and careful follow-up studies are required.

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model.

Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P=0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P=0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor- and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P=0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.

Transforming Growth Factor-beta superfamily: evaluation as breast cancer biomarkers and preventive agents.

The Transforming Growth Factor-beta (TGFbeta) superfamily of cytokines is comprised of a number of structurally-related, secreted polypeptides that regulate a multitude of cellular processes including proliferation, differentiation and neoplastic transformation. These growth regulatory molecules induce ligand-mediated hetero-oligomerization of distinct type II and type I serine/threonine kinase receptors that transmit signals predominantly through receptor-activated Smad proteins but also induce Smad-independent pathways. Ligands, receptors and intracellular mediators of signaling initiated by members of the TGFbeta family are expressed in the mammary gland and disruption of these pathways may contribute to the development and progression of human breast cancer. Since many facets of TGFbeta and breast cancer have been recently reviewed in several articles, except for discussion of recent developments on some aspects of TGFbeta, the major focus of this review will be on the role of activins, inhibins, BMPs, nodal and MIS-signaling in breast cancer with emphasis on their utility as potential diagnostic, prognostic and therapeutic targets.

In vivo NMR micro-imaging of kidney and liver of mouse at 9.4 T.

NMR micro-images of the kidney and liver were measured at 9.4 T in intact mouse, schistosoma Mansoni-infected mouse, and lupus nephritis in an MRL/lpr mouse. High-field NMR imaging has the advantages of sensitivity, spatial resolution, and tissue contrasts based on longitudinal and transverse relaxations, magnetic susceptibility differences and blood flow.

[Preliminary evaluation of adjuvant chemotherapy against stage Ib or II gastric cancer].

The prognostic influence of post-operative adjuvant chemotherapy on stage I b or II gastric cancer was studied retrospectively. The immunohistochemical expressions of p53 protein and thymidine phosphorylase (TP) were also examined; the relations between these protein expressions and clinicopathological features along with the effect of adjuvant chemotherapy were also investigated. The 5-year survival rate of the patients who received adjuvant chemotherapy was 95.5%, which was better than that (89.8%) of those who did not, although the difference did not reach significance (p = 0.09). The venous invasion of tumor was slight frequently observed in p53 or TP positive cases than negative cases, respectively (p < 0.1), but no significant associations were found between the t-, n- or ly-factor, and p53 or TP expression. Moreover p53 and TP expression had no significant influence on post-operative survival. But, among the patients with p53- or TP-positive tumor, adjuvant chemotherapy conferred survival benefits, although the difference did not reach significance. The 5-year survival rate was 100% with adjuvant chemotherapy, 84.3% without chemotherapy in p53-positive patients (p = 0.137), 97.0% with adjuvant chemotherapy, and 90.8% without chemotherapy in TP-positive tumors (p = 0.326).

Factors influencing visual acuity after photocoagulation for subfoveal choroidal neovascularization of exudative age-related macular degeneration.

PURPOSE: To evaluate factors influencing visual acuity after laser photocoagulation for subfoveal choroidal neovascularization of exudative age-related macular degeneration. METHODS: Subfoveal choroidal neovascular membranes were photocoagulated. Factors favoring a visual acuity of 20/200 or better were analyzed using Fisher's exact probability test or chi-square test on 28 eyes in which visual acuity was 20/200 or better, and 23 eyes with a visual acuity below 20/200 at the most recent follow-up examination. RESULTS: Factors predicting a postoperative visual acuity of 20/200 or better were (1) distance between one lateral margin of the neovascular membrane and the center of the foveal avascular zone was one-third disc diameter or less, and (2) pretreatment retinal sensitivity at the fixation point was 10 dB or more. CONCLUSION: Good indications for photocoagulation treatment of subfoveal choroidal neovascular membrane were a neovascular membrane margin near the center of the foveal avascular zone and relatively good retinal sensitivity at the fixation point adjacent to the scotoma. These factors predict a visual acuity of 20/200 or better after treatment.

(R)-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines: novel optically active compounds with strong 5-HT1A receptor binding ability exhibiting anticonflict activity and lessening of memory impairment.

(R)-1,2,3,4-Tetrahydro[1]benzothieno[2,3-c]pyridine derivatives (60-114) were synthesized. The (R)-isomers have affinity for the 5-HT1A receptor while the (S)-isomers have no such ability. The affinity of the (R)-isomers was discussed on the basis of structure-activity relationships between the affinity and hydrophobicity of the (R)-isomers. Compounds 71 and 107, which are representative derivative compounds, have anticonflict activity and lessening of memory impairment. In particular, compound 107 cannot bind to receptors other than the 5-HT1A receptor, demonstrating that it is a unique compound with a different mechanism of action from that of conventional anxiolytics.

Restorative effect of neurotropin on maturation of bone marrow cells to IL-2-producing T-cells in aging BALB/c mice.

In a previous paper, we have demonstrated that Neurotropin, a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, restores decreasing immune responses through the recovery of interleukin-2 (IL-2) production in aging BALB/c mice. To clarify the mechanism by which Neurotropin restores IL-2 production, its effect on the recruitment of IL-2-producing T-cells from bone marrow cells was examined using syngenic radiation bone marrow chimeras. Two fundamental lesions in recruiting IL-2-producing T-cells in aging BALB/c mice were demonstrated: (1) a drastic decline of the maturation of bone marrow cells to IL-2-producing T-cells as demonstrated by old----young chimeras; and (2) an environment unable to support bone marrow cell differentiation to IL-2-producing T-cells by young----old chimeras. Neurotropin clearly restored the maturation of bone marrow cells to IL-2-producing T-cells when administered from 13 to 16 month-old mice, whereas the non-complementing environment was not normalized with Neurotropin administration. These results suggest that Neurotropin administration restores IL-2 production through the recovery of the maturation of bone marrow cells to IL-2-producing T-cells, resulting in restoration of in vivo T-cell immune response in aging BALB/c mice.

Potent anticonflict activity and lessening of memory impairment with a series of novel [1]benzothieno[2,3-c]pyridines and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines.

[1]Benzothieno[2,3-c]pyridines (10a-c, 11, 12a-t, and 13a,b) and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines (3a-c, 7, 8a-c, and 9) were synthesized. The compounds are bioisosteres of beta-carbolines and 1,2,3,4-tetrahydro-beta-carbolines where the indole nitrogen is replaced by sulfur. Their pharmacological activity was evaluated in a water lick conflict test in rats and a passive avoidance test in mice. In the 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine series, the presence of ethyl ester (3b) or cyclohexyl carboxamide (7) groups at C-3 conferred good anticonflict activity and lessening of memory impairment, while N-acylation of 3b abolished activity. In the [1]benzothieno(2,3-c]pyridine series, the aminoethyl carboxamide (12a) group at C-3 also conferred activity, but other amides studied were not active. The most potent compounds (3b, 7, and 12a) were also administered orally and had potent anticonflict and antiscopolamine amnesia-reversal activity. These compounds did not bind to the BZP receptor in spite of having structures similar to those of beta-carbolines. Compound 7 bound strongly to 5-HT1A receptors and would be expected to be a novel anxiolytic.