Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials.

BACKGROUND: The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC. PATIENTS AND METHODS: The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies). RESULTS: Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received. CONCLUSION: This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.

[Intraparenchymal hemorrhage related to cerebral venous air embolism secondary to mesenteric ischemia]. / Hemorragia intraparenquimatosa relacionada con embolismo venoso secundario a isquemia mesentérica.

INTRODUCTION: The presence of air in vascular structures of the brain can lead to neurological symptoms and significant morbidity. It usually occurs as a consequence of invasive therapeutic procedures and is very rarely triggered by any other cause. CASE REPORT: We report the case of a 76-year-old woman with a history of atrial fibrillation anticoagulated with acenocoumarol who visited the Emergency department because of sudden-onset abdominal pain, vomiting and diarrhoea. After starting symptomatic treatment and finding analytical evidence of underdosing of the anticoagulant, she suddenly presented with neurological focus. A cranial computed tomography scan revealed an acute intraparenchymal haemorrhage. The patient was transferred to the stroke unit of the referral hospital. Within a few hours, she developed haemodynamic instability due to a septic shock that had its origin in the abdomen. A computed tomography scan of the abdomen evidenced extensive pneumatosis intestinalis and an obstruction of contrast indicating mesenteric ischaemia. A mechanical thrombectomy was performed in an attempt to embolise the thrombus at a more distal level, but the patient died. CONCLUSIONS: Mesenteric ischaemia can cause significant pneumatosis intestinalis, which, by a retrograde mechanism through the portal system, can cause air bubbles to reach the cerebral venous system, leading to acute stroke.

TITLE: Hemorragia intraparenquimatosa relacionada con embolismo venoso secundario a isquemia mesentérica.Introducción. La presencia de aire en estructuras vasculares cerebrales puede condicionar una sintomatología neurológica y una importante morbilidad. Suele producirse como consecuencia de procedimientos terapéuticos invasivos y es muy infrecuente que el desencadenante sea otro. Caso clínico. Mujer de 76 años con antecedente de fibrilación auricular anticoagulada con acenocumarol. Acudió a urgencias por dolor abdominal de inicio brusco, vómitos y diarrea. Tras iniciar tratamiento sintomático y evidenciar analíticamente infradosificación del anticoagulante, presentó bruscamente focalidad neurológica. La tomografía computarizada craneal evidenció una hemorragia intraparenquimatosa aguda. Se trasladó a la paciente a la unidad de ictus del hospital de referencia. En cuestión de unas horas, presentó inestabilidad hemodinámica por shock séptico de causa abdominal. La tomografía computarizada abdominal evidenció extensa neumatosis intestinal y una interrupción al paso de contraste subsidiario de una isquemia mesentérica. Se intentó una trombectomía mecánica para embolizar el trombo a un nivel más distal, pero la paciente falleció. Conclusiones. La isquemia mesentérica puede causar una importante neumatosis intestinal, que, por un mecanismo retrógrado a través del sistema portal, consiga la llegada de burbujas de aire al sistema venoso cerebral, causando un ictus agudo.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

[Pattern analysis of inflammatory skin diseases according to A. B. Ackerman-always up to date]. / Patternanalyse entzündlicher Hauterkrankungen nach A. B. Ackerman ­ stets aktuell.

The exact microscopic diagnosis of inflammatory skin diseases requires the linking of histopathological findings with clinical features. This is not easy when skin biopsies are rarely assessed and the terminology of dermatopathology and dermatology is itself unfamiliar.The infiltrates of almost all inflammatory skin diseases tend to show eight specific patterns in high magnification. By further classifying according to architectural and cytological features, a specific diagnosis can be made in most cases. At the same time, clinically suspected diagnoses are simply excluded or greatly reduced in number. This procedure, starting with the overview magnification and the recognition of clearly defined histomorphological features, corresponds to an algorithm.Another algorithmic approach uses histomorphological changes under high magnification. Here, "nonspecific" findings are added to the pattern analysis as a diagnostic vehicle.Occasionally, inflammatory skin diseases cannot be assessed conclusively with current modern methods. Such pathology reports should be written descriptively and possible differential diagnoses should be mentioned as notes. The report should be written in a language understandable to the clinician.Artificial intelligence, with its ability to transform and integrate extensive clinical as well as image data, will play an important role in the future of decision making, diagnosing, and personalizing medicine. In the field of pathology, it could be seen as a second opinion. It is important that physicians always contribute their opinion where important algorithmic decisions are made, such as in algorithm design, data quality, interpretation, action, and feedback.

Rapid advances in auto-segmentation of organs at risk and target volumes in head and neck cancer.

Advances in technical radiotherapy have resulted in significant sparing of organs at risk (OARs), reducing radiation-related toxicities for patients with cancer of the head and neck (HNC). Accurate delineation of target volumes (TVs) and OARs is critical for maximising tumour control and minimising radiation toxicities. When performed manually, variability in TV and OAR delineation has been shown to have significant dosimetric impacts for patients on treatment. Auto-segmentation (AS) techniques have shown promise in reducing both inter-practitioner variability and the time taken in TV and OAR delineation in HNC. Ultimately, this may reduce treatment planning and clinical waiting times for patients. Adaptation of radiation treatment for biological or anatomical changes during therapy will also require rapid re-planning; indeed, the time taken for manual delineation currently prevents adaptive radiotherapy from being implemented optimally. We are therefore standing on the threshold of a transformation of routine radiotherapy planning via the use of artificial intelligence. In this article, we outline the current state-of-the-art for AS for HNC radiotherapy in order to predict how this will rapidly change with the introduction of artificial intelligence. We specifically focus on delineation accuracy and time saving. We argue that, if such technologies are implemented correctly, AS should result in better standardisation of treatment for patients and significantly reduce the time taken to plan radiotherapy.

[Digital papillary adenocarcinoma : Four case reports with brief literature review]. / Digitales papilläres Adenokarzinom : Vier Fallberichte mit kurzer Literaturübersicht.

Digital papillary adenocarcinoma is a rare but well characterized carcinoma of the sweat glands, which apart from very few exceptions is localized in acral skin. This type of sweat gland carcinoma tends to recur locally and may cause delayed metastases in a few cases. We describe the clinical findings and the broad histopathologic spectrum of four cases of this rare adnexal carcinoma and give a short summary of the literature.

Correction to: Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling.

In the original publication of the article, Table 1 was published with incorrect caption and values. The Table 1 with corrected caption and values is given in this Correction.

Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling.

BACKGROUND: Persistent alopecia (PA) after docetaxel has been recently described. The aim of our study is to establish the incidence and characteristics of PA following adjuvant docetaxel for breast cancer (BC) and to test the ability of scalp cooling in prevention. PATIENTS AND METHODS: BC patients receiving adjuvant chemotherapy followed or not by endocrine therapy (and a control group receiving only endocrine therapy) were interviewed in a single institution at 1.5 to 5 years following primary diagnosis searching for PA. A confirmatory prevalence study was later performed in other two institutions. Finally, a prevention study using prophylactic scalp cooling (PSC) with ELASTO-GEL hypothermia caps in patients receiving adjuvant docetaxel was performed. RESULTS: In the initial prevalence study (492 patients), minor forms of PA (grade 1) were recorded with all chemotherapy regimens and aromatase inhibitors. Patients receiving docetaxel regimens at cumulative dose (CD) ≥ 400 mmg/m2 presented a significantly higher prevalence of grades 1 PA (33-52%) and 2 PA (5-12%). Prevalence of grade 2 PA with docetaxel CD ≥ 400 mmg/m2 was confirmed in two other institutions. Overall, grade 2 PA was seen in 10.06% (95% CI 7.36-13.61) of 358 patients with docetaxel regimens reaching CD ≥ 400 mmg/m2, but not in patients with lower docetaxel CD, other chemotherapy regimens, or endocrine therapy alone. In prevention trial, no grade 2 PA occurred among 116 patients receiving adjuvant docetaxel (≥ 400 mmg/m2) and PSC followed-up after a 96 months median time. PSC was well tolerated. No scalp relapses were seen among 30 patients (22% of all inclusions) having disease relapse. CONCLUSION: Adjuvant treatment with docetaxel (CD ≥ 400 mmg/m2) is associated with a significant rate of grade 2 PA, leading to wearing a wig, in around 10% of patients. This toxicity was completely prevented with scalp cooling. Clinical Trial Reference: NCT00515762.

Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet-induced obesity model.

BACKGROUND: Obesity is associated with numerous cardiac complications, including arrhythmias, cardiac fibrosis, remodeling and heart failure. Here we evaluated the therapeutic potential of mesenchymal stromal cells (MSCs) and their conditioned medium (CM) to treat cardiac complications in a mouse model of high-fat diet (HFD)-induced obesity. METHODS: After obesity induction and HFD withdrawal, obese mice were treated with MSCs, CM or vehicle. Cardiac function was assessed using electrocardiography, echocardiography and treadmill test. Body weight and biochemical parameters were evaluated. Cardiac tissue was used for real time (RT)-polymerase chain reaction (PCR) and histopathologic analysis. RESULTS/DISCUSSION: Characterization of CM by protein array showed the presence of different cytokines and growth factors, including chemokines, osteopontin, cystatin C, Serpin E1 and Gas 6. HFD-fed mice presented cardiac arrhythmias, altered cardiac gene expression and fibrosis reflected in physical exercise incapacity associated with obesity and diabetes. Administration of MSCs or CM improved arrhythmias and exercise capacity. This functional improvement correlated with normalization of GATA4 gene expression in the hearts of MSC- or CM-treated mice. The gene expression of connexin 43, troponin I, adiponectin, transforming growth factor (TGF) ß, peroxisome proliferator activated receptor gamma (PPARγ), insulin-like growth factor 1 (IGF-1), matrix metalloproteinase-9 (MMP9) and tissue inhibitor of metalloproteinases 1 (TIMP1) were significantly reduced in MSCs, but not in CM-treated mice. Moreover, MSC or CM administration reduced the intensity of cardiac fibrosis. CONCLUSION: Our results suggest that MSCs and CM have a recovery effect on cardiac disturbances due to obesity and corroborate to the paracrine action of MSCs in heart disease models.

Neoadjuvant treatment for borderline and resectable pancreatic ductal adenocarcinoma.

Nowadays and given the improvement in response rate with the new schemes of treatment with chemotherapy, the interest in neoadjuvant treatment for pancreatic ductal adenocarcinoma, allowing the early application of systemic therapies, has also increased. However, treatment selection fundamentally depends on decisions taken by multidisciplinary committees due to the absence of randomized trials on this indication and because the available evidence is based primarily on small studies. The present manuscript tries to establish recommendations based on the available evidence and expert opinion to correctly select the indication, the type of treatment, as well as its duration and how to correctly follow-up patients during treatment with chemotherapy.

Encefalopatía crónica postraumática: aquella gran desconocida / Chronic traumatic encephalopathy: the unknown disease

La encefalopatía crónica postraumática es una enfermedad neurodegenerativa fruto de la acumulación de numerosos traumatismos craneoencefálicos, para la cual no existe un diagnóstico premórtem definitivo ni un tratamiento específico. Entre los factores de riesgo asociados con la encefalopatía crónica postraumática se encuentran: la exposición a deportes de contacto, la presencia de la apolipoproteína E4 y la edad avanzada. Histopatológicamente, aunque comparte ciertas características con la enfermedad de Alzheimer, tiene una presentación más específica (depósito de proteína tau fosforilada en forma de ovillos neurofibrilares, asociados a acúmulo de elementos del neuropilo, acompañados en ocasiones de placas de beta-amiloide). Clínicamente se caracteriza por un curso lento que se inicia con síntomas cognitivos leves y emocionales, y progresa hacia la aparición de síntomas parkinsonianos y demencia. A pesar de que existen elementos diagnósticos prometedores, no son, actualmente, una realidad, y la clave en el manejo de esta enfermedad es la prevención y la detección precoz de sus primeros síntomas (AU)

Chronic traumatic encephalopathy is a neurodegenerative disease produced by accumulated minor traumatic brain injuries; no definitive premortem diagnosis and no treatments are available for chronic traumatic encephalopathy. Risk factors associated with chronic traumatic encephalopathy include playing contact sports, presence of the apolipoprotein E4, and old age. Although it shares certain histopathological findings with Alzheimer disease, chronic traumatic encephalopathy has a more specific presentation (hyperphosphorylated tau protein deposited as neurofibrillary tangles, associated with neuropil threads and sometimes with beta-amyloid plaques). Its clinical presentation is insidious; patients show mild cognitive and emotional symptoms before progressing to parkinsonian motor signs and finally dementia. Results from new experimental diagnostic tools are promising, but these tools are not yet available. The mainstay of managing this disease is prevention and early detection of its first symptoms (AU)

Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic cancer in Spain.

The management of patients with pancreatic cancer has advanced over the last few years. We convey a multidisciplinary group of experts in an attempt to stablish practical guidelines for the diagnoses, staging and management of these patients. This paper summarizes the main conclusions of the working group. Patients with suspected pancreatic ductal adenocarcinoma should be rapidly evaluated and referred to high-volume centers. Multidisciplinary supervision is critical for proper diagnoses, staging and to frame a treatment plan. Surgical resection together with chemotherapy offers the highest chance for cure in early stage disease. Patients with advanced disease should be classified in treatment groups to guide systemic treatment. New chemotherapeutic regimens have resulted in improved survival. Symptomatic management is critical in this disease. Enrollment in a clinical trial is, in general, recommended.

Chronic traumatic encephalopathy: The unknown disease. / Encefalopatía crónica postraumática: aquella gran desconocida.

Chronic traumatic encephalopathy is a neurodegenerative disease produced by accumulated minor traumatic brain injuries; no definitive premortem diagnosis and no treatments are available for chronic traumatic encephalopathy. Risk factors associated with chronic traumatic encephalopathy include playing contact sports, presence of the apolipoprotein E4, and old age. Although it shares certain histopathological findings with Alzheimer disease, chronic traumatic encephalopathy has a more specific presentation (hyperphosphorylated tau protein deposited as neurofibrillary tangles, associated with neuropil threads and sometimes with beta-amyloid plaques). Its clinical presentation is insidious; patients show mild cognitive and emotional symptoms before progressing to parkinsonian motor signs and finally dementia. Results from new experimental diagnostic tools are promising, but these tools are not yet available. The mainstay of managing this disease is prevention and early detection of its first symptoms.

Low-dose estradiol and endothelial and inflammatory biomarkers in menopausal overweight/obese women.

OBJECTIVE: We aimed to investigate the effects of low-dose transdermal estrogen on endothelial and inflammatory biomarkers in menopausal overweight/obese women. METHODS: We recruited 44 menopausal women (47-55 years; body mass index 27.5-34.9 kg/m(2)) and divided them into estradiol (1 mg/day; n = 22) or placebo groups (n = 22). They were double-blinded, followed and treated for 3 months. At baseline and post-intervention, inflammatory biomarkers (hs-CRP, IL-1ß, IL-6, MCP-1 and TNF-α) and of vascular injury (activated circulating endothelial cells, CEC-a) and repair (endothelial progenitor cells, EPC) were quantified. Resting CECs (CEC-r) were also assessed. Microvascular reactivity and vasomotion were analyzed by laser-Doppler flowmetry. RESULTS: Volunteers (51.8 ± 2.3 years; mean body mass index 31.5 ± 2.5 kg/m(2)) had been menopausal for 3 (range 2-5) years. After treatment, no changes were observed in the placebo group, while levels of CEC-r and EPC increased in the estradiol group. In this group, no changes in inflammatory biomarkers were observed but it required a lower cumulative dose of acetylcholine to achieve peak velocity during endothelial-dependent vasodilatation and there was increased endothelial-independent vasodilatation. CONCLUSIONS: The short-term use of low-dose transdermal estradiol therapy in overweight/obese menopausal women increased markers of vascular repair and improved microvascular reactivity without changing the inflammatory biomarkers. CLINICAL TRIAL REGISTRATION: NCT01295892 at www.clinicaltrials.gov .

Prognostic significance of tumor regression in lymph nodes after neoadjuvant therapy for rectal carcinoma.

Neoadjuvant therapy (NAT) is mainly indicated for locally advanced rectal carcinoma. Many reports have shown that regression of the primary tumor is a prognostic factor. However, few reports to date have analyzed the potential prognostic significance of lymph node regression in rectal carcinoma. The aim of the present study is to describe the pattern of tumor regression in lymph nodes after NAT for rectal carcinoma and its potential prognostic significance. We have retrospectively reviewed 106 cases of rectal carcinoma treated at a single institution. We have retrieved data from the patients and reviewed the histopathological slides to evaluate tumor regression both of the primary tumor and of LN metastases. Prognosis has been defined both in terms of disease-free survival (DFS) and disease-specific survival (DSS). Of the patients, 16% showed complete response of the primary tumor, while 24% showed poor response, according to the CAP regression grading system. Absence of lymph node involvement after therapy was found in 80% of the patients (ypN0 cases), while 20% were ypN+. We reviewed 639 LN; 85 were involved by tumor, and 170 showed histological signs of tumor regression. The main pattern of tumor regression in lymph nodes was fibrosis (66.3%), followed by hystiocytosis (29.1%) and mucin pools (4.6%). We found histological signs of regression in 57% of ypN0 cases and 76% of ypN+ cases. We found a significant association between regression grade of the primary tumor and of lymph node metastases. For ypN0 patients with persistence of the primary tumor after NAT, the median DFS was significantly shorter in patients showing tumor regression in the LN. In a Cox multivariate survival model for DFS, this prognostic influence was independent of the regression grade of the primary tumor and also of the ypTNM stage. We found no significant association between any factor and DSS. The pattern of tumor regression in lymph nodes was not significantly associated with prognosis. Tumor regression in lymph nodes is an important prognostic factor in rectal carcinoma after NAT and should be specifically looked for and included in pathology reports.

BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X.

Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon-intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing.

Fumarate hydratase immunohistochemical staining may help to identify patients with multiple cutaneous and uterine leiomyomatosis (MCUL) and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome.

AIMS: Multiple cutaneous and uterine leiomyomatosis (MCUL) also named as hereditary leiomyomatosis and renal cancer syndrome (HLRCC) is an autosomal dominant disorder caused by heterozygotic germline mutations in fumarate hydratase (FH) with incomplete penetrance and clinically challenging to diagnose. To test immunohistochemistry for FH as a potential marker for the detection of FH-deficiency. METHODS AND RESULTS: We have tested 42 smooth muscle neoplasms, 13 lesions of patients with suspicious or confirmed HLRCC, 20 sporadic piloleiomyomas, two angioleiomyomas and 7 leiomyosarcomas. FH staining grades from 1 to 3. Ten of the 13 lesions from the patients with HLRCC syndrome showed negative FH staining. Most sporadic piloleiomyomas presented grade 3 FH staining although five cases presented grade 1 FH staining. Sensitivity of FH staining in our series is 83.3% but specificity is 75%. CONCLUSIONS: This staining could indicate a high risk of HLRCC in most of the confirmed cases but it could also suggest the presence of a syndrome in up to 25% of sporadic cases. HLRCC syndrome should be rule out in FH negative piloleiomyomas after complete anamnesis if multiple lesions or positive familiar history is found.

Realization of the Hofstadter Hamiltonian with ultracold atoms in optical lattices.

We demonstrate the experimental implementation of an optical lattice that allows for the generation of large homogeneous and tunable artificial magnetic fields with ultracold atoms. Using laser-assisted tunneling in a tilted optical potential, we engineer spatially dependent complex tunneling amplitudes. Thereby, atoms hopping in the lattice accumulate a phase shift equivalent to the Aharonov-Bohm phase of charged particles in a magnetic field. We determine the local distribution of fluxes through the observation of cyclotron orbits of the atoms on lattice plaquettes, showing that the system is described by the Hofstadter model. Furthermore, we show that for two atomic spin states with opposite magnetic moments, our system naturally realizes the time-reversal-symmetric Hamiltonian underlying the quantum spin Hall effect; i.e., two different spin components experience opposite directions of the magnetic field.