A quantitative comparison of bone resection margin distances in virtual surgical planning versus histopathology: a prospective study.

BACKGROUND: Positive bone margins have been shown to be associated with worse locoregional control and survival performance in oral oncology patients. With the application of computer-assisted surgery and patient-specific surgical guides, the authors can accurately execute the preoperative osteotomy plan. However, how well the authors can predict the margin distance in the final histopathology with a preoperative computed tomography (CT) scan, the factors associated with it, and how much leeway CT should spare when designing the osteotomy planes during virtual surgical planning (VSP) remain to be investigated. MATERIALS AND METHODS: Patients from January 2021 to December 2022 with benign or malignant jaw tumors and with signs of bone marrow involvement in the preoperative CT scan in our center were prospectively recruited to the study. VSP and measurement of the closest margin distance in the CT scan were performed by the single team of surgeons. The resection specimen was processed, and the margin distances were measured by a dedicated senior pathologist with the knowledge of orientation of the osteotomy planes. RESULTS: A total of 35 patients were recruited, with 21 malignant and 14 benign cases. Sixty-eight bone margins were quantitatively analyzed. No significant difference in margin distances measured from the CT scan and final histopathology was detected ( P =0.19), and there was a strong correlation between the two (r s =0.74, P <0.01). A considerable amount of variance was detected in the level of discrepancy between margin distances measured in the CT scan and final histopathology (overall SD=6.26 mm, malignancy SD=7.44 mm, benign SD=4.40 mm). No significant correlation existed between the two margin distances when only maxilla tumor margins were assessed ( P =0.16). CONCLUSION: The bone margin distance in VSP is reliably correlated to the final pathological margin distance. A leeway distance of 15mm and 9mm should be considered when designing the osteotomy planes for malignancy and benign cases, respectively. Extra attention should be paid to maxilla cases when predetermining the osteotomy planes during VSP.

A Rare Case of Metastatic Primary Peritoneal Ependymoma: A Case Report and Literature Review.

BACKGROUND: Primary peritoneal ependymoma is an exceedingly rare tumour with only four cases reported in the literature. It typically follows an indolent disease course. We describe a rare case of metastatic primary peritoneal ependymoma which was treated with chemotherapy and radiotherapy resulting in prolonged survival to date for 10 years. Case Presentation. The patient was a 23-year-old female on presentation. She presented with right upper quadrant pain associated with an abdominal mass. Computed tomography demonstrated a large mass displacing the liver. Debulking surgery was done revealing a tumour arising from the peritoneum as well as multiple metastatic pleural and peritoneal nodules. Pathology was consistent with primary peritoneal ependymoma. The patient was then treated with multiple lines of chemotherapy containing etoposide as the backbone. She also received palliative radiotherapy to the thoracic metastases with good and durable response. CONCLUSION: We reported a rare case of metastatic primary peritoneal ependymoma. Etoposide containing the chemotherapy regimen is effective in the treatment of peritoneal ependymoma. Radiotherapy is also effective for palliation of local symptoms with durable response.

Do predetermined surgical margins compromise oncological safety in computer-assisted head and neck reconstruction?

OBJECTIVES: Computer assisted head and neck reconstruction has gained popularity over the past few years. In computer assisted surgery (CAS), surgical margins are predetermined in virtual surgery and resection guides are designed to be fitted intra-operatively. However, concerns have been raised regarding the oncological safety of predetermined surgical margins. Therefore, the aim of this study was to compare surgical margins, recurrence and survival outcomes in patients underwent CAS and non-CAS in head and neck reconstruction. METHODS: We retrospectively reviewed the patients underwent oral and maxillofacial malignancies surgical excision and free flap reconstruction from October 2014 to December 2019 by the same chief surgeon. Patients were divided into two groups depending on whether CAS and predetermined surgical margins were adopted. The primary outcome was surgical resection margin and the secondary outcomes included recurrence and survival. RESULTS: A total of 66 subjects were recruited with 37 in the CAS group and 29 in the non-CAS group. The follow-up rate was 100%. The average follow-up time was 24.5 months. No significant difference in resection margin was identified between the groups (p = 0.387). Tumor staging, margin status, perineural invasion, lymphovascular invasion and extranodal extension were identified as significant factors influencing survival. Both before and after adjustment for these prognostic factors identified, CAS and non-CAS group showed no significant difference in survival outcome. CONCLUSION: Predetermined surgical margins do not compromise oncological safety in terms of resection margin, disease recurrence and patient survival.

Donor-Derived Genotype 4 Hepatitis E Virus Infection, Hong Kong, China, 2018.

Hepatitis E virus (HEV) genotype 4 (HEV-4) is an emerging cause of acute hepatitis in China. Less is known about the clinical characteristics and natural history of HEV-4 than HEV genotype 3 infections in immunocompromised patients. We report transmission of HEV-4 from a deceased organ donor to 5 transplant recipients. The donor had been viremic but HEV IgM and IgG seronegative, and liver function test results were within reference ranges. After a mean of 52 days after transplantation, hepatitis developed in all 5 recipients; in the liver graft recipient, disease was severe and with progressive portal hypertension. Despite reduced immunosuppression, all HEV-4 infections progressed to persistent hepatitis. Four patients received ribavirin and showed evidence of response after 2 months. This study highlights the role of organ donation in HEV transmission, provides additional data on the natural history of HEV-4 infection, and points out differences between genotype 3 and 4 infections in immunocompromised patients.

Interactome and reciprocal activation of pathways in topical mesenchymal stem cells and the recipient cerebral cortex following traumatic brain injury.

In this study, GFP-MSCs were topically applied to the surface of cerebral cortex within 1 hour of experimental TBI. No treatment was given to the control group. Three days after topical application, the MSCs homed to the injured parenchyma and improved the neurological function. Topical MSCs triggered earlier astrocytosis and reactive microglia. TBI penumbra and hippocampus had higher cellular proliferation. Apoptosis was suppressed at hippocampus at 1 week and reduced neuronal damaged was found in the penumbral at day 14 apoptosis. Proteolytic neuronal injury biomarkers (alphaII-spectrin breakdown products, SBDPs) and glial cell injury biomarker, glial fibrillary acidic protein (GFAP)-breakdown product (GBDPs) in injured cortex were also attenuated by MSCs. In the penumbra, six genes related to axongenesis (Erbb2); growth factors (Artn, Ptn); cytokine (IL3); cell cycle (Hdac4); and notch signaling (Hes1) were up-regulated three days after MSC transplant. Transcriptome analysis demonstrated that 7,943 genes were differentially expressed and 94 signaling pathways were activated in the topical MSCs transplanted onto the cortex of brain injured rats with TBI. In conclusion, topical application offers a direct and efficient delivery of MSCs to the brain.

Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma.

Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in regulating the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating immune cells (TILs) in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Archival formalin-fixed, paraffin-embedded ESCC samples from treatment-naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy were collected between 2004 and 2014. Expression of PD-L1 in ESCC tumor specimens was assessed by immunohistochemistry (IHC), and the degree of TIL infiltration was evaluated by examining hematoxylin and eosin-stained (H&E) specimens. PD-L1+ as defined as ≥1% of tumor cell membranes showing ≥1+ intensity. In 428 patients, specimens from 341 (79.7%) were PD-L1+. In the definitive treatment group (patients who received curative esophagectomy or definitive [chemo-]radiation therapy), PD-L1 positivity was associated with a significantly shorter DFS and OS. In the palliative chemotherapy group exhibited, neither PFS nor OS correlated significantly with PD-L1 expression. PD-L1 expression was positively associated with TIL density. In 17 paired tumor tissues collected before and after treatment, an increase in PD-L1 expression was associated with disease progression, whereas a decrease in PD-L1 expression was associated with response to chemotherapy or disease control. So, PD-L1 expression was associated with a significantly worse prognosis in patients with ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.

Dual-Tracer PET/CT Using 18F-FDG and 11C-Acetate in Gastric Adenocarcinoma With Liver Metastasis.

Dual-tracer F-FDG and C-acetate PET/CT has been shown to demonstrate good sensitivity and specificity for the diagnosis of hepatocellular carcinoma. We present a case of gastric adenocarcinoma with liver metastasis with positive uptake of F-FDG and C-acetate highlighting an unusual appearance in dual-tracer PET/CT.

Correlation of PD-L1 Expression of Tumor Cells with Survival Outcomes after Radical Intensity-Modulated Radiation Therapy for Non-Metastatic Nasopharyngeal Carcinoma.

PURPOSE: We investigated if programmed death-ligand 1 (PD-L1) expression levels were prognostic of survival outcomes after intensity-modulated radiation therapy (IMRT) for non-metastatic nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: 104 patients with non-metastatic NPC treated with radical IMRT were investigated for their PD-L1 expression by immunohistochemistry (IHC) which were correlated with survival endpoints including locoregional failure-free survival (LRFFS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and overall survival (OS). RESULTS: After a median follow-up of 7.6 years, 21 (20.2%), 19 (18.3%) and 31 (29.8%) patients suffered from locoregional failure, distant metastases and overall disease progression, respectively, and 31 (29.8%) patients died. Patients whose tumors had PD-L1 IHC 2+ (moderate to strong membrane staining in ≥ 25% of tumor cells) enjoyed longer LRFFS (5-year 100% vs. 74.4%, Hazard ratio [HR], 0.159, 95% confidence interval [CI], 0.021-0.988; P = 0.042) and marginally longer PFS (5-year 95.0% vs. 65.2%, HR, 0.351, 95% CI, 0.08-0.999, P = 0.067) compared to those whose tumors had PD-L1 IHC 0 (minimal membrane staining with PD-L1 in < 5% tumor cells or no staining with PD-L1) or 1+ (minimal to moderate membrane staining with PD-L1 in between 5-24% tumor cells). PD-L1 IHC 2+ was independently prognostic of both LRFFS (P = 0.014) and PFS (P = 0.045) in multivariable analyses. Only induction chemotherapy followed by concurrent chemoradiation was prognostic of DMFS (P = 0.003) and no prognostic factor for OS was identified. CONCLUSION: PD-L1 expression levels correlated with LRRFS and PFS in non-metastatic NPC treated with radical IMRT. It may play a role in radiosensitivity for NPC, which should be further confirmed in prospective studies using immunotherapy together with IMRT.

Natural history and outcome in Chinese patients with gastroenteropancreatic neuroendocrine tumours: - a 17-year retrospective analysis.

BACKGROUND: There is rising incidence of gastroenteropancreatic neuroendocrine tumours (GEP- NETs) in many parts of the world, but epidemiological data from Asian populations is rare. METHODS: We conducted a retrospective study in a tertiary medical centre in Hong Kong, using updated diagnostic criteria. The presentation, clinical features, and disease outcome were reviewed for all patients with GEP-NETs confirmed histopathologically at the Prince of Wales Hospital, the Chinese University of Hong Kong, between 1996 and 2013, according to the latest 2010 World Health Organization Classification. RESULTS: Among 126 patients, GEP- NETs were found in pancreas (34.9 %), rectum (33.3 %), and stomach (8.7 %), and most of them were non- functional GEP- NETs (91.3 %), mostly of grade 1 (G1) (87.3 %), and about 20 % had metastases on presentation. Age under 55 years, G1 tumours and absence of metastases were significant favourable predictors for survival in univariate analysis; whereas G2/3 tumours, size ≥2 cm, and metastases were significant predictors for disease progression (p < 0.05). In multivariate analysis, age and metastases on presentation were significant predictors of mortality (respective hazard ratios [HR] 1.05 [95 % confidence interval {CI} 1.02-1.08] and 6.52 [95 % CI 3.22-13.2]) and disease progression (respective HRs 1.05 [95 % CI 1.02-1.07] and 4.12 [95 % CI 1.96-8.68]), while higher tumour grade also independently predicted disease progression (HR 5.17 [95 % CI 2.05-13.05]) (all p < 0.05). CONCLUSION: Non-functional tumours with non-specific symptoms account for the vast majority of GEP-NETs in this Chinese series. Multidisciplinary approach in the management of patients with GEP-NETs may help improve the treatment efficacy and outcome.

Reproducibility of immunohistochemical scoring for epidermal growth factor receptor expression in non-small cell lung cancer: round robin test.

CONTEXT: The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0-300). OBJECTIVE: To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3+) and the percentage of cells staining at each intensity. DESIGN: In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low- (<200) and high- (≥200) EGFR expression groups. RESULTS: After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean κ coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively. CONCLUSIONS: After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non-small cell lung cancers into clinically relevant high- or low-EGFR expression groups.

Institution learning curve of laparoscopic colectomy--a multi-dimensional analysis.

BACKGROUND: This study aimed to evaluate the learning curve for laparoscopic colorectal resection of a university colorectal unit, the operative outcome in its developing and established period of laparoscopic colorectal resection is compared. METHODS: We analyzed 1,031 consecutive patients who underwent laparoscopic colorectal resections for colorectal carcinoma performed in a colorectal unit between April 1992 and December 2008. Multi-dimensional analyses of the learning curves of the institution and seven individual surgeons were performed. RESULTS: The operative outcomes of period 2 (2002-2008) was generally better than period 1 (1992-2001), in terms of operative time, number of lymph nodes retrieved, intra-operative blood loss and transfusion. The conversion rate of period 1 was higher than period 2 (19.7% vs. 5.1%, p < 0.001). There were no difference in the rates of intra-operative complications (2% vs. 3.3%, p = 0.32) and major post-operative complications (6% vs. 4.5%, p = 0.28). Analysis of the operative time using moving average method showed that the operative time of period 2 was generally shorter than that of period 1. The operative time transiently increased when there were new trainee surgeons joining the program. The CUSUM analysis of institutional conversion rate showed a steady state being reached at 310 cases. For the rates of intra-operative and major post-operative complications, steady states were both achieved at around 50 cases, and these rates were maintained during the whole study period. CONCLUSIONS: Operative outcome of laparoscopic colorectal resection improved with experience. Continuous training of new trainee would not affect the operative outcomes of an established specialized unit.

Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT [corrected] in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.

Schneiderian papillomas and carcinomas: a retrospective study with special reference to p53 and p16 tumor suppressor gene expression and association with HPV.

Schneiderian papillomas are uncommon benign tumors of the sinonasal area. They are prone to local aggressiveness and recurrence, and some undergo malignant progression. We analyzed specimens obtained from 67 Chinese patients who had presented to the ENT department of a regional hospital with biopsy-proven schneiderian papilloma. Seven of these patients had either synchronous or metachronous carcinoma, 1 of whom had pure carcinoma in situ. For each case, we documented the morphology, immunohistochemical expression of tumor suppressor genes p53 and p16, and any association with human papillomavirus (HPV) infection as detected by either polymerase chain reaction or in situ hybridization techniques. We found that severe dysplasia and p53 positivity were strongly associated with malignant progression. Association with HPV was demonstrated in 22 of the 67 patients (33%); the association was strongest among patients with exophytic papillomas and carcinomas. The effect of HPV in papilloma oncogenesis probably begins during the early phase, while other factors are responsible for progression to carcinoma. We conclude that p53-positive, dysplastic schneiderian papillomas warrant aggressive surgical treatment.

The learning curve for endorectal ultrasonography in rectal cancer staging.

BACKGROUND: Endorectal ultrasound (ERUS) is an emerging technique for preoperative rectal cancer staging. It is an operator-dependent examination with accuracy closely related to endosonographer experience. In this study, we prospectively analyzed our results of ERUS staging for rectal cancer, aiming to determine its accuracy and to define the learning curve of the procedure. METHODS: Between July 2007 and August 2009, consecutive patients with rectal cancer were recruited for preoperative ERUS staging performed by a single colorectal surgeon. We compared results of ERUS tumor (uT) and nodal (uN) staging with pathological staging of surgical specimens in patients who had surgery without neoadjuvant chemoradiation. To evaluate the learning-curve effect on ERUS, patients were divided into two equal halves for analysis (early group and late group). RESULTS: In the 26-month study period, 50 patients (36 males) with median age of 67 years (range 47-89 years) underwent ERUS staging. The overall accuracy rates of uT and uN staging were 86 and 66%. For uT staging, 10% of tumors were overstaged and 4% were understaged. For uN staging, 22% of patients were overstaged and 12% were understaged. With experience accumulation from early group to late group, accuracy improvement was observed in uN staging (52 vs. 80%, P = 0.037), while the accuracy rate remained consistently high in uT staging (84 vs. 88%, P = 1.0). CONCLUSIONS: ERUS was accurate in preoperative staging of rectal cancer. It was an easy-to-learn procedure for accurate tumor staging, but considerable experience was required to attain accuracy for nodal staging.

In vitro porcine training model for colonic endoscopic submucosal dissection: an inexpensive and safe way to acquire a complex endoscopic technique.

BACKGROUND: Colonic endoscopic submucosal dissection (ESD) has developed in recent years to permit en bloc resection of larger colorectal lesions that cannot be done by standard polypectomy or mucosal resection techniques. Colonic ESD is technically demanding and has a steep learning curve. Adequate training is essential to make ESD a reliable treatment for colorectal neoplasms. We aim to share our early experience with an in vitro porcine training model for colonic ESD. METHOD: Resected porcine distal colon was used to set up a training model for ESD, which was performed as in human using a standard endoscope and dissecting devices. Size of the lesions, operation time, en bloc resection rate, and perforation rate were recorded. RESULTS: Ten consecutive colonic ESD procedures were performed by a single endoscopist. Incomplete resection and perforation were encountered during the first two procedures. No perforation occurred in subsequent procedures and the operation time per task also decreased gradually. The setup cost for this model was only around US $30. CONCLUSIONS: The in vitro porcine model is easy and inexpensive to set up. Our initial experience showed that the model could simulate colonic ESD in human and technical proficiency improved by repetition. This simple setup may be a promising training model for endoscopists working in areas with a low incidence of early gastric cancer.