Immune cell patterns before and after neoadjuvant immune checkpoint blockade combined with chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. PATIENTS AND METHODS: A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. RESULTS: In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. CONCLUSIONS: Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Analysis of urethral blood flow by high-resolution laser speckle contrast imaging in a rat model of vaginal distension.

OBJECTIVE: To investigate the feasibility of laser speckle contrast imaging (LSCI) for monitoring urethral blood flow (UBF). MATERIALS AND METHODS: In this study, 18 healthy, virgin female Sprague-Dawley rats aged 8-week-old were used. The animals were divided into the sham group (n = 9) and the vaginal distension (VD) group (n = 9). The sham group underwent one catheterization of the vagina without distension and the VD group underwent one VD. Following the VD or sham treatment for one week, LSCI assessment of urethral blood flow was performed during bladder filling and leak point pressure (LPP) process. RESULTS: During the LPP process, in the VD group, the mean LPP was significantly lower than in the sham group (p < 0.05) and the mean UBF level was also significantly lower than in the sham group (p < 0.05) in the LPP condition. The mean relative change of UBF (Δ Flow) was significantly different between the sham group and VD group. The value was 0.646 ± 0.229 and 0.295 ± 0.19, respectively (p < 0.05). During the bladder filling process, the VD group had a significant lower mean UBF level than the sham group under full bladder conditions (p = 0.008). The mean ΔFlow was also significantly lower than in the sham group. The value was 0.115 ± 0.121 and 0.375 ± 0.127, respectively (p = 0.016). CONCLUSIONS: The results confirmed that LSCI was able to determine UBF in female rats. The VD group had lower baseline UBF and lower increases in UBF during bladder filling and LPP process compared with the sham group.

Morphological and histological changes in the urethra after intraurethral nonablative erbium YAG laser therapy: an experimental study in beagle dogs.

The purpose of this study was to investigate the morphological and histological changes in the urethra in beagle dogs after intraurethral Er:YAG laser irradiation in nonablative mode to confirm the safety of this therapy. Six 2-year-old healthy female virgin beagle dogs (13 ± 1.51 kg) were used in this study. The animals were divided into 2 groups: the sham group, which received sham treatment (n = 3) involving insertion of an intraurethral cannula and laser delivery handpiece into the urethra without laser irradiation, and the experimental group (n = 3), which received intraurethral Er:YAG laser irradiation. The laser irradiation parameters were set according to clinical criteria (4 mm spot size, 1.5 J/cm2, 1.4 Hz, and 4 pulses) in nonablative mode. All animals received three sequential sessions at 4-week intervals. Urethrography and urethroscopy were performed in the 12th week and 13th week, respectively, after the first treatment. After urethroscopy, the animals were sacrificed, and urethral tissue was harvested for histological investigations. All procedures were performed under general anesthesia (40 mg/kg 3% sodium pentobarbital, i.v.). Transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) expression levels were measured to evaluate the biochemical characteristics of the scar. Urethral stricture was not found by urethrography or urethroscopy in either group. Urethral epithelium thickness and collagen expression under the urethral mucosa were significantly increased in the experimental group compared with the sham group. However, there were no significant differences in TGF-ß1 and α-SMA expression between the experimental group and sham group (p > 0.05). Urethral stricture is not found in beagle dogs after clinically relevant intraurethral nonablative mode Er:YAG laser irradiation. Proliferation of urethral collagen and the urethral mucosa may be one of the mechanisms by which urine leakage symptoms can be improved.

Prophylactic Antibiotics for Urinary Tract Infections after Urodynamic Studies: A Meta-Analysis.

AIM: We aimed to perform a meta-analysis to determine whether antibiotic prophylaxis reduces the incidence of urinary tract infections (UTIs) after urodynamic studies (UDS). METHODS: We conducted a systematic search of PubMed, Web of Science, Ovid, Elsevier, ClinicalKey, Embase, Cochrane Library, Medline, and Wiley Online Library. Randomized controlled trials (RCTs) comparing the effectiveness of prophylactic antibiotics with placebo or no treatment in preventing UTI after UDS were included. Two reviewers extracted data independently, and RevMan 5.3 software was used to analyze relative risk (RR) with 95% confidence intervals (CI). Heterogeneity was assessed by the Q test and I 2 test. RESULTS: The final meta-analysis included 1829 patients in 13 RCTs. Compared with the placebo or no treatment group, prophylactic antibiotics could significantly reduce the risk of bacteriuria (RR = 0.42, 95% CI: 0.30-0.60) and the risk of symptomatic UTI (RR = 0.65, 95% CI: 0.48-0.88). In addition, there was no statistically significant difference in the risk of adverse events (RR = 4.93, 95% CI: 0.61-40.05). No significant heterogeneity or publication bias was found in this study. CONCLUSIONS: Current evidence showed that prophylactic antibiotics could reduce the risk of asymptomatic bacteriuria and symptomatic UTI after UDS without increasing the incidence of adverse events.

Comparison of three kinds of mid-urethral slings for surgical treatment of female stress urinary incontinence.

AIMS: A study was conducted to compare the efficacy and complications of tension-free vaginal tape (TVT), transobturator vaginal tape inside-out TVT-O and transobturator vaginal tape out-inside (TOT) procedures for the surgical treatment of female stress urinary incontinence SUI. METHODS: This study is a prospective randomized trial involving 187 women with primary SUI; 77 received TVT, 65 received TVT-O, and 45 patients were treated with TVT-O between June 2002 and December 2009. Before the operation, a complete medical history was taken and a gynecologic examination was performed, including subjective symptoms, history and urodynamic studies. Postoperative data included mean operation time, days of hospitalization, postoperative complications and efficacy evaluation. Therapeutic effect was assessed by presence or absence of incontinence when abdominal pressure increased. RESULTS: The history, physical examination and urodynamic studies among the three groups have no significant difference (P>0.05). The total cure rate was 91.4%. The cure rate in TVT, TVT-O and TOT groups were 90.9%, 92.3% and 91.1%, respectively. There was no significant difference (P>0.05). Mean operative time showed no significant difference between TVT-O and TOT groups, but both were significantly shorter than TVT group (26.90±16.80, 20.00±13.50 vs 48.20±21.90). The mean postoperative hospital stay showed no significant difference between TVT and TVT-O groups, but both groups were significantly longer than TOT group. Mean postoperative hospital stay of TVT, TVT-O and TOT were 5.00±2.40 days, 4.00±2.20 days and 2.30±0.80 days, respectively. The complication rate in TVT, TVT-O and TOT groups was 15.60%, 9.20% and 8.90%, respectively. In TVT group, 4 patients experienced bladder perforation, postoperative dysuria or retention occurred in 7 cases and was cured by urethral dilation, hematomas of retropubic space in 1 patient. No bladder injury occurred in TVT-O and TOT group, 3 patients had postoperative dysuria or retention and 3 patients had transient dysfunction of both lower limbs postoperatively in TVT-O group, 2 patients had postoperative dysuria or retention and 2 patients had transient dysfunction of both lower limbs postoperatively in TOT group. SUMMARY: The three tension-free urethral suspension techniques have similar efficacy, all of them are safe and effective procedures for the treatment of female SUI. Compared with TVT, TVT-O and TOT are simpler, less invasive and have fewer complications.

[The urodynamic diagnosis of benign prostatic hyperplasia with coexisting overactive bladder].

OBJECTIVE: To investigate the urodynamic features in patients of benign prostatic hyperplasia (BPH) with coexisting overactive bladder (OAB). METHODS: Clinical data of 235 patients with symptomatic BPH who underwent urodynamic examination during January 2009 to May 2010 were retrospectively analyzed. Patients were divided into group of pure BPH, BPH with detrusor overactivity (DO), BPH with coexisting OAB without DO and BPH with coexisting OAB with DO. The difference of age, International Prostate Symptom Score (IPSS), transrectal ultrasound (TRUS)-volume, maximum flow rate, residual urine volume, bladder volume of first sensation, bladder volume of strong sensation, bladder outlet obstruction index (BOOI) and the prevalence of decreased detrusor contractility were compared between these groups. The urodynamic characteristics of DO between group of BPH with DO and group of BPH coexisting OAB and DO were analyzed. RESULTS: A total of 219 cases were included in the final analysis, with mean age of (66 ± 8) years, mean TRUS-volume was (35 ± 24) ml, mean maximum flow rate was (11 ± 6) ml/s. Of the 219 patients, 93 patients (42.5%) had pure BPH, 11 patients (5.0%) had BPH with DO, 52 patients (23.7%) had BPH coexisting OAB without DO, 63 patients (28.8%) had BPH coexisting OAB and DO. Comparing to group of BPH (n = 104), patients with BPH and OAB (n = 115) were older, had higher IPSS, bigger TRUS-volume, less bladder volume of first sensation and strong sensation, higher BOOI and higher prevalence of decreased detrusor contractility. Comparing to group of BPH with coexisting OAB without DO patients, patients of BPH with coexisting OAB and DO had higher IPSS score (19 ± 12 vs 17 ± 10), bigger TRUS-volume [(51 ± 33) ml vs (43 ± 27) ml], higher BOOI (49 ± 18 vs 37 ± 14). Comparing to patients pure BPH, patients of BPH with DO had less bladder volume of first sensation and bladder volume of strong sensation [(82 ± 41) ml vs (118 ± 35) ml;(335 ± 67) ml vs (419 ± 53) ml]. Comparing to group of BPH with DO, patients of BPH with coexisting OAB and DO had higher maximum DO pressure [(45 ± 36) cmH2O vs (39 ± 30) cmH2O (1 cmH2O = 0.098 kPa)] and longer DO time [(7 ± 4) s vs (6 ± 4) s]. CONCLUSIONS: The urodynamic features in patients with BPH differ greatly and these information should be helpful in making choice of treatment and in predicting treatment outcomes.

The co-administration of CpG-ODN influenced protective activity of influenza M2e vaccine.

In this report, we investigated the adjuvant effect of CpG-ODN on the immunogenicity and protective efficacy of influenza M2e peptide vaccine. We found that the addition of CpG-ODN 1826 into aluminum-adjuvant M2e peptide vaccine increased M2e-specific Th1 immune response, indicated by higher titers of M2e-specific IgG2a and more IFN-gamma-secreting lymphocytes. However, according to the result from virus challenge, enhancement of M2e-specific Th1 immune response failed to increase the protection against influenza virus. Moreover, when challenged with high dose of influenza virus, the addition of CpG-ODN even weakened the protective activity. These results suggested that the intensity of immune responses was not simply correlated with protective activity of influenza M2e vaccine and more comprehensive criterion should be built up for the evaluation of M2e-based vaccine.

Heterosubtypic protection conferred by combined vaccination with M2e peptide and split influenza vaccine.

There is urgent need to develop influenza vaccines with broad-spectrum protection against the potential influenza pandemic. The extracellular domain of influenza M2 protein (M2e) is considered as an appropriate target to induce heterosubtypic protection. We investigated the immunity and protection induced by combined vaccination with synthetic M2e peptide and traditional split influenza vaccine. The combined vaccination was able to induce similar strain-specific hemagglutinin inhibition (HI) antibodies as vaccination of split virus alone. However, aluminum-adjuvant but not oil-in-water-emulsion adjuvant combined vaccination was able to induce high titers of anti-M2e antibodies and provoke M2e-specific T lymphocyte response. Furthermore, we found that the addition of M2e peptide greatly enhanced the cross-protective efficacy of split virus in aluminum adjuvant but slightly weakened the efficacy of vaccination in oil-in-water-emulsion adjuvant. Moreover, aluminum-adjuvant combined vaccination conferred complete cross-protection against heterosubtypic influenza virus. According to the results, we suggest that the M2e peptide should be added into split influenza vaccine in the preparation for the potential influenza pandemic.

Characterization of immunity induced by M2e of influenza virus.

The extracellular-domain of influenza Matrix 2 protein (M2e) is considered as a putative target for designing universal influenza vaccines. However, the mechanism by which M2-based vaccine induces protection has not been clear. In this study, we analyzed the immunity induced by free synthetic M2e peptide and found the peptide was highly immunogenic. Without carrier proteins, the synthetic M2e peptide could induce M2e-specific IgG antibodies in both incomplete Freund's and aluminum adjuvant. The peptide could also provoke M2e-specific T cell response, which could not be mounted by influenza virus. Moreover, immunization with M2e peptide could protect mice from a lethal challenge with influenza virus. These results provide useful information for the development of M2e-based influenza vaccine.

Biofeedback therapy for chronic pelvic pain syndrome.

AIM: To evaluate the efficacy of biofeedback therapy in patients with chronic pelvic pain syndrome (CPPS). METHODS: From November 2001 to April 2002, patients visiting the Urological Outpatient Clinic of this Hospital were evaluated by means of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and classified by the NIH classification standard. Sixty-two patients of CPPS category III were involved in this study. All patients had been treated by conventional approaches such as antibiotics and alpha-blockers for more than half a year without any improvement. The expressed prostatic secretion results were as follows: WBC 5 to 9/high power field, lipid + approximately +++ and bacterial culture negative. Their NIH-CPSI were 12 approximately 40. All the 62 cases complained of micturitional irritation (frequency, urgency, splitted stream and sense of residual urine), 32 cases, of pain or discomfort at the testicular, penile, scrotal, pelvic or rectal region and 13 cases, of white secretion-dripping. The patients were treated by the Urostym Biofeedback equipment (Laborie Co., Canada) 5 times a week for 2 weeks with a stimulus intensity of 15 mA approximatley 23 mA and duration of 20 minutes. RESULTS: Sixty patients were significantly improved or cured, while no significant improvement in the remaining 2. No apparent side effect was observed. The NIH-CPSI dropped to 6 to 14 with an average reduction of 21 (P<0.01). In the 60 improved cases, pain was relieved after 2 approximately 3 treatment courses and other symptoms disappeared after 4 approximately 5 courses. CONCLUSION: Biofeedback therapy is a safe and effective treatment for CPPS. Large randomized clinical trials are needed to confirm its efficacy and to explore the mechanism of action.