Determinants of Long-term Survival Decades After Esophagectomy for Esophageal Cancer.

BACKGROUND: Long-term survival in esophagectomy patients with esophageal cancer is low due to tumor-related characteristics, with few reports of modifiable variables influencing outcome. We identified determinants of overall survival, time to recurrence, and disease-free survival in this patient cohort. METHODS: Adult patients who underwent esophagectomy for primary esophageal cancer from January 5, 2000, through December 30, 2010, at our institution were identified. Univariate Cox models and multivariable logistic regression analyses were used to identify associations between modifiable and unmodifiable patient and clinical variables and outcome of survival for the total cohort and a subgroup with locally advanced disease. RESULTS: We identified 870 patients with esophageal cancer who underwent esophagectomy. The median follow-up time was 15 years, and the 15-year overall survival rate was 25.2%, survival free of recurrence was 57.96%, and disease-free survival was 24.21%. Decreased overall survival was associated with the following unmodifiable variables: older age, male sex, active smoking status, history of coronary artery disease, advanced clinical stage, and tumor location. Decreased overall survival was associated with the following modifiable variables: use of neoadjuvant therapy, advanced pathologic stage, resection margin positivity, surgical reintervention, and blood transfusion requirement. The overall survival probability 6 years after esophagectomy was 0.920 (95% CI, 0.895-0.947), and time-to-recurrence probability was 0.988 (95% CI, 0.976-1.000), with a total of 17 recurrences and 201 deaths. CONCLUSIONS: Once patients survive 5 years, recurrence is rare. Long-term survival can be achieved in high-volume centers adhering to National Comprehensive Cancer Network guidelines using multidisciplinary care teams that is double what has been previously reported in the literature from national databases.

Genomic, transcriptomic, and metabolomic analysis of Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti-cancer metabolites.

Plants accumulate a vast array of secondary metabolites, which constitute a natural resource for pharmaceuticals. Oldenlandia corymbosa belongs to the Rubiaceae family, and has been used in traditional medicine to treat different diseases, including cancer. However, the active metabolites of the plant, their biosynthetic pathway and mode of action in cancer are unknown. To fill these gaps, we exposed this plant to eight different stress conditions and combined different omics data capturing gene expression, metabolic profiles, and anti-cancer activity. Our results show that O. corymbosa extracts are active against breast cancer cell lines and that ursolic acid is responsible for this activity. Moreover, we assembled a high-quality genome and uncovered two genes involved in the biosynthesis of ursolic acid. Finally, we also revealed that ursolic acid causes mitotic catastrophe in cancer cells and identified three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking. Altogether, these results constitute a valuable resource to further characterize the biosynthesis of active metabolites in the Oldenlandia group, while the mode of action of ursolic acid will allow us to further develop this valuable compound.

[Efficacy and safety of daratumumab in patients with relapsed/refractory multiple myeloma].

Objective: To investigate the efficacy and safety of daratumumab in relapsed/refractory multiple myeloma (RRMM) patients. Methods: Fifty-two RRMM patients treated with daratumumab from September 2019 to November 2021 in West China Hospital were retrospectively enrolled, including 31 males and 21 females. The mean age of these patients at the first diagnosis of multiple myeloma was (58±10) years. According to the dosage of daratumumab, patients were divided into low dosage group (n=10) and high dosage group (n=42). Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse event rates were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of the 52 patients, 8 received daratumumab monotherapy, 27 received daratumumab plus immuno-modulatory drug (IMiD) treatment, 4 received daratumumab plus proteosome inhibitor (PI) treatment, and 11 received daratumumab plus dexamethasone treatment. The diagnosis age of high dosage group patients was (57±9) years, which was significantly younger than that of low dosage group [(66±10) years] (P=0.009). The baseline creatinine level of high dosage group patients [M (Q1, Q3)] was 91 (68, 196) µmol/L, which was significantly higher than that of low dosage group [66 (51, 76) µmol/L] (P=0.021). There was no significant difference in other baseline clinical characteristics, previous treatment regimens, previous lines of treatment, and regimen and cycles of daratumumab between the high dosage group and low dosage group (all P>0.05). The ORR for the 52 patients was 71.2% (37/52). The ORR for daratumumab plus IMiD group was 81.5% (22/27), which was significantly higher than that in monotherapy or dexamethasone group [ORR: 52.6% (10/19), P=0.036). With a median follow-up [M (Q1, Q3)] of 7 (5, 26) months, the median PFS for overall cohort was 17 (95%CI: 9.6-24.4) months. The median PFS for daratumumab plus IMiD group was 26 (95%CI: 6.0-46.0) months, which was significantly better than that in monotherapy or dexamethasone group [12 (95%CI: 3.5-20.5) months] (HR=0.231, 95%CI: 0.075-0.715, P=0.011). Higher diagnosis age was the risk factor of progression (HR=1.085, 95%CI: 1.016-1.158, P=0.014), while more cycles of daratumumab treatment was the protective factor of progression (HR=0.669, 95%CI: 0.495-0.904, P=0.009). There was no significant influence of daratumumab dosage on progression (high dosage vs low dosage, HR=1.016, 95%CI: 0.221-4.668, P=0.984). The median OS for overall cohort was 26 (95%CI: 13.1-38.9) months. Higher serum calcium was the independent risk factor of death (HR=12.190, 95%CI: 1.170-127.048, P=0.037). There was no significant influence of daratumumab dosage on death (high dosage vs low dosage, HR=0.818, 95%CI: 0.171-3.917, P=0.802). Adverse events included infections (43.2%, 16/37), infusion-associated reactions (29.7%, 11/37), and thrombocytopenia (27.0%, 10/37). Conclusions: Daratumumab is effective to treat RRMM. The dosage of daratumumab has no significant influence on prognosis when used in combined treatment. The incidence of adverse events is relatively low, with a favorable safety profile.

[Analysis of the factors influencing adjuvant chemotherapy decisions for triple negative breast cancer].

Objective: To analyze adjuvant chemotherapy decisions for triple negative breast cancer (TNBC), and explore the influencing factors in the multidisciplinary treatment (MDT) modality. Methods: A retrospective analysis was performed. The cases with invasive TNBC who underwent surgery and MDT discussion for adjuvant treatment in Ruijin Hospital, from April 2013 to June 2015, were recruited. The patients' clinicopathological characteristics were analyzed and adjuvant treatment suggestions from MDT were obtained. Here the chemotherapy decision alteration was defined as a disagreement in chemotherapy or not, or inconsistence in regimens between the attending doctor and the multidisciplinary team. Results: A total of 194 patients aged ≤70 years old were enrolled in the multidisciplinary discussion, and 187 patients (96.4%) were suggested to receive chemotherapy. When compared the opinions of the attending doctor to suggestions of the multidisciplinary team, we found that the percentage of chemotherapy decision alteration reached 22.7% (39/172), of which 94.9% (37/39) were inconsistence in chemotherapy regimens. There were 119 patients who were recommended to receive epirubicin plus cyclophosphamide (EC) followed by docetaxel (T) or weekly paclitaxel (wP) regimens. Before the announcement of results for the E1199 trial, EC-T accounted for 62.5% (55/88), and EC-wP accounted for 37.5% (33/88) for this group of patients. After that, the proportion of EC-T was decreased to 22.6% (7/31) and proportion of EC-wP increased to 77.4%(24/31) (P<0.001). In addition, a total of 20 patients were suggested to receive platinum based chemotherapy. The proportions were 9.3% in cases with invasive ductal carcinoma, and 33.3% in cases with metaplastic carcinoma, respectively (P=0.016). Conclusions: The adjuvant chemotherapy decision for TNBC patients is altered in 22.7% of the patients after MDT discussion. After the announcement of SABCS E1199 results, more patients are suggested to receive EC followed by weekly paclitaxel. There is a lack of detailed evidence for platinum based adjuvant chemotherapy for TNBC, and more patients with metaplastic carcinoma receive platinum based adjuvant chemotherapy.

Water extract of Zizyphus Jujube attenuates ischemia/reperfusion-induced liver injury in rats (PP106).

AIMS: Ischemia and reperfusion (I/R) injuries in the liver remain important clinical problems. Free oxygen radicals and nitrosative stress have been shown to be involved in the pathogenesis I/R-related liver injury. The purpose of this study was to characterize the effects of an extract of Zizyphus Jujube (ZJ), which has strong antioxidant effects, on I/R-induced liver injury. MATERIALS AND METHODS: Ischemia (I) was induced in rat livers by clamping the common hepatic artery and portal vein for 40 minutes, after which flow was restored, and the liver was reperfused for 90 minutes. Blood samples were collected prior to I and after reperfusion to assay blood levels of alanine transaminase (ALT), lactic dehydrogenase (LDH), oxygen radical (OH), and nitric oxide (NO). In the pharmacologic intervention group a water extract of the fruit of ZJ was administered orally to rats (100 mg/mL for 7 days) that were subsequently exposed to the I/R liver injury. RESULTS: The data showed that reperfusion (R) of the liver produced increases in blood concentrations of ALT (41.9+/-8.2 vs 338.0+/-89.6; P<.01; N=7) and LDH (317+/-129 vs 4073+/-950; P<.001; N=7). Oxygen radicals (55.1+/-14.3 vs 262.4+/-60.3; P<.001; N=7) and NO (69.3+/-14.9 vs 121.6+/-27.1; P<.01; N=7) also increased significantly in this R group. In the ZJ intervention group the liver injury, oxidative stress, and nitrosative stress were all significantly attenuated. CONCLUSION: These results suggested that I/R-induced liver injury with white blood cell activation, oxidative stress, and nitrosative stress. Pretreatment with an extract of ZJ, which shows high antioxidant effects, significantly attenuated the I/R-induced liver injury.

A randomized controlled trial of bupivacaine through intracostal catheters for pain management after thoracotomy.

BACKGROUND: Optimal management of pain after thoracotomy can be challenging. Continuous infusion of local anesthetic into the incision may help reduce the amount of narcotics required to control postoperative pain. To address this issue, we performed a randomized, double-blinded, controlled trial of infusion of bupivacaine versus placebo through intercostal and subcutaneous catheters after thoracotomy. METHODS: From April 2006 to June 2007, 124 patients had intercostal catheters placed at thoracotomy and connected to continuous infusion pain pumps. Each patient had catheters placed in the intercostal space near the head of the rib and subcutaneously beneath the incision; both were connected to an infusion pump through a Y connector. Patients were randomly assigned to receive placebo (normal saline solution) or 0.25% bupivacaine as a 4 cc per hour infusion for 100 hours after thoracotomy. All personnel caring for the patients were blinded to the content of the infusion. Demographic information, visual analog pain scores, and oral morphine equivalent usage was recorded for each patient. In addition to the infusion catheters, all patients had epidural analgesia that remained in place until postoperative day 3. RESULTS: There were 60 patients in the bupivacaine arm and 64 in the placebo group. Overall mean age was 64.7 years and 65 (52.4%) were men. Mean body mass index was 28.8 kg/m(2). There were no statistical differences in any demographic parameter except that there were more men in the placebo group. Pulmonary resection was performed in 100 patients, an antireflux procedure in 16, and other miscellaneous procedures in 8. There was no statistical difference in the morphine equivalent usage between the two groups. There was also no difference between the average daily pain scores between the two groups. Length of stay was not significantly different between groups: mean (SD) of 6.2 (3.4) and 6.7 (5.0) for placebo and bupivacaine, respectively (p = 0.51). There was no operative mortality, and complications occurred in 28% of patients (placebo group, 25%; bupivacaine group, 32%; p = 0.41). CONCLUSIONS: This randomized, double-blinded, controlled trial demonstrated that the infusion of local anesthetic into the subcutaneous area and around the rib fracture site in addition to epidural analgesia did not reduce the amount of narcotic usage after a thoracotomy, nor did it affect visual analog pain scores. Pain control with intercostal catheters infusing local anesthetics did not produce a measurable pain relief beyond that provided by epidural analgesia.

Concomitant chemoradiation treatment in the management of patients with extrahepatic biliary tract recurrence of gastric carcinoma.

BACKGROUND: The aim of this study was to determine the role of concomitant chemoradiation in the alleviation of obstructive jaundice in patients with extrahepatic biliary tract metastases from gastric carcinoma. METHODS: Thirteen patients with good performance status who had obstructive jaundice resulting from extrahepatic biliary metastases after gastrectomy for gastric carcinoma were treated with palliative intent. Treatment consisted of insertion of a percutaneous transhepatic choledochal drainage (PTCD) catheter followed by external radiation up to a total dose of 40-60 grays in combination with chemotherapy (cisplatin 20 mg/m(2)/day, 5-fluorouracil 600 mg/m(2)/day, and leucovorin 90 mg/m(2)/day for 96 hours during the first and fifth weeks) on an outpatient basis. RESULTS: The concomitant chemoradiation produced a good palliative effect in all 13 patients. Hyperbilirubinemia continued to improve after treatment, patients' clay-colored stool resolved within an average of 4 weeks (range, 2-6 weeks), and bilirubin levels returned to normal. The PTCD catheter could be removed after treatment was completed (the seventh week); the mean duration of PTCD placement was 2 months. The entire treatment course was performed on an outpatient basis; hospital admission was necessary only for PTCD insertion and chemotherapy. Ten patients died of their disease, with an average survival of 14.4 months (range, 4-31 months) from the time of PTCD insertion. Three patients are still alive at 16, 21, and 8 months. Biliary tract patency was maintained until death. No serious treatment-related complications occurred, and no endoprothesis or intraluminal brachytherapy was needed in this study. CONCLUSIONS: Satisfactory palliation can be achieved by concomitant chemoradiation for patients with obstructive jaundice resulting from extrahepatic biliary metastases from gastric carcinoma, providing an alternative treatment choice for these patients.

A versatile microporation technique for the transfection of cultured CNS neurons.

The application of molecular techniques to cultured central nervous system (CNS) neurons has been limited by a lack of simple and efficient methods to introduce macromolecules into their cytosol. We have developed an electroporation technique that efficiently transfers RNA, DNA and other large membrane-impermeant molecules into adherent hippocampal neurons. Microporation allowed the use of either in vitro transcribed RNA or cDNA to transfect neurons. While RNA transfection yielded a higher percentage of transfected neurons and produced quantitative co-expression of two proteins, DNA transfection yielded higher levels of protein expression. Dextran-based calcium indicators also were efficiently delivered into the cytosol. Microporated neurons appear to survive poration quite well, as indicated by their morphological integrity, electrical excitability, ability to produce action potential-evoked calcium signals, and intact synaptic transmission. Furthermore, green fluorescent protein (GFP)-tagged marker proteins were expressed and correctly localized to the cytosol, plasma membrane, or endoplasmic reticulum. The microporation method is efficient, convenient, and inexpensive: macromolecules can be introduced into most adherent neurons in a 3 mm2 surface area while requiring as little as 1 microl of the material to be introduced. We conclude that the microporation of macromolecules is a versatile approach to investigate signaling, secretion, and other processes in CNS neurons.

[Effect of xueling on relating substances of renal hypertension in rats].

Xueling(p.o.) obviously reduces the aldosterone content of renal hypertension rats, but not affecting markedly the endothelin, atrial natriuretic factor, calcitonin gene-related peptide, thromboxane B2 and 6-keto-prostaglandin F1 alpha. The content reduction of aldosterone is one of the mechanisms to lower blood pressure.

The prognosis of biopsy-proven lupus nephritis in chinese patients: long term follow-up of 86 cases.

OBJECTIVE: To investigate the prognosis of lupus nephritis (LN) and its influencing factors in patients with lupus nephritis in China. METHODS: A retrospective study was carried out in 86 patients followed up for at least 5 years. Clinical features, serological and immunological tests were investigated. Renal biopsies were performed at the beginning of the study and repeated in some cases during the follow-up period. All the 86 patients had serum creatinine (Scr) level less than 132.6 mumol/L at the initial presentation and were divided into three groups according to the level of Scr at the end of the study. Group I: the patients with normal renal function (Scr < 132.6 mumol/L); Group II: the patients with mild-moderate renal insufficiency (132.6 mumol/L < or = SCR < or = 530.4 mumol/L); Group III: the patients with end stage renal failure (ESRF) (Scr > or = 530.4 mumol/L). RESULTS: Forty-seven patients reached clinical remission with normal renal function, 11 had with stabilization of renal function, although the systemic lupus erythematosis (SLE) activity relapsed repeatedly, while 28 subjects developed renal insufficiency after 60-170 (mean 88.12 +/- 28.23) months of observation. ESRF rate was 11.6% in this group of patients. Eight patients died (2 died of infections and 6 died of ESRF) during the follow-up period. At the beginning of the study the rates of hypertension, persistent anemia and hematuria in Group II were 50%, 70%, and 70% respectively, being much higher than those in Group I. The calculation of AI and CI in 60 patients revealed that there were 65% of patients with AI > or = 7 and 70% of patients with CI > or = 3 in Groups II and III, while in Group I there were only 32% of patients with AI > or = 7 and 19% of patients with CI > or = 3. Sixteen cases had pathologic class changed in 48 repeated biopsies. Seven cases changed to Class IV, 5 to Class II, 3 to Class V from other classes and one to class III from Class II. CONCLUSIONS: Factors associated with the development of renal insufficiency in these lupus patients included hypertension, anemia and hematuria. Renal biopsy evaluation offered additional prognostic information and showed that patients with severe active and chronic histologic changes were at risk for developing renal insufficiency. During the clinical course, the renal classification of LN changed in certain patients, thus the histologic classification of renal morphology at initial presentation did not fully predict the outcome. Renal involvement is very common in systemic lupus erythematosis (SLE) patients. Lupus nephritis (LN) is the most common form of secondary renal disease in China. It has various and unpredictable clinical features. The risks associated with its treatment have challenged investigators to detect the factors which may influence the survival rate of patients with LN and to develop the rational approaches to therapy. Decades of intensive investigation at many centers around the world had underscored the predictive value of demographic, clinical and laboratory data prior to treatment. Controversies still existed due to the difference in environment, race and the selection criteria of patients as well as the method used to evaluate the outcome. There are still some factors which are thought to have an impact on the prognosis of LN. Most of the articles on the prognosis of patients with LN were reported from Europe and America either about Caucasian or African-American patients. The prognosis of LN and its influence in Chinese patients need more elucidation.

[Cox proportion hazard model multivariate analysis of prognosis of 1,484 axillary node-negative breast cancer patients].

OBJECTIVE: To study the prognosis of axillary node-negative breast cancer patients. METHODS: The data were analyzed in 1,484 consecutive axillary node-negative breast cancer patients. Twenty-two individual variables were evaluated statistically using the cumulative survival rate by the computer's Cox multivariate analysis model. RESULTS: Menopausal status, times of pregnancy, duration before diagnosis, pregnancy-associated, tumor size, intramammary lymph node, postoperative radiotherapy and postoperative adjuvant tamoxifen therapy were independent predictors of prognosis. CONCLUSION: Parts of high risk group among axillary node-negative breast cancer patients could be identified by clinical parameters. Postoperative radiotherapy or ovarian ablation was not indicated for axillary node-negative breast cancer patients. Tamoxifen as postoperative adjuvant therapy should not be restricted to postmenopausal or ER-positive patients. The selection of high risk patients with axillary node-negative breast cancer who should receive adjuvant chemotherapy remains to be investigated at present.

Effect of selenium on 1,2-dimethylhydrazine-induced intestinal cancer in rats.

PURPOSE: This study was designed to determine the cancer prevention and therapeutic effects of selenium on rats treated with 1,2-dimethylhydrazine (DMH). METHODS: One hundred sixty Spraque-Dawley male rats were divided into seven groups and received 20 mg/kg/week DMH, subcutaneously for 20 weeks. Two different dosages of selenium (8 and 4 ppm) were administered to the rats through drinking water during DMH treatment (B and C groups) or one month before and during DMH treatment (D and E groups). The rats of Groups A (control group), B, C, D, and E were killed immediately after the last DMH injection. The incidence of intestinal cancer in each group was compared. Eight ppm selenium was also administered to rats after DMH treatment (Group F), and survival times were observed and compared with Group G (treated with DMH only). RESULTS: Rats of Groups B and D received 8 ppm selenium and had a significantly decreased incidence of intestinal cancer (from 65.8 percent (Group A) to 33.3 percent (Group B) and 27.8 percent (Group D); P = 0.0225 and 0.0038). Rats receiving 4 ppm selenium had a relatively decreased incidence of intestinal cancer (from 65.8 percent (Group A) to 44.4 percent (Group C) and 47.1 percent (Group E) but P > 0.05). Survival time of Groups F and G showed no difference. CONCLUSIONS: Eight ppm selenium provided via drinking water has a significant intestinal cancer prevention effect in the presence of a high dose of DMH (20 mg/kg x 20 weeks), and the cancer therapeutic effect of selenium is doubtful in this animal model.

Calcium-activated potassium channels expressed from cloned complementary DNAs.

Calcium-activated potassium channels were expressed in Xenopus oocytes by injection of RNA transcribed in vitro from complementary DNAs derived from the slo locus of Drosophila melanogaster. Many cDNAs were found that encode closely related proteins of about 1200 aa. The predicted sequences of these proteins differ by the substitution of blocks of amino acids at five identified positions within the putative intracellular region between residues 327 and 797. Excised inside-out membrane patches showed potassium channel openings only with micromolar calcium present at the cytoplasmic side; activity increased steeply both with depolarization and with increasing calcium concentration. The single-channel conductance was 126 pS with symmetrical potassium concentrations. The mean open time of the channels was clearly different for channels having different substituent blocks of amino acids. The results suggest that alternative splicing gives rise to a large family of functionally diverse, calcium-activated potassium channels.

Cholinergic mechanisms in the rat's hypothalamus mediate the stimulatory effect of thyrotropin-releasing hormone on gastric secretion.

To assess the possible involvement of cholinergic mechanisms in the hypothalamic nuclei in the stimulatory effect of TRH on gastric secretion, rats were infused with thyrotropin-releasing hormone (TRH), cholinergic agonist or antagonist, and normal saline through previously implanted hypothalamic cannulae. Administration of TRH or pilocarpine into the lateral cerebral ventricle or the anterior hypothalamus caused a dose-related increase in gastric volume and acidity in rats. On the other hand, administration of either atropine or D-tubocurarine into the same brain sites caused the opposite effects. Furthermore, the stimulatory effect of TRH or pilocarpine on gastric secretion was completely abolished by pretreatment of the CSF or the anterior hypothalamus with atropine and to a lower degree, D-tubocurarine. Administration of TRH, pilocarpine, atropine or D-tubocurarine into the lateral hypothalamus produced only a slight effect on gastric volume and acidity. However, the gastric volume or acidity was not affected by administration of either TRH, pilocarpine, atropine or D-tubocurarine into the ventromedial hypothalamus in our rats. The data indicate that the cholinergic muscarinic receptor mechanisms in the anterior hypothalamus may mediate the stimulatory effect of TRH on gastric secretion in rats.

Influence of medicinal herbs decocted with different utensils on colony formation of gastric carcinoma cells.

In order to elucidate the different results obtained in cancer patients with similar condition and symptoms treated by the same medicinal herbs, an investigation of the utensils used for making decoctions was carried out. It was found that the decoction made by means of glassware, enamel and earthenware pots had the best effect of inhibiting the colony formation of human gastric carcinoma cells, the next were the decoctions made by means of unrefined iron pots, stainless steel pots and copper pots, and the worst was that made with aluminium pots. It was also found that there was no difference between the water contained in those utensils and normal saline in the influence on the colony formation of human gastric carcinoma cells. Therefore, it is believed that the difference in effect of the decoctions made by means of different kinds of utensils is not due to the trace dissolution of the utensil materials, but is most likely due to the occurrence of some chemical reactions while making the decoction. That the decoctions made by means of different utensils had different peak values in the absorption spectrum also supports this proposition.

Effect of stimulation of bulbar reticular formation on long latency discharges in the region of nucleus centralis lateralis of thalamus.

Electrical stimulation of medial medullary reticular formation of rabbits was found to have marked inhibitory effect on nociceptive discharges of neurons in the region of centrolateral nucleus of thalamus. Among the 32 nociceptive units tested, 15 showed the inhibitory effect, 3 the facilitatory, and 14 no effect. Comparison between the effect of direct stimulation of medial medullary reticular formation and that of the electric needling on the same neurons revealed a general resemblance of the two in many respects. These findings suggest that the nucleus reticularis gigantocellularis in medial bulbar reticular formation may serve as an important relay station in the transmission of the analgesic effect of acupuncture.