Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07.

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Note: Parameter-independent bounding of the stochastic Michaelis-Menten steady-state intrinsic noise variance.

Using the (slow-scale) linear noise approximation, we give parameter-independent bounds to the substrate and product intrinsic noise variance for the stochastic Michaelis-Menten approximation at steady state.

Massive Haematochezia due to Splenic Artery Bleeding into the Colon: Unusual Manifestation of Advanced Pancreatic Cancer.

We describe a case of an uncommon early pancreatic cancer presentation in a patient in his 60s who had haemorrhagic shock from extensive haematochezia and required blood transfusions as well as surveillance in an intensive care unit. A splenic artery pseudoaneurysm that had been effectively embolized by angiography was seen to be actively bleeding into the colon lumen on a computerized tomography (CT) scan along with a necrotic mass of the pancreatic tail. A pancreatic mucinous adenocarcinoma was diagnosed by a transgastric biopsy. A pancreatico-colic fistula was discovered by CT scan after a colic contrast enema. A transabdominal drainage of the necrotic collection and targeted antibiotic treatment had been performed with a satisfying patient outcome. In order to assess a potential secondary surgical resection, systemic chemotherapy was planned. In conclusion, haematochezia with hemodynamic instability originated from a splenic artery pseudoaneurysm fistulising into the colon (arterio-colic fistula) and sepsis originating from a tumoral pancreatic abscess fistulising into the colon (tumoral pancreatico-colic fistula).

A clinical and radiological comparison of sigmoid diverticulitis episodes 1 and 2.

AIM: After an initial uncomplicated attack, sigmoid diverticulitis may recur, but the morphological characteristics of recurrent diverticulitis have not been investigated. We compared the clinical and radiological severity, the respective location and clinical outcome of the first two episodes of sigmoid diverticulitis. METHOD: We reviewed the charts of 60 patients [median age 61 (range 31-90) years] who were admitted initially for a first episode of uncomplicated left colonic diverticulitis, and who were eventually readmitted for a second episode, both being documented by abdominal computed tomography (CT) scan. RESULTS: The median delay between the two episodes was 19 (3-97) months. Six (10%) patients developed a second complicated episode of diverticulitis [Hinchey II (n = 2), CT-guided percutaneous drainage; Hinchey III (n = 3), emergency Hartmann's operation; colovesical fistula (n = 1), elective sigmoid resection]. Fifty-four (90%) patients were admitted for a second episode of uncomplicated diverticulitis. In this group, the duration of hospital stay [11 (4-22) vs 10 (1-39) days, P = 0.28], serum levels of C-reactive protein [131 (31-350) vs 112 (22-333) mm, P = 0.62] and CT scan-based severity score [3 (1-6) vs 3 (0-7) points, P = 0.07] were similar between the two episodes. In 19 out of 54 (35%) patients with simple recurrent diverticulitis, although disease severity was similar, the disease topography differed and recurrence involved another segment of the left colon. CONCLUSION: The majority of patients who develop recurrence do so in a similar mode and location. However, 10% develop complicated diverticulitis and in 35% of patients recurrent diverticulitis occurs at a different location.

Healthcare-associated infections and antibiotic use in long-term care residents from two geographical regions in Switzerland.

BACKGROUND: The burden of healthcare-associated infections (HAIs) and antimicrobial use in Swiss long-term care facilities (LTCFs) is currently unknown. This study assessed the prevalence of HAIs and antibiotic use among LTCF residents in Switzerland. METHODS: A point-prevalence study was undertaken in LTCFs in eastern and western Switzerland from August to October 2019 according to the 'Healthcare-associated infections in long-term care facilities' (HALT) protocol. Characteristics of residents (age, sex, wounds, dementia, indwelling catheters) and institutions (specific factors, geographic region) were assessed. LTCF residents were screened for HAIs and current antibiotic treatment. Personal and institutional factors associated with HAIs were assessed. RESULTS: In total, 1185 residents from 16 LTCFs (eight per geographic region) were screened for HAIs and antibiotic treatment. Median age was 87 years (interquartile range 79-91) and 71% were female. The prevalence of HAIs was 4.2% (west 4.3% vs east 4.2%; P=0.93), with mucocutaneous skin infections (36%) and respiratory tract infections (30%) being the most common. Independent risk factors for the presence of HAIs were presence of a chronic wound [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.1-5.0; P=0.02] and being immobile (OR 1.8, 95% CI 1.0-3.3; P=0.04). Antibiotics were given to 2.9% of residents (west 3.9% vs east 1.8%; P=0.05) on the day of the survey. The most commonly prescribed antibiotics were amoxicillin-clavulanic acid and quinolones. CONCLUSIONS: The prevalence of HAIs in Swiss LTCFs is similar to that in other European countries, whereas antibiotic consumption is lower. Further point-prevalence surveys on a broader scale are recommended to improve understanding of the burden of HAIs and antibiotic consumption in this setting.

Nosocomial influenza in south-western Swiss hospitals during two seasonal epidemics: an observational study.

BACKGROUND: In Switzerland each year, influenza leads to between 112,000 and 275,000 medical consultations. Data on nosocomial influenza infection are limited. AIM: To describe nosocomial cases of seasonal influenza in south-western Switzerland. METHODS: This study was conducted during two seasonal influenza epidemics from 2016 to 2018 in 27 acute care public hospitals in south-western Switzerland. During these two time-periods, every patient hospitalized for >72 h who was positively screened by reverse transcription-polymerase chain reaction or antigen detection for influenza was included in the survey. Characteristics of patients included age, sex, and comorbidities. Included patients were followed up until discharge or death. Complications and administration of antineuraminidases and/or antibiotics were registered. FINDINGS: The median influenza vaccine coverage of healthcare workers was 40%. In all, 836 patients were included (98% with type A influenza virus in 2016-2017; 77% with type B virus in 2017-2018). Most patients (81%) had an unknown vaccine status. Overall, the incidence of nosocomial influenza was 0.5 per 100 admissions (0.35 per 1000 patient-days). The most frequent comorbidities were diabetes (20%), chronic respiratory diseases (19%), and malnutrition (17%). Fever (77%) and cough (66%) were the most frequent symptoms. Seventy-one percent of patients received antineuraminidases, 28% received antibiotics. Infectious complications such as pneumonia were reported in 9%. Overall, the all-cause mortality was 6%. CONCLUSION: The occurrence of nosocomial influenza underlines the importance of vaccinating patients and healthcare workers, rapidly recognizing community- or hospital-acquired cases, and applying adequate additional measures to prevent dissemination, including the timely administration of antineuraminidases to avoid antibiotic use (and misuse).

Combining gemcitabine, oxaliplatin and capecitabine (GEMOXEL) for patients with advanced pancreatic carcinoma (APC): a phase I/II trial.

BACKGROUND: Gemcitabine remains the mainstay of palliative treatment of advanced pancreatic carcinoma (APC). Adding capecitabine or a platinum derivative each significantly prolonged survival in recent meta-analyses. The purpose of this study was to determine dose, safety and preliminary efficacy of a first-line regimen combining all three classes of active cytotoxic drugs in APC. PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced or metastatic, histologically proven adenocarcinoma of the pancreas were treated with a 21-day regimen of gemcitabine [1000 mg/m² day (d) 1, d8], escalating doses of oxaliplatin (80-130 mg/m² d1) and capecitabine (650-800 mg/m² b.i.d. d1-d14). The recommended dose (RD), determined in the phase I part of the study by interpatient dose escalation in cohorts of three to six patients, was further studied in a two-stage phase II part with the primary end point of response rate by RECIST criteria. RESULTS: Forty-five patients were treated with a total of 203 treatment cycles. Thrombocytopenia and diarrhea were the toxic effects limiting the dose to an RD of gemcitabine 1000 mg/m² d1, d8; oxaliplatin 130 mg/m² d1 and capecitabine 650 mg/m² b.i.d. d1-14. Central independent radiological review showed partial remissions in 41% [95% confidence interval (CI) 26% to 56%] of patients and disease stabilization in 37% (95% CI 22% to 52%) of patients. CONCLUSION: This triple combination is feasible and, by far, met the predefined efficacy criteria warranting further investigations.

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02).

BACKGROUND: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. PATIENTS AND METHODS: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery. RESULTS: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. CONCLUSIONS: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.

Universal screening and decolonization for control of MRSA in nursing homes: follow-up of a cluster randomized controlled trial.

In 2010-11, a trial conducted in nursing homes showed no benefit of meticillin-resistant Staphylococcus aureus (MRSA) universal screening and decolonization over standard precautions to reduce the prevalence of MRSA carriage. Accordingly, no routine screening was performed from 2012. A five-year follow-up shows no new evidence supporting the intervention. Recommendations issued after trial (no screening and decolonization of MRSA residents) were retained.

Sequential treatment of arterial occlusions with porcine plasmin and low dose streptokinase.

Sequential treatment of arterial occlusions of the leg with porcine plasmin and low dose streptokinase results in a strong systemic proteolysis as already seen in deep leg vein thrombosis. In 31 of 45 patients the blood flow through major arterial segments could be restored. Thrombolytic success is possible within the first two treatment days but for the majority of the cases fibrinolytic therapy for 3-6 days is needed. On the average treatment was 1 day shorter than in DVT cases. No statistical relationship between local thrombolysis and systemic proteolysis was detected. The thrombolytic efficacy of this regimen compares favourably with earlier experience on fibrinolytic therapy in arterial occlusions.

Sequential treatment of deep leg vein thrombosis with porcine plasmin and low dose streptokinase.

Sequential treatment of deep leg vein thrombosis with porcine plasmin and low dose streptokinase (10,000-20,000 U/h) produces strong systemic fibrinolysis as demonstrated by the sustained decrease of euglobulin lysis time, of thromboplastin time values in percent, fibrinogen and factor V levels. There is a statistically significant negative correlation between thrombolytic results and euglobulin lysis time. Treatment period below 3 days are unlikely to give satisfactory results. Occluded vein segments with an apparent median age of 4 days including thrombi older than 10 days (20% of cases) are cleared with an average chance of 50%. Complete dissolution of all thrombi proximal to the crural veins has been demonstrated in 47/114 = 41.2%, some thrombolytic effects in 31/114 = 27.2% and treatment failure in 36/114 = 31.6%. The data favour laboratory monitoring of thrombolytic therapy.

Side effects of thrombolytic treatment with porcine plasmin and low dose streptokinase.

In the sequential thrombolytic therapy with porcine plasmin and low dose streptokinase side effects are mainly due to bleeding, intolerance reactions are less important. Treatment had to be prematurely stopped in 42 (37%) of 114 DVT cases because of severe bleeding and in 12 (10%) due to intolerance reactions. The corresponding figures for the 45 cases with arterial occlusions are 15 (33%) and 2 (4%) respectively. The intensity of systemic proteolysis as represented by the thromboplastin time is significantly correlated with haemorrhagic manifestations. Macrohematuria and bleeding from puncture sites are the most frequent haemorrhagic complications followed by spontaneous bleeding into skin and muscles. Non-fatal intracranial bleeding occurred in 1 DVT case (0.9%) and in 2 patients with arterial occlusions (4.4%). The benefit of this potent thrombolytic regimen would greatly improve if a strong reduction of premature treatment stop could be achieved.

Developing and implementing a pharmaceutical care model in an ambulatory care setting for patients with diabetes.

This study evaluated pharmaceutical care as an adjunct to an existing, coordinated-care program at a Regional Diabetes Center. The progress of a control group receiving the standard pharmacist instruction was compared with two treatment groups receiving additional small group or individual supplementary education for a 2-month period. Outcome evaluation included assessment of individual diabetes management through blood glucose monitoring and responses on a pretest and posttest questionnaire. Patients in the treatment groups demonstrated significantly lower average weekly blood glucose levels and a decreased incidence of hyperglycemic episodes compared with the control group. Questionnaire data for both treatment groups demonstrated a significant increase in patient understanding of diabetes medications and medications for associated illnesses, an increase in knowledge about blood glucose monitoring, and a positive difference in perceptions/attitudes toward diabetes and communication with the pharmacist. This approach is consistent with the concept of pharmaceutical care in which the pharmacist helps patients avoid long-term complications and thus improve their quality of life.

Incidence and course of occlusive peripheral artery disease in geriatric patients. Possibilities and limits of prevention.

The fate of patients with chronic and acute OPAD was analysed in order to delimit needs and limits of preventive measures. Chronic disease. A high 5 year incidence of OPAD and a strong correlation with the risk factors at entry was observed in 2630 men initially free of disease. The incidence was at 114% in men with 3 risk factors vs 20% in the subgroup free of risk at entry. In a 11 year follow-up study of 239 men with OPAD a high mortality of 37% was observed vs 13% in the age-matched randomized controls. Death was due to coronary heart disease (CHD) in 15.1% of OPAD vs 1.7%. The mortality was significantly correlated with the risk profile at entry 46% in persons with several risk factors vs 19% in those free of risk. The strong correlation between the risk profile and morbidity/mortality indicates that primary prevention by reduction or elimination of risk factors could successfully avoid or postpone CHD and OPAD, if started early and not only at the threshold of the 3d life. Acute disease. The analysis of a geriatric subgroup, 141 patients older than 70 years, demonstrated that acute artery occlusion is a limb-and life-threatening event with an in-hospital mortality of 33% and an amputation-rate of 19%. Life together with limb salvage was obtained, in spite of thrombectomy thrombolysis or anti-coagulants, in only 57%. The subgroup at increased risk could have been recognised in advance by antecedent atrial fibrillation, OPAD and/or myocardial infarction; 50% presented indeed with several, 33% with one and only 17% without the mentioned conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Doxium 500 in chronic venous insufficiency: a double-blind placebo controlled multicentre study.

The aim of this double-blind placebo-controlled study was to evaluate the therapeutic efficacy of Doxium in chronic venous insufficiency (CVI). 225 patients were treated randomly for 4 weeks with 1.5 g (3 capsules/day) of Doxium or placebo. The evolution of the leg oedema was determined by measuring calf and ankle circumferences. Pain and discomfort were assessed by visual analogue scale. The results show that at the end of the trial, all the examined parameters (leg oedema, pain, day and night cramps, discomfort, heavy legs, paresthesia and restless legs) were significantly more improved in the Doxium group than in the placebo group: the leg volume was diminished by 3.8% in the Doxium group compared to 1.2% in the placebo (p less than 0.005). The overall assessment by the physicians showed an improvement in 82% of the Doxium-treated patients compared to 42% of the placebo group (p less than 0.0001). The tolerance of the treatment was comparable in both groups.

[Late sequelae of deep venous thrombosis: a 13-year follow-up of 223 patients]. / Spätfolgen der tiefen Venenthrombose: ein 13-Jahres Follow-up von 223 Patienten.

To investigate late sequelae of deep vein thrombosis, 223 consecutive patients, 148 men, 75 women, aged 61.5 +/- 14.7 years, with phlebographically documented unilateral deep vein thrombosis were reexamined 13 years after the acute event. 29 had an isolated calf vein thrombosis, 45 a 2-level- (calf an popliteal), 72 a 3-level- (calf, popliteal and femoral), 62 a 4-level- (calf, popliteal, femoral and pelvic) thrombosis and 15 had a special location, for example an isolated popliteal or pelvic involvement. In the acute stage all patients were given full dose heparin followed by a six month period of oral anticoagulation. 144 were initially treated by thrombolytic treatment with streptokinase. Control phlebography 5-14 days after the onset of the treatment revealed no clearance in a so called negative group of 123 patients, aged 63.5 +/- 14.9 years, namely the 79 "only" anticoagulated and 44 unsuccessfully thrombolysed. In this negative group natural course of deep vein thrombosis can be studied. The positive group, comprising 100 patients, aged 59.4 +/- 13.9 years (25 with complete and 75 with partial lysis, after streptokinase), is compared with the negative group. The global incidence of postthrombotic syndrome in the natural course, 13 years after deep vein thrombosis, was 39%, 9.8% with and 29.2% without ulcer. Slight changes were noted in 25% and no change in 36%. The incidence of postthrombotic syndrome was correlated with the extent of the original thrombosis: 3.7% after isolated calf vein thrombosis vs. 55.2% after 4-level thrombosis. Moreover, the mortality after deep vein thrombosis and the frequency of recurrence in the interval and of venous symptoms were also correlated to the extent of the thrombosis. The incidence of post phlebitic syndrome in the positive group is significantly lower in patients with 3- and 4-level thrombosis (p = 0.01). Patients with complete and partial lysis also have less venous symptoms (for 3- and 4-level thrombosis p < 0.0001). Thus, the successful thrombolysis seems to be beneficial in long terms for patients with extended thrombosis. Therefore, in our hospital thrombolytic treatment is offered as an additional treatment to anticoagulation to patients with recent, less than 7 days old, 3- and 4-level-thrombosis without contraindications.

[Classification of varices and venous insufficiency]. / Classification des varices et de l'insuffisance veineuse.

The problem of the classification of varicose veins is as old as phlebology itself. A number of attempts have been made to define and assess this anatomical entity, which is progressively better investigated and better treated. Chronic venous insufficiency is a more recent pathophysiological concept, which covers both superficial venous lesions and deep lesions, regardless of their cause and their expression, especially trophic, unequivocal and dominant. A brief review of the principal classifications clearly demonstrates the difficulty of reaching a consensus. The precise definition of varicose veins and chronic venous insufficiency suggests the proposal of a simple clinical classification into five stages of chronic venous insufficiency. Beyond stage II of symptomatic varicose veins, treatment is required and complementary investigations, especially functional, are justified.

[Sequelae of venous thrombosis. Incidence in of the post-thrombosis syndrome after 5 years]. / Séquelles de la thrombose veineuse. Incidence en 5 ans du syndrome post-thrombotique.

The authors report on an epidemiological study carried out in Basle, Switzerland, which prospectively included 341 consecutive patients (226 men, 115 women, mean age 52 +/- 16 years) who had developed deep venous thrombosis evidenced by phlebography. The treatment of the acute phase most often consisted in thrombolysis, conventional heparin being reserved for the contra-indications of thrombolysis. A second phlebographic examination allowed dividing up the series into two groups, ie. positive and negative, according to the presence or absence of a complete or partial return of patency. Each group was subdivided according to the location and extension of the thrombosis. Both groups (positive vs. negative) are different as regards the location and extent of the thrombosis. The selective comparison of both groups according to the objective subdivision demonstrated: the absence of post-phlebitis disease in sural phlebitis; the same risk of post-phlebitis disease in thrombosis extending to 4 levels, whether patency was restored or not; lower incidence of post-phlebitis disease in the positive group for single -, two - or three-level phlebitis. Leg ulcers occur within an average of 5.5 +/- 2.1 years after the acute episode in 6.7% of all patients. Complete return of patency is obtained in 23% of cases only.

[Basle family study. Organization and 1st results]. / Basler Familienstudie Organisation und erste Resultate.

The organisation of the Basle Family Study and preliminary results outlining the data analysis are presented. The study investigates in 500 families the familial influence on risk factors for cardiovascular diseases. In addition the distribution of hemostatic variables is studied. Analysis of the data according to age, sex and intrafamilial relations in 211 families demonstrate the influence of the mother on the development of the life style of the children.