The Role of Adjuvant Therapy in Duodenal Adenocarcinoma and Intestinal Subtype Ampullary Carcinoma after Curative Resection.

OBJECTIVE: Defining the role of adjuvant therapy in duodenal adenocarcinoma (DAC) and intestinal subtype ampullary carcinoma (iAC). SUMMARY BACKGROUND DATA: DAC and iAC share a similar histological differentiation but the benefit of adjuvant therapy remains unclear. METHODS: Patients undergoing curative-intent surgical resection for DAC and iAC between 2010 and 2021 at five high-volume centers were included. Patient baseline, perioperative and long-term oncological outcomes were evaluated. Statistical testing was performed with SPSS 25 (IBM). RESULTS: A total of 136 patients with DAC and 171 with iAC were identified. Patients with DAC had more advanced tumors than those with iAC. Median overall survival (OS) in DAC patients was 101 months versus 155 months for iAC patients (P=0.098). DAC had a higher rate of local (14.1% vs. 1.2%, P<0.001) and systemic recurrence (30.4% vs. 3.5%, P<0.001). Adjuvant therapy failed to improve overall survival in all patients with DAC and iAC. For DAC, patients with perineural invasion, but not other negative prognostic factors had improved OS rates with adjuvant therapy (72 m vs. 44 m, P=0.044). IAC patients with N+ (190 m vs. 57 m, P=0.003), T3-4 (177 m vs. 59 m, P=0.050) and perineural invasion (150 m vs. 59 m, P=0.019) had improved OS rates with adjuvant therapy. CONCLUSION: While adjuvant therapy fails to improve OS in all patients with DAC and iAC in the current study, it improved overall survival in DAC patients with perineural invasion and in iAC patients with T3-4 tumors, positive lymph nodes, and perineural invasion.

Evaluation of response using FDG-PET/CT and diffusion weighted MRI after radiochemotherapy of pancreatic cancer: a non-randomized, monocentric phase II clinical trial-PaCa-DD-041 (Eudra-CT 2009-011968-11).

BACKGROUND: Pancreatic cancer is a devastating disease with a 5-year survival rate of 20-25%. As approximately only 20% of patients diagnosed with pancreatic cancer are initially staged as resectable, it is necessary to evaluate new therapeutic approaches. Hence, neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e., [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy. METHODS: Patients with histologically proven resectable, borderline resectable or unresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the standardized uptake value (SUV) measured with FDG-PET. Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was performed using contrast-enhanced CT and contrast-enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen. RESULTS: A total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal SUV (SUVmax) during therapy (p < 0.001). Using the mean apparent diffusion coefficient (ADC), response was not detectable with DW-MRI. After neoadjuvant treatment 16 patients underwent surgery. In 12 (48%) patients tumor resection could be performed. The median overall survival of all patients was 25 months (range: 7-38 months). CONCLUSION: Based on these limited patient numbers, it was possible to show that this trial design is feasible and that the neoadjuvant therapy regime was well tolerated. FDG-PET/CT may be a reliable method to evaluate response to the combined therapy. In contrast, when evaluating the response using mean ADC, DW-MRI did not show conclusive results.

[Open thoracic and thoracoabdominal aortic repair vs. f/bTEVAR - complementary or competitive?] / Offener thorakaler und thorakoabdominaler Aortenersatz vs. f/b(T)EVAR ­ komplementär oder kompetitiv?

The classical approach of open repair (OR) for thoracic and thoracoabdominal aortic pathologies, including aneurysms and dissection, has been outnumbered by the use of fenestrated/branched (thoracic) endovascular aortic repair (f/b[T]EVAR) in recent years. Providing OR for complex cases in an aortic service requires a dedicated surgical setup and a huge body of expertise in this particular field.In order to reduce specific complications, such as perioperative mortality, kidney failure, spinal cord ischemia, stroke or bowel ischemia, it is necessary to apply cerebrospinal-spinal fluid drainage, point-of-care coagulation therapy, distal and retrograde aortic perfusion and sequential clamping. Despite the predominance of endovascular solutions, the specific OR expertise is still needed for specific indications, such as young patients, connective tissue disorder or aortic graft infections.Currently, the short and mid term results for f/b(T)EVAR outweigh those for OR, including the shorter hospital stay and less invasive procedures. However, OR provides better long-term results for overall mortality, re-intervention rates and secondary complications.In conclusion, in our opinion OR is a service that is still necessary for dedicated aortic centres, but will most likely become more frequent again in the years to come.

Adjuvant therapy is associated with improved overall survival in patients with pancreatobiliary or mixed subtype ampullary cancer after pancreatoduodenectomy - A multicenter cohort study.

BACKGROUND/OBJECTIVE: The benefit of adjuvant therapy in ampullary cancer (AMPAC) patients following pancreatoduodenectomy (PD) is debated. The aim of this study was to determine the role of adjuvant therapy after pancreatoduodenectomy (PD) in histological subtypes of AMPAC. METHODS: Patients undergoing PD for AMPAC at 5 high-volume European surgical centers from 1996 to 2017 were identified. Patient baseline characteristics, surgical and histopathological parameters, and long-term overall survival (OS) after resection were evaluated. RESULTS: 214 patients undergoing PD for AMPAC were included. ASA score (ASA1-2 149 vs. ASA 3-4 82 months median OS, p = 0.002), preoperative serum CEA (CEA <0.5 ng/ml 128 vs. CEA >0.5 ng/ml 62 months, p = 0.013), preoperative serum CA19-9 (CA19-9 < 40 IU/ml 147 vs. CA19-9 > 40IU/ml 111 months, p = 0.042), T stage (T1-2 163 vs. T3-4 98 months, p < 0.001), N stage (N0 159 vs. N+ 110 months, p < 0.001), grading (G1-2 145 vs. G3-4 113 months, p = 0.026), R status (R0 136 vs. R+ 38 months, p = 0.031), and histological subtype (intestinal subtype 156 vs. PB/M subtype 118 months, p = 0.003) qualified as prognostic parameters. In multivariable analysis, ASA score (HR 1.784, 95%CI 0.997-3.193, p = 0.050) and N stage (HR 1.831, 95%CI 0.904-3.707, p = 0.033) remained independent prognostic factors. In PB/M subtype AMPAC, patients undergoing adjuvant therapy showed an improved median overall survival (adjuvant therapy 85 months vs. no adjuvant therapy 65 months, p = 0.005), and adjuvant therapy remained an independent prognostic parameter in multivariate analysis (HR 0.351, 95%CI 0.151-0.851, p = 0.015). There was no significant benefit of adjuvant therapy in intestinal subtype AMPAC patients. CONCLUSION: Adjuvant treatment seems indicated in pancreatobiliary or mixed type AMPAC.

Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure.

Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient KitW-sh/W-sh (Sash) and MCPT5-Cre+iDTR+ mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8+ tissue-resident memory T (TRM) cells. The CD8+ T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous TRM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8+ TRM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition.

Membrane-bound stem cell factor is the major but not only driver of fibroblast-induced murine skin mast cell differentiation.

The maintenance and modulation of cutaneous mast cell (MC) numbers is held to be important for skin immune responses to allergens and pathogens. The increase in MC numbers in the skin is achieved by proliferation and the differentiation of precursor to mature MCs. Fibroblast-derived SCF is thought to be the major skin MC growth factor and it potently induces MC proliferation. The mechanisms of fibroblast-induced skin MC differentiation, including the role of SCF, however, remain insufficiently characterized and understood. Using cocultures of immature murine MCs and fibroblasts, we found that the adhesion of immature MCs to fibroblasts via VCAM-1 and α4 ß7 integrin is very important for subsequent differentiation, which is driven by fibroblast membrane-bound SCF and additional fibroblast-derived membrane-bound signals. Thus, our results show that fibroblast-induced MC differentiation is induced by direct cell-cell contact and involves both Kit-dependent and Kit-independent pathways. Our findings add to the understanding of how immature mast cells mature in murine skin and encourage further analyses of the underlying mechanisms, which may result in novel targets for the modulation of skin mast cell driven diseases.

Clinical impact of duodenal pancreatic heterotopia - Is there a need for surgical treatment?

BACKGROUND: Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. METHODS: A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich's classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). RESULTS: A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. CONCLUSIONS: PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

Do Hernias Contribute to Increased Severity of Aneurysmal Disease among Abdominal Aortic Aneurysm Patients?

BACKGROUND: Connective tissue disorders could contribute to the pathogenesis of both abdominal aortic aneurysms (AAA) and hernias. We tested the hypothesis that hernias in AAA patients contribute to increased severity of the aneurysmal disease. METHODS: A questionnaire was used to collect information from 195 AAA patients divided into four groups: (1) survivors (n = 22) of ruptured AAA, (2) patients (n = 90) after elective open repair, (3) patients (n = 43) after elective endovascular repair (EVAR), and (4) patients (n = 40) under surveillance of AAA. The control group consisted of 100 patients without AAA whose abdominal computed tomography (CT) scans were examined for the presence of hernias. Mann-Whitney U-test, Chi-squared (χ 2) test, or Fisher's exact test (as appropriate) were used for statistical analyses. Multivariate logistic regression was used to control for potential confounding variables such as sex and age. RESULTS: The prevalence of inguinal hernias was significantly higher in the AAA than the control group (25 vs. 9%, p = 0.001) and did not differ between the AAA subgroups (9, 24, 35, and 23% in subgroups 1 through 4, respectively, p = 0.15) based on univariate analysis. The prevalence of inguinal hernias did not differ (p = 0.15) between the two open surgery groups (groups 1 and 2), or when comparing all three operative procedures as a combined group to group 4 (p = 0.73). The prevalences of incisional hernias were 18 and 24% for groups 1 and 2, respectively, with no significant difference (p = 0.39). Inguinal hernia demonstrated a significant association with AAA on multivariate analysis (p = 0.006; odds ratio [OR] = 4.00; 95% confidence interval [CI] = 1.49-10.66). CONCLUSIONS: Our study confirms previous observations that patients with AAA have a high prevalence of hernias. Our results suggest that hernias do not contribute to increased severity of the aneurysmal disease.

The pathohistological subtype strongly predicts survival in patients with ampullary carcinoma.

Ampullary cancer represents approximately 6% of the malignant periampullary tumors. An early occurrence of symptoms leads to a 5-year survival rate after curative surgery of 30 to 67%. In addition to the tumor stage, the immunohistological subtypes appear to be important for postoperative prognosis. The aim of this study was to analyze the different subtypes regarding their prognostic relevance. A total of 170 patients with ampullary cancer were retrospectively analyzed between 1999 until 2016 after pancreatic resection. Patients were grouped according to their pathohistological subtype of ampullary cancer (pancreatobiliary, intestinal, mixed). Characteristics among the groups were analyzed using univariate and multivariate models. Survival probability was analyzed by the Kaplan-Meier method. An exact subtyping was possible in 119 patients. A pancreatobiliary subtype was diagnosed in 69 patients (58%), intestinal in 41 patients (34.5%), and a mixed subtype in 9 patients (7.6%). Survival analysis showed a significantly worse 5-year survival rate for the pancreatobiliary subtype compared with the intestinal subtype (27.5% versus 61%, p < 0.001). The mean overall survival of patients with pancreatobiliary, intestinal, and mixed subtype was 52.5, 115 and 94.7 months, respectively (p < 0.001). The pathohistological subtypes of ampullary cancer allows a prediction of the postoperative prognosis.

Chymase-Cre; Mcl-1fl/fl Mice Exhibit Reduced Numbers of Mucosal Mast Cells.

Mast cells (MCs) are considered as key effector cells in the elicitation of allergic symptoms, and they are essential players in innate and adaptive immune responses. In mice, two main types of MCs have been described: connective tissue MCs (CTMCs) and mucosal MCs (MMCs). However, little is known about the biological functions of MMCs, which is due to the lack of suitable models to investigate MMCs in vivo. Here, we aimed to generate a mouse model selectively deficient in MMCs. It has been previously described that Cre expressed under the control of the baboon α-chymase promotor is predominantly localized in MMCs. Therefore, we mated α-chymase-Cre transgenic mice with mice bearing a floxed allele of the myeloid cell leukemia sequence 1 (Mcl-1). Mcl-1 encodes for an intracellular antiapoptotic factor in MCs; hence, a selective reduction in MMCs was expected. Our results show that this new mouse model contains markedly reduced numbers of MMCs in mucosal tissues, whereas numbers of CTMCs are normal. Thus, Chm-Cre; Mcl-1fl/fl mice are a useful tool for the investigation of the pathophysiological functions of MMCs in vivo.

Prognosis of patients after hemicraniectomy in malignant middle cerebral artery infarction.

BACKGROUND AND PURPOSE: There are unsatisfactory therapeutic options for treatment of large infarctions of the middle cerebral artery with secondary development of life threatening brain edema. In most cases, post-ischemic brain edema can not be adequately treated by conservative means. However, several studies have shown that operative procedures such as decompressive hemicraniectomy can decrease mortality. Apart from mortality, the morbidity and quality of life are major features with which to estimate therapeutic benefit. The aim of this study was to acquire follow-up data on quality of life and outcome in patients treated with hemicraniectomy after stroke. METHODS: Eighteen patients were treated with decompressive hemicraniectomy after life threatening middle cerebral artery infarction between July 1997 and April 2000 in our clinic. Six patients (33 %) died within the first six months after the procedure. All twelve surviving patients were seen in a follow-up examination 7 to 26 months after the stroke and tested using the Rankin-Scale, Barthel Index (BI), Aachener Life Quality Inventory (ALQI) and Zung Self-Rating Depression Scale. RESULTS: Survivors with a mean age of 40.7 +/- 16.5 years were significantly younger than non-survivors with a mean age of 64.5 +/- 9.2 years (p = 0.006). Mean Barthel-Index of surviving patients was 61.1 +/- 26.1 points, mean Rankin-Scale 3.3 +/- 1.2 points. Two patients were able to return to work. Patients younger than 45 years (n = 7) had a significantly better outcome (BI 75.7 +/- 20.7) than patients over 45 years (n = 5) (BI 42.0 +/- 22.7 points, p = 0.026). Among five patients with an infarction of the left hemisphere, four had a slight to moderate Broca aphasia and one patient a global aphasia. Quality of life assessment by ALQI showed moderate disability (58.0 +/- 22.7 of 107 points) with no significant difference between left- and right-hemispheric infarctions. Using the Zung Self-Rating Depression Scale six patients were ranked as slightly depressive, one patient as moderately depressive and five patients as not depressive. Eleven out of twelve survivors, as well as their relatives, approved of the decision to have the operation. CONCLUSIONS: The study provides evidence that hemicraniectomy as treatment of severe space occupying ischemic brain edema saves lives and results in good quality of life in a high proportion of patients, especially in the young. This conclusion is restricted by the lack of a control group, which was deemed unethical in studying a potentially life saving therapy.

Neoadjuvant therapy in patients with pancreatic cancer: a disappointing therapeutic approach?

Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed.

L-arginine-mediated vasoreactivity in patients with a risk of stroke.

OBJECTIVES: L-arginine is the substrate for nitric oxide (NO) production and has been shown to induce an endothelium-dependent increase in cerebral blood flow in humans. We studied the hypothesis that L-arginine-mediated vasoreactivity is impaired in patients with cardiovascular risk factors and a risk of stroke. METHODS: 55 patients with cardiovascular risk factors (mean age 63.0 +/- 8.5 years) were included in the study. 45 of them had a history of previous minor stroke or transient ischemic attack (TIA) while 10 patients had cardiovascular risk factors but no previous cerebral ischemic event. Endothelium-dependent changes in cerebral blood flow during the infusion of 30 g L-arginine were assessed by continuous transcranial Doppler sonography of both middle cerebral arteries, intima-media thickness (IMT) of the common carotid artery, by Duplex sonography. Associations between risk factors, IMT, L-arginine reactivity and previous cerebrovascular events were analyzed by stepwise multiple linear regression analysis and patient groups were compared. RESULTS: Normal young volunteers showed an L-arginine-mediated increase in mean flow velocity of 22 +/- 8%; L-arginine reactivity of the 55 patients was 28 +/- 10%. Patients with a history of stroke or TIA had significantly higher flow velocity responses to L-arginine (29 +/- 10%) than patients with cardiovascular risk factors but no previous cerebrovascular event (21 +/- 8%, p < 0.05). Stepwise multiple linear regression analysis showed a significant association of enhanced L-arginine reactivity with previous stroke/TIA (p < 0.001) and elevated fibrinogen levels (p < 0.05) but not with age, IMT, hypertension, cholesterol or other risk factors. The same regression model showed an association between IMT and previous stroke/TIA (p < 0.001) and serum cholesterol levels (p < 0.05) but not L-arginine reactivity. CONCLUSIONS: L-arginine reactivity of the cerebral vessels may be assessed by Doppler sonography and was enhanced in patients with a history of stroke or TIA. It was independent of IMT of the carotid arteries. We conclude that enhanced L-arginine reactivity is a potential marker for cerebral endothelial dysfunction and an independent indicator for an increased risk of stroke.