Risk factors for early recurrence in patients with pancreatic ductal adenocarcinoma who underwent curative resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and surgical resection is the only potentially curative approach. However, the rate of recurrence remains high, particularly within the first 6 months, and is associated with a poor prognosis. The present study evaluated the clinical characteristics and risk factors for early recurrence in pancreatic ductal adenocarcinoma (PDAC) patients who underwent curative resection, regardless of the use of neoadjuvant chemotherapy, to identify predictive factors associated with early recurrence and poor outcomes as well as to determine the optimal treatment strategy for patients at high risk of early recurrence after surgical resection. METHODS: Patients who underwent pancreatic resection for PDAC at our institution from 2013 to 2021 were included in this study. We investigated the clinicopathological features of patients in groups: those with recurrence within 6 months, recurrence between 6 and 12 months, and recurrence beyond 12 months or no recurrence. A logistic regression analysis identified covariates associated with early recurrence at 6 and 12 months. RESULTS: The study included 403 patients with a median follow-up of 25.7 months. Recurrence was observed in 279 patients, with 14.6% recurring within 6 months, 23.3% within 6-12 months, and 62% after 12 months or not at all. The preoperative CA19-9 level, modified Glasgow prognostic score (mGPS), and positive peritoneal cytology were significant risk factors for early recurrence within 6 months, while positive peritoneal cytology, lymph node metastasis, and the absence of adjuvant chemotherapy were significant risk factors for recurrence within 12 months. For patients who received preoperative chemotherapy or chemoradiotherapy, the preoperative CA19-9 level, mGPS, and positive peritoneal cytology were significant independent risk factors for early recurrence within 6 months, while positive peritoneal cytology, lymph node metastasis, and the absence of adjuvant chemotherapy were significant independent risk factors for recurrence within 12 months. The study concluded that the overall survival after surgical resection for potentially resectable PDAC worsened according to the number of risk factors present in the patient. CONCLUSIONS: We clarified that preoperative CA19-9, positive peritoneal cytology, and the lack of adjuvant chemotherapy were consistent predictors for early recurrence within 6 and 12 months. In addition, an increased number of risk factors affecting the patient was associated with a poorer overall survival after potentially curable resection. Calculating the number of risk factors for early recurrence may be an essential predictive factor when considering treatment strategies.

O- and N-Selective Electrophilic Activation of Allylic Alcohols and Amines in Pd-Catalyzed Direct Alkylation.

Catalytic control of chemoselectivity is crucial in the synthesis of highly functionalized compounds. Although there are reports of efficient chemoselective reactions of alcohols and amines as nucleophiles, there are no reports of the chemoselective activation of alcohols and amines as electrophiles. In this study, highly O- and N-selective electrophilic activation of allylic alcohols and amines was achieved in Pd-catalyzed direct allylic alkylation. Allylamines were inherently more reactive than allylic alcohols (N-selectivity). On the other hand, the addition of catalytic amounts of 9-phenanthreneboronic acid preferentially activated allylic alcohols over allylamines (O-selectivity). Density functional theory (DFT) calculations suggested that the N-selectivity is due to the selective activation of allylic amines with ammonium cations, and boronate formation accelerates the activation of allylic alcohols.

Postoperative acute pancreatitis after pancreatic resection in patients with pancreatic ductal adenocarcinoma.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is one of the major critical complications after pancreatic resection. Recently, postoperative acute pancreatitis (POAP), a new concept for a pancreatic-specific complication following pancreatic resection, has been advocated, and its association with POPF has been reported. The present study examined the clinical features of POAP and identified the associations of POAP with POPF and other postoperative morbidities in pancreatic ductal adenocarcinoma (PDAC) patients undergoing pancreatic resection. METHODS: A total of 312 consecutive patients who underwent pancreatic resection for PDAC at our institution from 2013 to 2019 were enrolled in this study. POAP was defined as an elevated serum amylase level above the upper limit normal on postoperative day (POD) 0 or 1, based on Connor's definition. The severity of POPF was assessed by the International Study Group on Pancreatic Surgery definition. RESULTS: A total of 184 patients (58.9%) had POAP. POAP occurred in 58.5% of subtotal stomach-preserving pancreatoduodenectomy patients and 60% of distal pancreatectomy combined with splenectomy patients. The presence of POAP was significantly associated with the development of clinically relevant POPF, higher rates of severe morbidity, and a prolonged hospital stay after pancreatic resection. A multivariate analysis showed that the presence of POAP and elevated C-reactive protein levels on POD 3 were independent predictors of clinically relevant POPF after subtotal stomach-preserving pancreatoduodenectomy. CONCLUSIONS: POAP is associated with the development of POPF, higher rates of severe morbidity, and a prolonged hospital stay after pancreatic resection and is an independent risk factor for clinically relevant POPF after pancreatoduodenectomy. POAP represents an important indicator for planning treatment strategies to prevent serious complications, including POPF.

Chemoselective Catalytic α-Oxidation of Carboxylic Acids: Iron/Alkali Metal Cooperative Redox Active Catalysis.

We developed a chemoselective catalytic activation of carboxylic acid for a 1e- radical process. α-Oxidation of a variety of carboxylic acids, which preferentially undergo undesired decarboxylation under radical conditions, proceeded efficiently under the optimized conditions. Chemoselective enolization of carboxylic acid was also achieved even in the presence of more acidic carbonyls. Extensive mechanistic studies revealed that the cooperative actions of iron species and alkali metal ions derived from 4 Å molecular sieves substantially facilitated the enolization. For the first time, catalytic enolization of unprotected carboxylic acid was achieved without external addition of stoichiometric amounts of Brønsted base. The formed redox-active heterobimetallic enediolate efficiently coupled with free radical TEMPO, providing synthetically useful α-hydroxy and keto acid derivatives.

Amino Acid Schiff Base Bearing Benzophenone Imine As a Platform for Highly Congested Unnatural α-Amino Acid Synthesis.

Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers. The broad functional group compatibility highlights the mildness of the present catalysis. Notably, we achieved successive ß-functionalization and oxidation of amino acid Schiff bases to afford dehydroalanine derivatives bearing tetrasubstituted carbon. A three-component cross-coupling reaction of an amino acid Schiff base, alkyl bromides, and styrene derivatives demonstrated the high utility of the present method. The diastereoselective reaction was also achieved using menthol derivatives as a chiral auxiliary, delivering enantiomerically enriched α-amino acid bearing α,ß-continuous tetrasubstituted carbon. The synthesized highly congested unnatural α-amino acid could be derivatized and incorporated into peptide synthesis.

C-C Bond Cleavage of Unactivated 2-Acylimidazoles.

2-Acylimidazoles are widely used as post-transformable carboxylic acid equivalents in chemoselective and enantioselective reactions. Their transformations, however, require pretreatment with highly reactive, toxic methylating reagents to facilitate C-C bond cleavage. Here, we demonstrate that such pretreatment can be avoided and the C-C bond cleaved under neutral conditions without the use of additional reagents or catalysts. The scope of the reaction, including the use of products reported in the literature as substrates, and some mechanistic insights are described.

[A Case in Which Acotiamide Hydrochloride Was Effective for Reflux Esophagitis after Distal Gastrectomy with Billroth â Reconstruction for Gastric Cancer].

In a 65-year-old woman, anemia was observed during outpatient follow-up after right lung cancer surgery, and upper gastrointestinal endoscopy was performed for examination.Gastrointestinal endoscopy revealed a Type 2 tumor on the small curvature in the middle part of the stomach, and she was diagnosed with gastric cancer.Distal gastrectomy with D2 lymph node dissection and BillrothⅠ reconstruction was performed for the gastric cancer.There were no postoperative complications, and she was discharged on the ninth day after surgery.The pathological diagnosis was gastric cancer, ML, Less, Type 2, 67×55×15 mm, muc>sig>por, pT4a(SE)N2M0, fStage ⅢB.S -1 adjuvant chemotherapy was administered, but then discontinued in the second course due to the development of adverse events.Reflux symptoms appeared after the surgery, and her dietary intake was poor.Her body weight and serum albumin level at 3 and 5 months after surgery were 51 kg and 52.5 kg, respectively, and 3.2 g/dL and 2.7 g/dL, respectively.Because there was no improvement in the reflux symptom, oral administration of acotiamide hydrochloride was initiated 7 months after the surgery.After initiating oral intake of acotiamide hydrochloride, her dietary intake improved, and her body weight and serum albumin level at 11 and 15 months after surgery were 54 kg and 57 kg, respectively, and 3.0 g/dL and 2.7 g/dL, respectively.Peritoneal recurrence was observed 23 months after surgery, and her oral intake decreased, but the recurrence of reflux symptoms was not observed.Acotiamide hydrochloride could be an option for the treatment of reflux symptoms after gastrectomy.

[Curative Resection of Pancreatic Head Cancer with Liver Metastasis after GEM plus Nab-PTX Therapy].

A 63-year-old man was admitted to our hospital for examination and treatment of a pancreatic head tumor detected at a nearby hospital. After CT, EUS-FNA, and PET-CT, he was diagnosed with unresectable pancreatic cancer with liver metastasis. After 9 courses of gemcitabine and nab-paclitaxel therapy, the primary tumor was dramatically reduced in size and the liver metastasis had disappeared. He underwent subtotal stomach-preserving pancreaticoduodenectomy. The postoperative diagnosis according to the General Rules of the Study of Pancreatic Cancer(7th edition)was Ph, TS1(15mm), adenosquamous carcinoma, ypT3, ypRP1, ypPL1, R0, ypN0(0/29), M0, CY0, ypStage ⅡA. The histological response was Grade 2. The patient remains alive without recurrence 5 months after surgical resection.

Bioconjugation with Thiols by Benzylic Substitution.

A benzylic substitution of 3-indolyl(hydroxyl)acetate derivatives with thiols proceeded specifically in the presence of amino, carboxy, and phosphate groups in weakly acidic aqueous solutions under nearly physiological condition, while no reaction occurred at pH over 7. Kinetic studies revealed that the reaction followed second-order kinetics (first-order in the reactant and first-order in thiol) in contrast with the SN 1 mechanism of common benzylic substitution of alcohols. The utility of the present method for functionalization of biomacromolecules was demonstrated using several model proteins, such as lysozyme, insulin, trypsin, and serum albumin. The catalytic bioactivity of lysozyme in lysis of Micrococcus lysodeikticus cells was completely retained after the modification.

An Expeditious Route to trans-Configured Tetrahydrothiophenes Enabled by Fe(OTf)3 -Catalyzed [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes with Thionoesters.

A synthetic route to trans-configured tetrahydrothiophenes (THTs) through Fe(OTf)3 -promoted [3+2] cycloaddition of donor-acceptor cyclopropanes with thionoesters was developed. The cycloaddition proceeded in high yield with high diastereoselectivity, affording transient α-alkoxy THTs. Not only aromatic and aliphatic thionoesters, but also thionolactone were applicable to the present iron catalysis. Further transformation of the S,O-ketal functionality of the product was achieved in a highly trans diastereoselective manner. Moreover, the utility of our methodology was clearly demonstrated by the synthesis of enantioenriched trans-configured THTs.

3-Mono-Substituted BINOL Phosphoric Acids as Effective Organocatalysts in Direct Enantioselective Friedel-Crafts-Type Alkylation of N-Unprotected α-Ketiminoester.

Although BINOL-derived phosphoric acids are among the most widely used chiral Brønsted acid organocatalysts, their structures are mostly limited to 3,3'-disubstituted ones and simple 3-mono-substituted ones without any polar functionalities on the 3-substituent have not been used in highly enantioselective reactions. This work reports such 3-mono-substituted analogues as effective organocatalysts in direct highly enantioselective Friedel-Crafts-type alkylation of N-unprotected α-ketiminoester. The origin of the observed high enantioselectivity with the 3-mono-substituted catalyst is also discussed.

[A Case Report of Retroperitoneal Liposarcoma Resected Six Times for 16 Years].

We report of a long-surviving patient with retroperitoneal liposarcoma that required 6 surgeries in 16 years. A 62-year-old man was diagnosed with liposarcoma, which was first excised in 2001. Thereafter, we excised recurrences in the retroperitoneum with the left kidney in February 2004. We excised recurrences with the left half of the colon in November 2007 and February 2010 and recurrences with a part of the intestine in November 2014. This time, we excised recurrences under the right abdominal rectus muscle and near the left half of the colon. The pathological diagnosis was well-differentiated liposarcoma. There is currently no evidence of recurrence 16 years after the first recurrence excision. In this case, active excision of recurrences and identification of high-grade dedifferentiated-type liposarcomas were factors of long survival.

[A Case Report of Laparoscopy-Assisted Distal Gastrectomy for Early Gastric Cancer with Abortive Behçet Disease].

A 32-year-old woman with a history of undergoing upper gastrointestinal surgery was administered prednisolone for abortive Behçet's disease since 2015. In March 2017, upper gastrointestinal endoscopy revealed a 0-IIc type early stage gastric carcinoma at the posterior wall of the gastric antrum. The pathological diagnosis was signet-ring cell carcinoma. This gastric carcinoma was classified as cT1aN0M0; therefore, endoscopic submucosal dissection(ESD)was performed for the expanded indication lesion in April 2017. The pathological diagnosis after ESD indicated the need for non-curative resection; thus, laparoscopy-assisted distal gastrectomy and Billroth I anastomosis were performed in July 2017. A transient anastomotic structure was admitted after this surgery, but she was discharged from the hospital lighthearted. A preoperative important aspect was the careful examination of all intestinal tracts for ulcer lesions, and an intraoperative important aspect was hand-sewn anastomosis because using a metallic stapler conferred a high risk of ulcer lesions and suture failure. We encountered a case wherein laparoscopy-assisted distal gastrectomy was performed in a patient with abortive Behçet's disease, early stage gastric carcinoma, and a history of undergoing upper gastrointestinal surgery.

Direct Access to N-Unprotected α- and/or ß-Tetrasubstituted Amino Acid Esters via Direct Catalytic Mannich-Type Reactions Using N-Unprotected Trifluoromethyl Ketimines.

Direct catalytic C-C bond-forming addition to N-unprotected ketimines is an efficient and straightforward method of synthesizing N-unprotected tetrasubstituted amines that eliminates prior protection/deprotection steps and allows facile transformation of the products. Despite its advantages, however, N-unprotected ketimines have difficulties in C-C bond-forming reactions, and only a limited number of reactions and substrates are reported compared with their N-protected counterparts. Herein we report that N-unprotected trifluoromethyl ketimines are effective for C-C bond-forming reactions using Mannich-type reactions as a model case. We demonstrate that Lewis acid catalysis was effective for promoting reactions with various N-unprotected trifluoromethyl ketimines, and thiourea organocatalysis was effective for promoting highly enantioselective reactions with various carbonyl nucleophiles, providing direct access to various N-unprotected α- and/or ß-tetrasubstituted amino acid esters. Furthermore, direct construction of vicinal tetrasubstituted chiral carbon stereocenters was achieved for the first time in a highly enantio- and diastereoselective manner. These results demonstrate the potential of N-unprotected ketimines as substrates applicable to many other addition reactions.

Synthesis of 1-Tetrasubstituted 2,2,2-Trifluoroethylamine Derivatives via Palladium-Catalyzed Allylation of sp3 C-H Bonds.

This note describes the construction of tetrasubstituted carbon stereocenters via palladium-catalyzed allylation of sp3 C-H bonds of 2,2,2-trifluoroethylamine derivatives. The presence of 2-pyridyl group of the imines derived from 1-substituted-2,2,2-trifluoroethylamine was key to promoting the reaction efficiently, allowing an access to a variety of 1-allylated 2,2,2-trifluoroethylamine derivatives with tetrasubstituted carbon stereocenters.

Catalytic Chemoselective Conjugate Addition of Amino Alcohols to α,ß-Unsaturated Ester: Hydroxy Group over Amino Group and Conjugate Addition over Transesterification.

A highly chemoselective conjugate addition of amino alcohols to α,ß-unsaturated ester using a soft Lewis acid/hard Brønsted base cooperative catalyst was developed. This catalysis achieved chemoselective addition of a hydroxy group over an amino group. Moreover, soft metal alkoxide generation enabled chemoselective soft conjugate addition over hard transesterification. Various amino alcohols, including unprecedented cyclic ß-amino alcohol, were applicable to the present catalysis.

[A Case of Laparoscopic Repair of Internal Hernia after Laparoscope-Assisted Distal Gastrectomy with Antecolic Roux-en-Y Reconstruction].

A 72-year-old woman had undergone laparoscope-assisted distal gastrectomy with D1 plus lymph node dissection and antecolic Roux-en-Y reconstruction for early gastric cancer. She visited our department outpatient clinic with left upper abdominal pain 1 year and 9 months after the surgery. CT revealed a spiral sign of the superior mesenteric arteriovenous branch. An internal hernia was suspected on hospitalization. Although abdominal symptoms were relieved by conservative treatment, the hernia persisted. Laparoscopic surgery was performed and revealed that almost entire small intestine had been affected due to Petersen's defect. Since no ischemic changes were observed, the defect was repaired laparoscopically with suture closure. There has been no recurrence of internal hernia after the laparoscopic surgery. Internal hernia after distal gastrectomy is relatively rare. However, the risk of internal hernia is high due to the gap between the elevated jejunum and transverse colon mesentery in Roux-en-Y reconstruction and can lead to intestinal necrosis. Since an internal hernia can occur in patients who have undergone gastric resection with Roux-en-Y reconstruction, suture closure of Petersen's defect should be performed to prevent this occurrence.

A novel anti-microtubule agent with carbazole and benzohydrazide structures suppresses tumor cell growth in vivo.

BACKGROUND: The mitotic spindles are among the most successful targets of anti-cancer chemotherapy, and they still hold promise as targets for novel drugs. The anti-mitotic drugs in current clinical use, including taxanes, epothilones, vinca alkaloids, and halichondrins, are all microtubule-targeting agents. Although these drugs are effective for cancer chemotherapy, they have some critical problems; e.g., neurotoxicity caused by damage to neuronal microtubules, as well as innate or acquired drug resistance. To overcome these problems, a great deal of effort has been expended on development of novel anti-mitotics. METHODS: We identified novel microtubule-targeting agents with carbazole and benzohydrazide structures: N'-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-methylbenzohydrazide (code number HND-007) and its related compounds. We investigated their activities against cancer cells using various methods including cell growth assay, immunofluorescence analysis, cell cycle analysis, tubulin polymerization assay, and tumor inhibition assay in nude mice. RESULTS: HND-007 inhibits tubulin polymerization in vitro and blocks microtubule formation and centrosome separation in cancer cells. Consequently, it suppresses the growth of various cancer cell lines, with IC50 values in the range 1.3-4.6µM. In addition, HND-007 can inhibit the growth of taxane-resistant cancer cells that overexpress P-glycoprotein. Finally, HND-007 can inhibit HeLa cell tumor growth in nude mice. CONCLUSIONS AND GENERAL SIGNIFICANCE: Taken together, these findings suggest that HND-007 is a promising lead compound for development of novel anti-mitotic, anti-microtubule chemotherapeutic agents.

Direct Catalytic Chemoselective α-Amination of Acylpyrazoles: A Concise Route to Unnatural α-Amino Acid Derivatives.

A direct copper-catalyzed highly chemoselective α-amination is described. Acylpyrazole proved to be a highly efficient enolate precursor of a carboxylic acid oxidation state substrate, while preactivation by a stoichiometric amount of strong base has been used in catalytic α-aminations. The simultaneous activation of both coupling partners, enolization and metal nitrenoid formation, was crucial for obtaining the product, and wide functional group compatibility highlighted the mildness of the present catalysis. The bidentate coordination mode was amenable to highly chemoselective activation over ketone and much more acidic nitroalkyl functionality. Deuterium exchange experiments clearly demonstrated that exclusive enolization of acylpyrazole was achieved without the formation of a nitronate. The present catalysis was applied to late-stage α-amination, allowing for concise access to highly versatile α-amino acid derivatives. The product could be transformed into variety of useful building blocks.

Mechanistic Studies and Expansion of the Substrate Scope of Direct Enantioselective Alkynylation of α-Ketiminoesters Catalyzed by Adaptable (Phebox)Rhodium(III) Complexes.

Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-κ(2)O,O')(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to use (acetato-κ(2)O,O')(trimethylsilylethynyl)(phebox)rhodium(III) complexes as a general precatalyst for various (alkynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol % and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.