Pathologic tumor response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?

Neoadjuvant therapy (NAT) + surgical resection for pancreatic cancer (PC) has gained consensus in recent years. Pathological response (PR) is generally assessed according to the College of American Pathologists grading system, ranging from 0 (complete response) to 3 (no response). The aim of our study is to evaluate the PR in a series of resections for PC after NAT and its prognostic implication. 112 patients undergone NAT and resection for PC between 2011 and 2020 were retrospectively evaluated. PR was 0/1, 2 and 3 in 18 (15%), 79 (61%) and 29 (24%) cases, respectively. Chemotherapy regimens different from FOLFIRINOX and gemcitabine + nab-paclitaxel (OR 11.61 (2.53-53.36), p = 0.002) and lymphovascular invasion (OR 11.28 (1.89-67.23), p = 0.008) were associated to PR-3. Median follow-up was 25.8 (3.6-130.5) months. For PR-0/1, PR-2 and PR-3, median DFS was 45.8, 11.5, 4.6 months (p < 0.0001), respectively, while median OS was not reached, 27.1 and 17.5 months (p = 0.0006), respectively. At univariate analysis, PR-0/1 was significantly associated to better DFS and OS (HR 0.33 (0.17-0.67), p = 0.002; HR 0.20 (0.07-0.54), p = 0.002, respectively). At multivariate analysis, pancreaticoduodenectomy (HR 0.50 (0.30-0.84), p = 0.009), LNR (HR 27.14 (1.21-608.9), p = 0.038) and lymphovascular invasion (HR 1.99 (1.06-3.76), p = 0.033) were independently associated to DFS; pre-treatment CA 19.9 value (HR 1.00 (1.00-1.00), p = 0.025), post-treatment resectability status (HR 0.51 (0.28-0.95), p = 0.035), pancreaticoduodenectomy (HR 0.56 (0.32-0.99), p = 0.050), severe morbidity (2.99 (1.22-7.55), p = 0.017), LNR (HR 56.8 (2.08-1548.3), p = 0.017), lymphovascular invasion (HR 2.18 (1.08-4.37), p = 0.029) were independently associated to OS. PR did not reach statistical significance at multivariate analysis. A favorable PR is observed only in a limited number of cases. The prognostic role of PR, despite being promising, remains unclear and further multicentric studies are needed.

Long-term outcomes after pancreatoduodenectomy for ampullary cancer: The influence of the histological subtypes and comparison with the other periampullary neoplasms.

BACKGROUND: Ampullary carcinoma (AC) is histologically classified as intestinal (In-AC), pancreaticobiliary (Pb-AC) or mixed-AC. The prognostic role of AC subtypes has been debated and remains unclear. The aims of this study were to evaluate outcomes after pancreatoduodenectomy (PD) for each subtype of AC and to compare these with pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC]. METHODS: PDs performed for AC between 2010 and 2018 were retrospectively evaluated. Histological subtype was obtained for all patients. One-year, 3-year and 5-year disease-free-survival (DFS) and overall survival (OS) rates were calculated. Kaplan-Meier survival analysis was performed to compare Pb-AC, In-AC and mixed-AC. Comparison with PDs performed for PDAC and DCC during the same period was also performed. RESULTS: A total of 97 patients undergoing PD for AC were evaluated: 34 (35.1%) In-AC, 54 (55.7%) Pb-AC and 9 mixed-AC (9.3%). DFS and OS rates for Pb-AC were significantly lower compared to In-AC (p < 0.05 and p < 0.01), but similar to mixed-AC (p = 0.3 and p = 0.4). Adjuvant therapy was not associated with increased survival, regardless of the histological subtype (p > 0.05). During the same period, 337 and 53 PDs for PDAC and DCC, respectively, were performed. In-AC was associated with significantly better outcomes compared to PDAC and DCC (p < 0.001); DFS and OS rates for Pb-AC and mixed AC were significantly higher compared to PDAC (p < 0.001), but similar to DCC (p > 0.05). CONCLUSIONS: Pb-AC has significantly worse survival compared to In-AC. Moreover, mixed-AC should be considered as Pb-AC. Pb-AC and mixed-AC seem to have better prognosis compared to PDAC, but similar to DCC.

Immune infiltrating cells in duodenal cancers.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare yet aggressive malignancy, with increasing incidence in the last decades. Its low frequency has hampered a thorough understanding of the pathogenesis of the disease and of its biology, limiting the identification of tailored therapeutic options. A large body of evidence has clearly shown the clinical relevance of immune cells in solid tumors, correlating immune features with post-surgical prognosis. The aim of this study was to analyze the immune contexture in a cohort of duodenal adenocarcinomas surgically resected at our Institution and define its correlation with clinical variables. METHODS: Tissue slides from paraffin-embedded tumor specimens of 15 consecutive DA and 3 adenomas that underwent a pancreaticoduodenectomy in our center between 2010 to 2018 were immunohistochemically stained. The density (percentage of immune reactive area, IRA%) of immune markers CD45RO, CD8, CD20, IL-17, PD-1, CD68 was quantified by computer-assisted image analysis. Demographic, clinical, histopathological data were collected. RESULTS: In our population, median IRA % (IQR) of immune subsets was respectively CD45RO-TILs 2.19 (2.14), CD8-TIL 0.42 (0.81), CD20-TILs 0.22 (0.51), CD20-TLT 2.84 (4.64), CD68-TAM 2.19 (1.56), IL17+ cells 0.39 (0.39), PD1-TILs 0.19 (0.41). The median follow-up was 47.5 (22.4-63.3) months. At statistical analysis, the density of CD8-TILs inversely correlated with lymph node ratio (p = 0.013), number of metastatic lymph nodes (p = 0.019), and was lower in N+ adenocarcinomas compared to N0 (1.07 vs 0.29; p = 0.093), albeit not significantly. Stratifying patients for the N status, the density of CD8-TILs decreased with the increasing of the N stage (p = 0.065) and was lower in patients who experienced recurrence and died for the disease (0.276 vs 0.641; p = 0.044). Notably, also CD68-TAM distribution was different in patients who had recurrence versus patients who did not (1.028 vs 2.276; p = 0.036). CONCLUSIONS: Immune cells showed variable expression in correlation with common prognostic factors, suggesting T cell infiltration may play a protective role towards lymphatic spread of disease and nodal metastatization. Furthermore, T cell density and macrophage infiltration were associated to a lower risk of recurrence and disease related death. A multicentric approach may be indicated to allow analysis of larger cohorts of patients, potentially increasing the power of our observations.

The Number of Metastatic Lymph Nodes is a Useful Predictive Factor for Recurrence after Surgery for Nonmetastatic Nonfunctional Neuroendocrine Neoplasm of the Pancreas.

Nodal involvement (actually categorized as positive or negative) is an important prognostic factor after surgery for pancreatic neuroendocrine neoplasms (pNENs). We aim to evaluate the predictive role of the number of nodal metastases after pancreatic resection for pNENs. We analyzed from a prospectively maintained database all pancreatic resections for nonmetastatic nonfunctioning pNENs performed in our institution from 2011 to 2016. According to the number of nodal metastases, enhancing the actual categorization, we distinguished the following: N0, no nodal metastases; N1, 1-3 metastatic lymph nodes; and N2, metastases in 4 or more regional lymph nodes. Recurrence and disease-free survival (DFS) were evaluated. The predictive value in terms of recurrence for each clinicopathological data, including the number of metastatic lymph nodes, was calculated. Univariate and multivariate analyses were conducted. 77 patients underwent pancreatic surgery for pNENs. N0, N1, and N2 resections were found in 52 (67.5%), 16 (20.8%), and 9 (11.7%) cases, respectively. Mean follow-up of the entire cohort was 48 (±25) months. The recurrence rate was 11.8%, and the mean time of recurrence was 12 (±14) months. DFS was 83.7 months (76.0 - 91.5). At a univariate analysis, factors associated with recurrence were mitotic count (OR 1.19, p = 0.001), Ki67 value (OR 1.06, p = 0.001), the presence of nodal metastases (OR 11.54, p = 0.002), and metastases in 4 or more regional lymph nodes (N2) (OR 30.19, p = 0.002). At a multivariate analysis, only mitotic count (OR 1.51, p = 0.005) and N2 resection (OR 134.74, p = 0.002) were found to be predictive factors of recurrence. The number of metastatic lymph nodes and mitotic count is the most significant predictive factors of recurrence after pancreatic surgery for nonmetastatic nonfunctioning pNENs.

Treatment of symptomatic lumbar spinal degenerative pathologies by means of combined conservative biochemical treatments.

Research in spine surgery has proposed new soft and less invasive techniques. These are the results of our experience with oxygen-ozone therapy, which we could experiment within the Italian National Health System over 3 years. A total of 1,920 patients were admitted on the basis of unselected enrolment because of lumbosciatic pain. Patients were divided into three groups: (A) Patients with degenerative disc disease and arthropathy: 509 (26.5%), (B) Patients with failed back surgery syndrome (FBSS): 1,027 (53.489%), and (C) Patients with pure herniated lumbar disc: 384 (20%). The rationale of the treatment for all these different pathologies we have taken into consideration is the biochemical mechanism by which they can engender pain and dysfunction. Treatment for group A: paravertebral injection and phleboclysis (two cycles of 6 sessions, one each 3 days) +endoscopic neurolysis. Treatment for group B: paravertebral injection and phleboclysis (two cycles of 6 sessions, one each 3 days) + endoscopic neurolysis with intradiscal procedure (named percutaneous peridurodiscolysis). Treatment for group C: paravertebral injection (two cycles of 6 sessions, one each 3 days) + percutaneous discolysis.The perceived quality of result for this minimally invasive procedure makes oxygen-ozone therapy an interesting weapon in the hands of doctors. Furthermore, if the technique loses its clinical effectiveness, it can be repeated without harm for the patient, and costs for the health organization are notably very low, above all if compared to surgical procedures.We underline the need that this treatment should be performed in protected structures, in operative rooms, under anesthesiologic control, and in the hands of specialists.

Melkersson-Rosenthal syndrome associated with parvovirus B19 viraemia and haemophagocytic lymphohistiocytosis.

We describe a 23-year-old patient who presented acutely with haemophagocytic lymphohistiocytosis (HL) and Melkersson-Rosenthal syndrome (MRS). MRS and HL are two unusual and complex clinical patterns that may present acutely and to our knowledge, an association between them has never been reported. The clinical investigations in this patient led to identification of parvovirus B19 (PB19) viraemia by PCR. Parvovirus infection has been reported as a cause of virus-associated HL, but the presence of PB19 has never been sought or reported as a possible trigger for MRS. This observation suggests a possible association between PB19 and HL, and opens the possibility of its association also with acute-onset MRS. Further investigations for the presence of PB19 in cases of MRS are warranted.

The impact of biopsy number and site on the accuracy of intestinal metaplasia detection in the stomach A morphometric study based on virtual biopsies.

BACKGROUND: Intestinal metaplasia is a risk factor for gastric carcinoma. So far few studies have focused on the efficacy of endoscopic biopsies in detecting intestinal metaplasia in relation with the site and number of biopsies performed. The present study is aimed to assess the efficacy of single and multiple gastric biopsies in the detection and staging of intestinal metaplasia. MATERIAL AND METHODS: The study was conducted on 455 gastrectomies. We defined the extent of intestinal metaplasia on surgical specimens sampled by the "Swiss roll" technique and assessed the efficiency of an increasing number of "virtual" biopsies performed on the same rolls in recognising the true extent of intestinal metaplasia in the antro-angular region. RESULTS: Seventy-four out of 455 cases showed intestinal metaplasia in more than 5% of the antro-angular mucosa. The correlation between antro-angular intestinal metaplasia on rolls and on virtual biopsies was always highly significant, both when a single biopsy was considered and when groups of multiple biopsies (from 2 to 6 samples) were taken into account (por=20% and intestinal metaplasia <20% groups (p<0.0001). The highest value of concordance between intestinal metaplasia extent in virtual biopsies and in rolls was recorded for a set of 4 antral+1 angular biopsies whereas a set of 2 antral+1 angular biopsies turned out to be the most effective in terms of number/efficacy. CONCLUSIONS: A three biopsy set (2 antral+1 angular) allows correct detection of intestinal metaplasia extent in 90% of cases.

Cell proliferation of squamous epithelium in gastro-oesophageal reflux disease: correlations with clinical, endoscopic and morphological data.

BACKGROUND: The microscopic assessment of squamous epithelium lesions in gastro-oesophageal reflux disease (GERD) is subjective. The Ki67 nuclear antigen expressed by proliferating cells provides an objective measure of regeneration in the squamous epithelium. AIM: To evaluate Ki67 expression in GERD patients and controls, in comparison with histological lesions, pH-metry and endoscopic data. METHODS: Eighty-seven patients with GERD symptoms and 20 symptom-free controls underwent endoscopy and 24-h pH monitoring. Oesophageal biopsies (4 cm, 2 cm and Z-line) were stained with Ki67/MIB-1 antibodies; the Ki67-positive nuclear area was assessed with an image analysis system and expressed as percentage of the whole epithelial area (Ki67-%). RESULTS: Ki67-% was significantly higher in 32 patients with erosive oesophagitis, 44 endoscopy-negative GERD and 11 patients with functional heartburn than in controls (P = 0.0001). Both controls and patients showed a progressive increase in Ki67-% from 4 cm to the Z-line (P < 0.0001). Ki67-% showed a significant correlation with other conventional histological lesions (P ranged between 0.0151 and <0.0001). CONCLUSIONS: Ki67 evaluation provides quantitative and objective data on squamous epithelium proliferative activity. This marker can be applied in the distinction of endoscopy-negative GERD from healthy controls.

Carditis in patients with gastro-oesophageal reflux disease: results of a controlled study based on both endoscopy and 24-h oesophageal pH monitoring.

BACKGROUND: There are conflicting reports on the role of gastro-oesophageal reflux disease (GERD) and Helicobacter pylori infection in the aetiology of carditis. AIM: The role of reflux and H. pylori infection in causing carditis was assessed in 113 consecutive patients with GERD and in 25 controls. METHODS: All subjects underwent endoscopy and pH test and carditis was diagnosed on biopsies taken across the squamocolumnar junction. Helicobacter pylori was assessed by histology and rapid urease test. GERD was diagnosed by endoscopic oesophagitis or abnormal pH test. RESULTS: Carditis was detected in 53 of 71 GERD patients and in 15 of 20 controls. Among patients, 18 showed absent, 39 mild and 14 marked cardia inflammation and their H. pylori infection rates were 17, 23 and 57%, respectively (P < 0.025). Most patients with carditis (68%) lacked H. pylori infection. pH-metry was abnormal in 15 of 18 patients with normal cardia, 33 of 39 with mild carditis and 12 of 14 with marked inflammation. CONCLUSIONS: Carditis is a frequent finding in GERD and controls. Mild, non-active carditis is frequent in GERD patients. Marked inflammation is associated with both H. pylori and abnormal pH testing. Thus, both GERD and H. pylori infection may play a role in inducing carditis.

Helicobacter pylori infection is not involved in the pathogenesis of either erosive or non-erosive gastro-oesophageal reflux disease.

BACKGROUND: The majority of reflux patients have non-erosive reflux disease. AIM: To evaluate the influence of Helicobacter pylori on oesophageal acid exposure in patients with both non-erosive and erosive reflux disease and in a group of controls. The pattern and distribution of chronic gastritis were also assessed. METHODS: One hundred and twelve consecutive patients with symptoms of gastro-oesophageal reflux disease agreed to undergo both upper gastrointestinal endoscopy and 24-h oesophageal pH-metry. Patients were grouped as H. pylori-positive or H. pylori-negative on the basis of both CLO-test and histology, and as cases with or without oesophagitis on the basis of endoscopy. The controls consisted of 19 subjects without reflux symptoms and with normal endoscopy and oesophageal pH-metry. RESULTS: H. pylori was positive in 35 patients (31%) and in six controls (31%); oesophagitis was found in 44 patients (39%) and non-erosive reflux disease in 68 (61%). The prevalence of chronic gastritis in the antrum and corpus was higher in H. pylori-positive than in H. pylori-negative patients (P < 0.001), but was more frequently mild (P < 0.001) than moderate or severe. The percentage total time the oesophageal pH < 4.0 was higher in patients than in controls (P < 0.008-0.001), but there was no difference between H. pylori-positive and H. pylori-negative patients (12.3% vs. 12%, P = 0.43) or H. pylori-positive and H. pylori-negative controls (1.07% vs. 1.47%, P = 0.19). CONCLUSIONS: H. pylori infection had the same prevalence in reflux patients and in controls. It did not affect oesophageal acid exposure, as there was no difference between H. pylori-positive and H. pylori-negative individuals. The high prevalence of mild body gastritis in H. pylori-positive patients suggests that H. pylori eradication is unlikely to lead to gastric functional recovery, which might precipitate or worsen symptoms and lesions in patients with gastro-oesophageal reflux disease.

Security concept in 'MyAngelWeb((R))' a website for the individual patient at risk of emergency.

We describe the Security Plan for the 'MyAngelWeb' service. The different actors involved in the service are subject to different security procedures. The core of the security system is implemented at the host site by means of a DBMS and standard Information Technology tools. Hardware requirements for sustainable security are needed at the web-site construction sites. They are not needed at the emergency physician's site. At the emergency physician's site, a two-way authentication system (password and test phrase method) is implemented.

Security concept in 'MyAngelWeb' a website for the individual patient at risk of emergency.

We describe the Security Plan for the 'MyAngelWeb' service. The different actors involved in the service are subject to different security procedures. The core of the security system is implemented at the host site by means of a DBMS and standard Information Technology tools. Hardware requirements for sustainable security are needed at the web-site construction sites. They are not needed at the emergency physician's site. At the emergency physician's site, a two-way authentication system (password and test phrase method) is implemented.

Protective action of L-carnitine and coenzyme Q10 against hepatic triglyceride infiltration induced by hyperbaric oxygen and ethanol.

This investigation was conducted to ascertain whether administration of L-carnitine and coenzyme Q10 could protect from the experimentally-induced hepatic lipid infiltration and glutathione content decrease in rats exposed to hyperbaric oxygen and prolonged alcohol administration. The results indicate that administration of L-carnitine and coenzyme Q10 in association reduces damage induced by chronic alcohol poisoning and hyperbaric oxygen. This protective action is more marked when L-carnitine and coenzyme Q10 are administered together. The combined complementary biochemical activity of these two compounds is discussed.

Adenosine and carnitine derivatives and calcium movements in rat heart sarcoplasmic reticulum.

Many researches indicate that some Ca antagonists modulate Ca fluxes not only at the level of the cytoplasmic membrane but also across the sarcoplasmic reticulum. The present study investigates whether certain compounds like propionylcarnitine or acetylcarnitine which have the capacity to influence cardiac activity might interfere with intracellular Ca movements. The results demonstrate that acetylcarnitine and propionylcarnitine do not affect the calcium intracellular movement in sarcoplasmic reticulum.

Are increased ATP blood levels responsible for PGI2 release from endothelium?

Defibrotide, a polydeoxyribonucleotide with profibrinolytic and antithrombotic properties obtained from mammalian lungs was shown capable of favoring the release of prostacyclin from endothelial cells. We previously evidenced that the use of defibrotide i.p. (32 mg/kg for 30 min) or orally (50 mg/kg for 1 h) induced a significant increase in 2,3-diphosphoglycerate (2,3-DPG) content of blood cells in rats. We tested the in-vivo capacity of defibrotide to modify over 90 min the blood content of ATP, cAMP and 2,3-DPG. Male Wistar rats were anaesthetized with pentobarbital (20 mg/kg) i.p.; the left carotid artery was cannulated with a polyethylene tube, from which 0.4 ml of blood was drawn at 0, 5, 10, 15, 20, 30, 40, 50, 60 and 90 min. At 0 min, defibrotide was administered i.p. or i.v. (through the femoral vein) at the dose of 1 ml containing 80 mg of drug or orally at the dose of 1 ml containing 160 mg of drug. The control rats employed received either the vehicle of the drug or physiologic saline. Our results demonstrated a significant drug-related increase with time (maximal levels were revealed about 20 min after i.v., i.p., or oral defibrotide treatment) of blood ATP content and a significant decrease in cAMP content as compared with the controls. Our data confirm the relation between increased drug-induced prostacyclin production and that of ATP of in blood.

Prostacyclin release from endothelial cells, induced by defibrotide treatment, favours the function of grafted rat hearts and kidneys.

Defibrotide, a single-stranded DNA fraction obtained from mammalian lungs and able to increase prostacyclin production by endothelial cells, has been shown to be efficient in protecting rat organs (heart, kidney and liver) from ischaemic damage. We studied the efficacy of the drug in preserving the function of rat heart and kidney submitted to isotransplantation. Defibrotide was administered to donor Wistar rats at the dose of 32 mg/kg in 1.5 ml of saline. Heart and kidney were isolated and cold-preserved in buffered phosphate medium and continuously infused with defibrotide (32 mg/h) through the innominate or renal artery. Recipient Wistar rats were treated with defibrotide before and after transplantation at the dose of 32 mg/kg/day. Controls were treated with the vehicle of the drug. The function of isografted organs was evaluated at 12 and 24 h and at 2, 4 and 7 days from grafting. Heart function was evaluated by studying creatinine phosphokinase (CPK) and lactic dehydrogenase (LDH) activities of myocardial tissue. Renal function was evaluated by studying serum creatinine and urea levels of kidney-grafted rats. CPK and LDH activities were found to be significantly higher in defibrotide-treated rats than in controls. Creatinine and urea levels remained significantly lower in defibrotide-treated rats than in the controls. The results of the present work indicate that defibrotide treatment is useful to maintain the functionality of grafted hearts and kidneys.

Protective synergic effect of coenzyme Q10 and carnitine on hyperbaric oxygen toxicity.

The comparative biochemical activities of coenzyme Q10 and carnitine can explain the protective synergistic effect of combination of these two substances in preventing the hyperbaric oxygen toxicity in mice. Both convulsions and mortality percentages are more significantly reduced in treated animals with these two substances in combination rather than separately.