Abstract Background Programmed cell death 1 (PD-1) receptor triggering by PD ligand 1 (PD-L1) inhibits T cell activation. PD-L1 expression was detected in different malignancies and associated with ...poor prognosis. Therapeutic antibodies inhibiting PD-1/PD-L1 interaction have been developed. Materials and methods A tissue microarray ( n = 1491) including healthy colon mucosa and clinically annotated colorectal cancer (CRC) specimens was stained with two PD-L1 specific antibody preparations. Surgically excised CRC specimens were enzymatically digested and analysed for cluster of differentiation 8 (CD8) and PD-1 expression. Results Strong PD-L1 expression was observed in 37% of mismatch repair (MMR)-proficient and in 29% of MMR-deficient CRC. In MMR-proficient CRC strong PD-L1 expression correlated with infiltration by CD8+ lymphocytes ( P = 0.0001) which did not express PD-1. In univariate analysis, strong PD-L1 expression in MMR-proficient CRC was significantly associated with early T stage, absence of lymph node metastases, lower tumour grade, absence of vascular invasion and significantly improved survival in training ( P = 0.0001) and validation ( P = 0.03) sets. A similar trend ( P = 0.052) was also detectable in multivariate analysis including age, sex, T stage, N stage, tumour grade, vascular invasion, invasive margin and MMR status. Interestingly, programmed death receptor ligand 1 (PDL-1) and interferon (IFN)-γ gene expression, as detected by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in fresh frozen CRC specimens ( n = 42) were found to be significantly associated ( r = 0.33, P = 0.03). Conclusion PD-L1 expression is paradoxically associated with improved survival in MMR-proficient CRC.
Nonoperative management of uncomplicated appendicitis is currently being promoted as treatment option, albeit 0.7-2.5% of appendectomies performed due to suspected acute appendicitis show ...histologically malignant findings. The purpose of this study was to investigate the incidence of neoplasm and malignancy of the appendix in patients presenting with suspected acute appendicitis in real world setting.
This is a retrospective single-centre investigation of 457 patients undergoing appendectomy between the years 2017-2020. The patients' demographics, symptoms and diagnosis, intraoperative findings, and histopathological results were analysed.
In 3.7% (n = 17) histological analysis revealed neoplasms or malignancies. Median age was 48 years (20-90 years), without sex predominance. Leukocytes (11.3 ± 3.7 G/l) and C-reactive protein (54.2 ± 69.0 mg/l) were elevated. Histological analysis revealed low-grade mucinous appendiceal neoplasia (n = 3), sessile serrated adenoma of the appendix (n = 3), neuroendocrine tumours (n = 7), appendiceal adenocarcinoma of intestinal type (n = 3), and goblet cell carcinoma (n = 1). Additional treatment varied between no treatment or follow-up due to early tumour stage (n = 4), follow-up care (n = 3), additional surgical treatment (n = 8), or best supportive care (n = 2).
Preoperative diagnosis of appendiceal tumours is difficult. Nonoperative management of patients with acute, uncomplicated appendicitis potentially prevents the correct diagnosis of malignant appendiceal pathologies. Therefore, close follow-up or surgical removal of the appendix is mandatory.
Neurological disturbances after open inguinal hernia repair affect approximately one in ten patients. Sutureless, self-gripping meshes were developed with the aim of reducing postoperative ...neurological disturbances or neuralgia. This study assessed short- and long-term outcomes after open inguinal hernia repair using a self-gripping light-weight mesh in a peripheral teaching hospital.
Patients with uni- or bilateral inguinal hernia were included in this study. Open inguinal hernia repair was performed according to the Lichtenstein technique with a self-gripping, lightweight macroporous mesh. Postoperative follow-up was at 6 weeks after surgery and any long-term complications or recurrences were recorded up to 5 years postoperatively.
The median follow up time for all patients was 5-6 years and the median operation time was 40.0 minutes (inter quartile range 25.0-55.8). Of the 162 included patients, the mean numeric rating scale for pain (0 = no pain, 10 = excruciating pain) before hospital discharge was 2.7 (standard deviation SD 2.6) and 1.1 (SD 1.1) at 6 weeks postoperatively. The overall incidence of neurological disturbances at 6 weeks postoperatively was 11% when surgery was performed by the chief of surgery and 40% when it was performed by a senior consultant, 49% by chief-residents and 47% by supervised residents (p = 0.005). Patients with neurological disturbances were younger than asymptomatic patients (age 50, SD 15 vs 62, SD 17, p <0.001). The 1-, 3- and 5-year recurrence rates were 1%, 2% and 3%, respectively.
This study shows that open inguinal hernia repair using a self-gripping mesh is feasible, with a short operation time and low hernia recurrence rates in a peripheral teaching hospital. However, significant differences in neurological disturbances dependent on the surgeons experience were identified. Especially younger patients should be operated on by an experienced surgeon to reduce neurological disturbances and neuralgia.
While studies show that antibiotic treatment for uncomplicated diverticulitis seems to have no benefit, most experts advocate antimicrobial therapy for complicated diverticulitis. However, even for ...uncomplicated diverticulitis, most clinicians are very reluctant to withhold antibiotics. Biomarkers could help to guide antibiotic therapy as this approach has been shown to be effective for acute respiratory infections. In this diagnostic cohort study we evaluated whether procalcitonin could be a biomarker to distinguish complicated from uncomplicated cases of diverticulitis.
Complicated diverticulitis was defined as having abscess formation or perforation diagnosed by abdominal computed tomography (CT) scan. In all patients with suspected diverticulitis, procalcitonin values were measured at admission and on day 2. These values were blinded for clinicians, and treatment was carried out according to the physician's judgement. Two groups (complicated vs uncomplicated diverticulitis) were defined. Patients who had received antibiotic treatment before admission were excluded. Difference in procalcitonin values was calculated for both groups using the Mann-Whitney test. Receiver operating characteristics (ROC) were calculated to determine cut-off values for procalcitonin according to the gold standard (abdominal CT scans).
115 patients were included for analysis. 35 patients (30%) suffered from complicated diverticulitis. The median procalcitonin value for uncomplicated diverticulitis was significantly lower compared to complicated diverticulitis (median 0.05, interquartile range IQR 0.05-0.06 ng/l vs median 0.13, IQR 0.05-0.23 ng/l; p <0.0001). In the ROC analysis, the sensitivity and specificity were 81% and 91% when the highest procalcitonin value (days 1 and 2) was considered, with a cut-off value of 0.1 ng/l.
Procalcitonin was able to differentiate with a high sensitivity and specificity between complicated and uncomplicated cases of diverticulitis when combined with abdominal CT scans. As most clinicians still treat uncomplicated diverticulitis with antibiotics, procalcitonin could be an interesting parameter for guiding therapy and decreasing antibiotic usage. This should be further evaluated in randomised trials.
Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic ...impact of CRC infiltration by neutrophil granulocytes (NG).
A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets.
MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO-.
High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may ...also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P = 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.
Successful R0 resection is crucial for the survival of patients with primary liver cancer (PLC) or liver metastases. Up to date, surgical resection lacks a sensitive, real-time intraoperative imaging ...modality to determine R0 resection. Real-time intraoperative visualization with near-infrared light fluorescence (NIRF) using indocyanine green (ICG) may have the potential to meet this demand. This study evaluates the value of ICG visualization in PLC and liver metastases surgery regarding R0 resection rates.
Patients with PLC or liver metastases were included in this prospective cohort study. ICG 10 mg was administered intravenously 24 h before surgery. Real-time intraoperative NIRF visualization was created with the Spectrum
fluorescence imaging camera system. First, all liver segments were inspected with the fluorescence imaging system and intraoperative ultrasound for identification of the known tumor, as well as additional lesions, and were compared to preoperative MRI images. PLC, liver metastases, and additional lesions were then resected according to oncological principles. In all resected specimens, the resection margins were analyzed with the fluorescence imaging system for ICG-positive spots immediately after resection. Histology of additional detected lesions, as well as ICG fluorescence compared to histological resection margins, were assessed.
Of the 66 included patients, median age was 65.5 years (IQR 58.7-73.9), 27 (40.9%) were female, and 18 (27.3%) were operated on laparoscopically. Additional ICG-positive lesions were detected in 23 (35.4%) patients, of which 9 (29%) were malignant. In patients with no fluorescent signal at the resection margin, R0 rate was 93.9%, R1 rate was 6.1%, and R2 rate was 0% compared to an ICG-positive resection margin with an R0 rate of 64.3%, R1 rate of 21.4%, and R2 rate of 14.3% (
= 0.005). One- and two-year overall survival rates were 95.2% and 88.4%, respectively.
The presented study provides significant evidence that ICG NIRF guidance helps to identify R0 resection intraoperatively. This offers true potential to verify radical resection and improve patient outcomes. Furthermore, implementation of NIRF-guided imaging in liver tumor surgery allows us to detect a considerable amount of additional malignant lesions.
The lymph node ratio (LNR), i.e. the number of positive lymph nodes (LN) divided by the total number of analyzed LN, has been described as a strong outcome predictor in node-positive colon cancer ...patients. However, most published analyses are constrained by relatively low numbers of analyzed LN. Therefore, the objective of the present study was to evaluate the prognostic impact of LNR in colon cancer patients with high numbers of analyzed LN.
One hundred sixty-six colon cancer patients underwent open colon resection. All node-positive patients were analyzed for this study. The number of analyzed LN, of positive LN, the disease-free (DFS) and overall survival (OS) time were prospectively recorded. Patients were dichotomously allocated to a high or a low LNR-group, respectively, with the median LNR (0.125) as a cut-off value. Median follow-up was 34.3 months.
Fifty-eight patients (34.9%) were node-positive. The median number of analyzed LN was 23 (range 8-54). DFS and OS were significantly shorter in pN2 vs pN1 patients (p < 0.001, and p = 0.001, respectively), and in LNR high vs low patients (p = 0.032, and p = 0.034, respectively). pN2 (vs pN1) disease showed hazard ratios (HR) of 6.2 (p < 0.001), and 6.8 (p < 0.005; for DFS and OS, respectively), while LNR high (vs low) showed HR of 3.0 (p =0.041), and 4.5 (p = 0.054).
LNR is a reasonable outcome predictor in node-positive colon cancer patients. However, LNR is inferior to pN-stage in predicting survival in patients with high number of harvested lymph nodes.
Advances in genomics and proteomics are dramatically increasing the need to evaluate large numbers of molecular targets for their diagnostic, predictive or prognostic value in clinical oncology. ...Conventional molecular pathology techniques are often tedious, time-consuming, and require a lot of tissue, thereby limiting both the number of tissues and the number of targets that can be evaluated. Here, we demonstrate the power of our recently described tissue microarray (TMA) technology in analyzing prognostic markers in a series of 553 breast carcinomas. Four independent TMAs were constructed by acquiring 0.6 mm biopsies from one central and from three peripheral regions of each of the formalin-fixed paraffin embedded tumors. Immunostaining of TMA sections and conventional “large” sections were performed for two well-established prognostic markers, estrogen receptor (ER) and progesterone receptor (PR), as well as for p53, another frequently examined protein for which the data on prognostic utility in breast cancer are less unequivocal. Compared with conventional large section analysis, a single sample from each tumor identified about 95% of the information for ER, 75 to 81% for PR, and 70 to 74% for p53. However, all 12 TMA analyses (three antibodies on four different arrays) yielded as significant or more significant associations with tumor-specific survival than large section analyses (
p < 0.0015 for each of the 12 comparisons). A single sample from each tumor was sufficient to identify associations between molecular alterations and clinical outcome. It is concluded that, contrary to expectations, tissue heterogeneity did not negatively influence the predictive power of the TMA results. TMA technology will be of substantial value in rapidly translating genomic and proteomics information to clinical applications.
OBJECTIVE:To compare long-term results of Lichtensteinʼs operation versus mesh plug repair for open inguinal hernia repair.
BACKGROUND:The technique of best choice in open prosthetic inguinal hernia ...repair remains a subject of ongoing debate.
METHODS:In this prospective, randomized controlled multicenter trial, patients with primary or recurrent inguinal hernias were randomized to undergo either Lichtensteinʼs operation or mesh plug repair. The primary endpoint was the long-term recurrence rate. Secondary endpoints included chronic pain, sensibility disorders, and reoperation rate.
RESULTS:In total, 697 hernias in 594 patients were randomized (297 patients per group). At a median follow-up of 6.5 years, 528 (76%) operated hernias in 444 (75%) patients were clinically evaluated. The recurrence rate was similar in both groups mesh plug21/268 hernias = 7.8%; Lichtenstein21/260 hernias = 8.1%; adjusted odds ratio (OR)0.92; 95% confidence interval (CI)0.51, 1.68; P = 0.795. We did not find a significant difference for chronic pain (Visual Analog Scale score >3) (OR0.58; 95% CI0.31, 1.09; P = 0.088) and sensory testing (17% vs 20% of patients; OR0.53; 95% CI0.21, 1.37; P = 0.190) between the 2 groups. There were less reoperations in the mesh plug than in the Lichtensteinʼs operation group (OR0.43; 95% CI0.22, 0.85; P = 0.016).
CONCLUSIONS:The long-term results of this trial indicate not enough evidence for differences in recurrence, chronic pain, and sensibility disorders between mesh plug repair and Lichtensteinʼs operation but a lower likelihood for reoperation for mesh plug repair. Estimates for all endpoints were statistically not significant or based on large CIs.
CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov IdentifierNCT01637818.
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