This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal ...adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.
The reference surveillance method in patients with Barrett's esophagus is careful endoscopic observation, with targeted as well as random four-quadrant biopsies. Autofluorescence endoscopy (AFE) may ...make it easier to locate neoplasia. The aim of this study was to elucidate the diagnostic accuracy of surveillance with AFE-guided plus four-quadrant biopsies in comparison with the conventional approach.
A total of 187 of 200 consecutive Barrett's esophagus patients who were initially enrolled (73 % male, mean age 67 years, mean Barrett's segment length 4.6 cm), who underwent endoscopy for Barrett's esophagus in four study centers, were randomly assigned to undergo either AFE-targeted biopsy followed by four-quadrant biopsies or conventional endoscopic surveillance, also including four-quadrant biopsies (study phase 1). After exclusion of patients with early cancer or high-grade dysplasia, who underwent endoscopic or surgical treatment, as well as those who declined to participate in phase 2 of the study, 130 patients remained. These patients were examined again with the alternative method after a mean of 10 weeks, using the same methods described. The main study parameter was the detection of early cancer/adenocarcinoma or high-grade dysplasia (HGD), comparing both approaches in study phase 1; the secondary study aim in phase 2 was to assess the additional value of the AFE-guided approach after conventional surveillance, and vice versa. Test accuracy measures were derived from study phase 1.
In study phase 1, the AFE and conventional approaches yielded adenocarcinoma/HGD rates of 12 % and 5.3 %, respectively, on a per-patient basis. With AFE, four previously unrecognized adenocarcinoma/HGD lesions were identified (4.3 % of the patients); with the conventional approach, one new lesion (1.1 %) was identified. Of the 19 adenocarcinoma/HGD lesions detected during AFE endoscopy in study phase 1, eight were visualized, while 11 were only detected using untargeted four-quadrant biopsies (sensitivity 42 %). Of the 766 biopsies classified at histology as being nonneoplastic, 58 appeared suspicious (specificity 92 %, positive predictive value 12 %, negative predictive value 98.5 %). In study phase 2, AFE detected two further lesions in addition to the initial alternative approach in 3.2 % of cases, in comparison with one lesion with conventional endoscopy (1.7 %).
In this referral Barrett's esophagus population with a higher prevalence of neoplastic lesions, the AFE-guided approach improved the diagnostic yield for neoplasia in comparison with the conventional approach using four-quadrant biopsies. However, AFE alone was not suitable for replacing the standard four-quadrant biopsy protocol.
Background and study aims
Patients with achalasia or malignancies of the head and neck are at increased risk for esophageal squamous cell carcinoma. The discussion of a screening and surveillance ...program is controversial. The aim of the present study was to determine the diagnostic potential of Lugol chromoendoscopy combined with brush cytology to diagnose esophageal squamous cell carcinoma and high-grade dysplasia. Secondly, the benefit of additional biomarkers was investigated.
Patients and methods
A total of 61 patients (21 patients with achalasia and 40 patients with malignancies of the head and neck) were included. Chromoendoscopy with 1.2% Lugol iodine solution with targeted biopsies and brush cytology processed by digital image cytometry (DICM) and fluorescence in situ hybridization (FISH) from unstained lesions (USLs) and stained mucosa were performed.
Results
Six of the 61 patients had USLs ≥2 cm. Four patients had high-grade dysplasia (HGD) or carcinoma in situ (CIS). One patient with HGD and one patient with CIS were detected only after Lugol chromoendoscopy. The sensitivity and specificity for detected HGD or CIS in USLs ≥2 cm were 100% and 96.5%. No dysplasia was found in USLs <2 cm. DNA ploidy by DNA cytometry and
p53
loss of heterozygosity (LOH) by fluorescence in situ hybridization showed no additional impact on diagnostic accuracy.
Conclusions
Lugol chromoendoscopy enhances the detection rate of high-risk lesions with dysplasia or carcinoma in situ in large unstained lesions. Biomarkers such as aneuploidy and
p53
LOH from brush cytology were not of additional benefit in this setting.
Background—Malignant colorectal polyps are defined as endoscopically removed polyps with cancerous tissue which has invaded the submucosa. Various histological criteria exist for managing these ...patients. Aims—To determine the significance of histological findings of patients with malignant polyps. Methods—Five pathologists reviewed the specimens of 85 patients initially diagnosed with malignant polyps. High risk malignant polyps were defined as having one of the following: incomplete polypectomy, a margin not clearly cancer-free, lymphatic or venous invasion, or grade III carcinoma. Adverse outcome was defined as residual cancer in a resection specimen and local or metastatic recurrence in the follow up period (mean 67 months). Results—Malignant polyps were confirmed in 70 cases. In the 32 low risk malignant polyps, no adverse outcomes occurred; 16 (42%) of the 38 patients with high risk polyps had adverse outcomes (p<0.001). Independent adverse risk factors were incomplete polypectomy and a resected margin not clearly cancer-free; all other risk factors were only associated with adverse outcome when in combination. Conclusion—As no patients with low risk malignant polyps had adverse outcomes, polypectomy alone seems sufficient for these cases. In the high risk group, surgery is recommended when either of the two independent risk factors, incomplete polypectomy or a resection margin not clearly cancer-free, is present or if there is a combination of other risk factors. As lymphatic or venous invasion or grade III cancer did not have an adverse outcome when the sole risk factor, operations in such cases should be individually assessed on the basis of surgical risk.
Three mechanisms of carbonate accretion can be observed in Phanerozoic mud-rich carbonate mounds: biomineralization which refers to skeletogenesis, organomineralization correspond to by mineral ...precipitation that involves a non-living organic substrate and finally marine cement precipitation formed by fluid flow-through. This thesis presents an assessment of the relative importance of these three main accretionary processes through time using a detailed study of Paleozoic, Mesozoic and modern mud-rich localities, all identified as carbonate mounds. At the Chute Montmorency locality (Middle Ordovician, Quebec), bioherms are lenticular bodies where in situ bryozoans dominate the bioclastic fraction. The reefal framework built by trepostomes bryozoans provides large growth cavities hosting polymud fabrics. Accretionary mechanisms rely mainly on biomineralization whereas organomineralization remains of minor importance and takes place within intra-reefal cryptic spaces. Cementation is absent. At the Anticosti Island locality (Lower Silurian, Quebec), mud-rich buildups display two distinct facies both characterized by the abundance of marine cement. The crinoid-fenestrate bryozoan mudstone-wackestone facies stands out by its volumetrically important polymud fabric as well as both shelter cavities and stromatactis. In this facies, biomineralization is limited whereas organomineralization and, to a lesser extent, marine cementation within stromatactis control the net accretion. Regarding the fenestrate bryozoan cementstone facies, the contribution of biomineralization remains minor and organomineralization is absent. In this case, net accretion is the result of extensive marine cementation. At the Foum Zidet locality (Lower Jurassic, Morocco), mounds display large amounts of macroscopically preserved, calcified siliceous sponges locally used as substrate by encrusting bryozoans and polychètes. Thus, mound accretion combines organomineralization and, to a lesser extent, biomineralization whereas marine cement precipitation is lacking. At the Jebel Assameur locality (Mid Jurassic, Morocco), mud-rich buildups display important amounts of scleractinian corals combined with a significant volume of epilithic bryozoan, annelids worms and calcified siliceous sponges. Thus, accretionary processes consist of biomineralization that develop classical patch reefs whereas organomineralization is restricted to cryptic spaces. Cement precipitation remains minor. The modern case study, the Pen Duick escarpment (offshore Morocco) locality, with its living and non-living deep-sea coral mounds, offers an excellent setting to explore whether organomineralization takes place in modern deep-water coral mounds. Reactive fluid that combines protein-like fluorescence (peak SR) with fresh, humic compounds (peak M2) is present at the surface, to a minor degree at ~ 20 cm depth, and in a distinct layer at 100 cm depth. However, no ISOM-related authigenic carbonate was observed. Hence, mound accretion at Pen Duick escarpment is mainly controlled by biomineralization whereas the development of organomineralization and marine cementation can only be assumed if relevant conditions occur along their diagenetic evolution (e.g. decrease in argillaceous material, enhanced bottom current). Our comparative approach was further extended to fifteen case studies from the mudmound literature chosen to document the mud-rich carbonate mound variability in space and time. This comparative study illustrates how mud-rich carbonate mounds sharing similar geometry, macro and micro fabrics can evolved from the varying input of the three main accretionary processes. Hence, mound accretionary mechanisms are not constant through time and mud-rich carbonate mounds (commonly named mudmound) are indeed a morphological convergence.
L’accrétion des monticules carbonatés phanérozoïques est contrôlée par trois principaux mécanismes de production de carbonates : la biominéralisation qui correspond à la squelettogénèse, l’organominéralisation qui correspond à la précipitation de carbonate de calcium en relation étroite avec des substrats organiques non vivants et la cimentation marine contrôlée par la circulation de fluides marins. Cette thèse présente une estimation de l’importance relative de ces trois processus d’accrétion dans la réalisation de la fabrique carbonatée in situ de différents cas de monticules carbonatés à faciès fins. Pour cela, une étude comparative détaillée de cinq exemples de « mudmounds » paléozoïque, mésozoïque et moderne a été menée. À la localité Chute Montmorency (Ordovicien moyen, Québec), les biohermes lenticulaires sont riches en bryozoaires in situ. La trame récifale bioconstruite par les bryozoaires trépostomes offre un large réseau de cavités où se développe la fabrique polymicritique. L’accrétion dépend principalement de la biominéralisation alors que l’organominéralisation qui prend place dans les espaces cryptiques intra-récifaux, demeure de faible importance. La cimentation marine est absente. Dans le cas de la localité Île d’Anticosti (Silurien inférieur, Québec), les monticules à bryozoaires et crinoïdes montrent deux faciès qui se distinguent par l’abondance des phases de ciment marin. Le mudstone-wackestone à bryozoaires fenestrés et crinoïdes se démarque par le volume important de la fabrique polymicritique et l’abondance des cavités d’abris et des cavités stromatactis. Pour ce faciès, le rôle joué par la biominéralisation est limité et c’est l’organominéralisation puis, dans un moindre degré, la cimentation marine associée aux stromatactis qui contrôlent l’accrétion. Pour le second faciès, le cementstone à bryozoaires fenestrés, la contribution de la biominéralisation demeure mineure et l’organominéralisation est absente. L’accrétion résulte d’une cimentation marine extensive. À la localité Foum Zidet (Jurassique inférieur, Maroc), les monticules sont riches en éponges siliceuses calcifiées très bien préservées et visibles à l’échelle macroscopique. Ces dernières, précocement indurées, ont localement servi de substrats pour les organismes encroûtants tels que les bryozoaires et les vers polychètes. L’accrétion des monticules de Foum Zidet résulte donc principalement de l’organominéralisation qui se combine, à plus petite échelle, à la biominéralisation. La cimentation marine est absente. Dans le cas de la localité Jebel Assameur (Jurassique moyen, Maroc), les monticules sont riches en coraux scléractiniens qui se combinent à d’importants volumes d’organismes épilithiques dont les bryozoaires, les vers polychètes et les éponges siliceuses calcifiées. L’accrétion est contrôlée par la biominéralisation qui a permis le développement de petits récifs de type « patch reefs ». L’organominéralisation est restreinte aux espaces cryptiques et la cimentation marine demeure de faible importance. Les monticules d’eaux profondes et froides de la localité Escarpement de Pen Duick (Océan Atlantique Est), avec leurs coraux d’eaux froides vivants en association étroite avec les faciès « coral rubble » offrent un contexte pertinent pour vérifier si l’organominéralisation est réalisée dans les monticules d’eaux profondes et froides modernes. Les fluides réactifs et potentiellement calcifiants qui combinent une signature de fluorescence protéique (pic SR) avec celle de composés humiques fraîchement produits (pic M2) ont été détectés à la surface, dans une moindre mesure à 20 cm de profondeur dans le sédiment, puis à 100 cm de profondeur. Cependant, aucune phase carbonatée authigène formée via organominéralisation n’a été observée. Dans le cas des monticules de l’Escarpement de Pen Duick, l’accrétion est principalement contrôlée par la biominéralisation. Le développement de l’organominéralisation puis de la cimentation marine ne peut être qu’envisagé lors de leur future évolution diagénétique si les conditions favorables sont réunies (e.g. courants de fond accrus, absence d’argiles). Notre approche comparative a été étendue à quinze cas d’études bien documentés dans la littérature et choisis pour illustrer la variabilité de ces objets géologiques à l’échelle spatiale et temporelle. Cette comparaison étendue illustre comment des objets géologiques comparables (géométrie, macro et micro fabrique) n’ont en réalité aucune unité génétique. L’importance relative des mécanismes d’accrétion n’apparaît pas constante au cours du temps et l’objet géologique « mudmound » est en réalité une convergence morphologique.
Background
&
Aims:
Germline mutations in the DNA mismatch repair (MMR) genes
MSH2,
MSH6, or
MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein ...encoded by
PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs.
Methods: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the
PMS2 gene.
Results: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The
PMS2 promoter was not hypermethylated in these cases. Despite interference of the
PMS2 pseudogenes, we identified several heterozygous germline mutations in the
PMS2 gene.
Conclusions:
PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in
PMS2 is considerably lower than that of mutations in other
MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.
A rare and potentially severe form of drug allergic reaction can lead to interstitial nephritis. Its pathophysiological mechanisms are not well understood.
We analyzed drug-specific T cell responses ...of twelve patients with presumably drug induced interstitial nephritis (most without skin symptoms) with the lymphocyte transformation test and generated drug specific T cell clones (TCC) from peripheral blood and from kidney. Cytokine and chemokine production of the drug-specific TCC was measured by ELISA. Kidney biopsies were analyzed by immunohistochemistry.
Proliferation assays of PBMCs or TCCs isolated from the twelve patients were performed but only two patients had a proliferative response to the drug. In particular, responses to flucloxacillin of cells generated from a male treated with rifampicin, flucloxacillin and gentamycin and to penicillin of cells from another patient treated with penicillin and vancomycin. The flucloxacillin-reactive cells showed an outgrowth of T cells bearing the T-cell receptor (TCR) Vβ9 and Vβ21.3, which suggests an oligoclonal immune response to the drug-antigen. We subsequently generated flucloxacillin-specific TCCs, all expressing CD4 and αβTCRs. Analysis of cytokines (IL-4, IL-5, IL-10, IFN-γ and TNF-α) revealed a quite heterogeneous secretion pattern, and cytotoxicity was lacking. Immunohistochemical stainings demonstrated an intertubular infiltration of CD4+ and CD8+ T cells.
Drug-specific T cells may play a decisive role in drug-induced interstitial nephritis. They may be difficult to detect in peripheral blood, as they might recognize a drug metabolite only presented in the kidney. Thus, the peculiar localization in the kidney may make these T cells more harmful.
Les bassins atlasiques exposent des dépôts mésozoïques et constituent le meilleur exemple de régime tectonique extensif/compressif sur la côte ouest africaine. Même si de nombreux travaux portent sur ...leur évolution tectonique et sédimentaire, les études portant spécifiquement sur les processus diagénétiques à l’œuvre au sein de ces bassins restent peu nombreuses. L’objectif de cette thèse est l’analyse détaillée des processus diagénétiques et de la variation de la composition des fluides en circulation pendant les différents stades de l’évolution des bassins atlasiques de rift inversés. Il s’agit d’une étude sédimentologique, diagénétique et géochimique de trois localités choisies au sein des bassins atlasiques (Moyen et Haut Atlas) afin de représenter trois secteurs géodynamiques bien distincts, à savoir le dépôt centre (localité Aït Moussa), une zone de faille majeure (localité Tunnel de la Légion) et la plate-forme carbonatée (localité Aït Athmane). L’établissement de la chronologie relative des différentes générations de fractures sur la base des entrecoupements permet d’identifier les générations de fractures associées à chacun des stades diagénétiques (éodiagénèse, mésodiagénèse et télodiagénèse). L’analyse pétrographique et géochimique des ciments en remplissage de ces fractures permet de discuter leur origine et d’établir un modèle paragénétique pour chacune des localités étudiées, depuis l’ouverture des bassins de rift jusqu'à la formation des chaînes atlasiques marocaines. Dans la localité d’Aït Athmane, le stade de l’éodiagenèse est le plus complexe, tandis que pour les localités d’Aït Moussa et de Tunnel de la Légion, c’est le stade de la mésodiagénèse qui est considéré comme le plus important en termes de nombre de générations de fractures ouvertes et de type de fluides associés. Le contexte structural a aussi une influence importante sur les stades diagénétiques et sur l’histoire thermique des dépôts sédimentaires. Dans la localité d’Aït Moussa, le modèle de l’évolution de la maturité thermique réalisé en utilisant les valeurs de la réflectance de la vitrinite a révélé que la profondeur maximale est de 3.7 km et qu’elle a été atteinte à la fin du Crétacé/début Paléogène avec une température diagénétique maximale d’environ 120ºC. Dans la localité du Tunnel de la Légion, les valeurs de Tmax (470ºC et 500ºC) obtenues indiquent que les dépôts sédimentaires ont atteint des températures diagénétiques dépassant la fenêtre à huile. Les bassins atlasiques renferment un système pétrolier de type rift et plate-forme et combinent un fort potentiel de roches mères – réservoirs. Le système pétrolier du domaine atlasique est assez bien documenté mais certains aspects tels que le stade de la génération et la migration des hydrocarbures sont mal connus. Dans cette étude, les données pétrographiques et les analyses géochimiques associées ont permis de déterminer la chronologie relative de la phase de génération des hydrocarbures ainsi que les conduits utilisés pendant le stade de la migration. Dans la localité d’Aït Moussa, le stade de la génération des hydrocarbures est enregistré sous forme d’inclusions fluorescentes dans les cristaux de dolomie (dolomie-2 et -3). Ce stade débute au Jurassique supérieur – Crétacé inférieur (ca. 150 Ma) et les hydrocarbures restent sous pression jusqu’à l’ouverture des fractures associées au début de la télodiagénèse (Éocène supérieur). Dans la localité du Tunnel de la Légion, le stade de la génération des hydrocarbures est synchrone à l’ouverture des fractures conjuguées (Crétacé supérieur – Paléocène inférieur) et continu jusqu’au début de la phase de la compression tectonique (Éocène supérieur). Dans la localité d’Aït Athmane, le stade de la génération des hydrocarbures est synchrone à l'ouverture de la deuxième génération de fractures et se poursuit après le début de la phase de la compression tectonique. Les chromatogrammes (CG et CG-SM) obtenus des échantillons prélevés des localités étudiées montre une distribution similaire des n-alcanes avec un maximum à n-C17 et n-C19. Les analyses des biomarqueurs révélent que la matière organique présente dans les localités d’Aït Moussa et de Tunnel de la Légion est d’origine marine (kérogène type II et I), et les faibles différences sont liées à la maturation thermique et à la migration. Une stratégie d'exploration devrait prendre en considération le stade du début de la génération des hydrocarbures et les fractures associées par rapport à la formation des roches réservoirs.
The Atlas basins of Morocco expose the history of two closely related Jurassic intracontinental rift basins corresponding to the Middle and the High Atlas. These sedimentary basins represent one of the best examples of extensive/compressive tectonic regime on the west coast of Africa and although they have a quite similar sedimentary history they have undergone different thermal evolution. This work is to explore the effect of these differences in terms of diagenesis and fluid flow. Several tectonic and sedimentary studies on the Atlas basins exist though very few of them focuse on the characterization of diagenetic processes. This study is based on an integrated petrographic and geochemical approach to further our basic understanding on petrogenesis and diagenetic fluid compositions. It focuses on diagenetic processes and fluid compositions related to different diagenetic stages in three locations representing: 1) the depocentre (loc. Aït Moussa); 2) a major fault zone (loc. Tunnel de la Légion); and 3) the carbonate platform (loc. Aït Athmane). Diagenetic stages are divided into three stages (eodiagenesis, mesodiagenesis and telodiagenesis) using stratiform and tectonic stylolites as markers. Relative chronology of fracture generations and stylolites based on cross-cutting relationships enables to assign fracture generations to each diagenetic stages. Detailed paragenetic and geochemical analysis on fracture and pore-filling cements help to establish the paragenetic sequences and to illustrate the relationship between different diagenetic mineral phases in a time/space-resolved petrogenetogram. Geochemical analyses have been done in ordre to investigate the nature and the origin of diagenetic fluids circulating in the study areas from the rifting period until the formation of the Atlas Mountains. Various diagenetic processes including cementation, dissolution, compaction, recrystallization, replacement, dolomitisation, and dedolomitisation are observed at the different locations. At Aït Athmane, eodiagenetic stage is essentially controlled by sea level fluctuations while telodiagenetic stage was tectonically controlled by the circulation of ascending fluids through major faults enriched in lead and hydrocarbon. The thermal maturity model based on vitrinite reflectance (Ro 0.85 and 1.34 %) analysis on samples from Aït Moussa indicates a maximum burial depth around 3.7 km, reached during Upper Cretaceous to Early Paleogene, with a maximum diagenetic temperature of approximatly 120ºC. Tmax values calculated from argillaceous limestones at Tunnel de la Légion range from 470ºC to 500ºC indicating overmature sedimentary successions in the area. Both Atlas rift basins contain a rift-type and a platform-type petroleum system, a situation that also applies to the numerous Atlantic-type, margin-related rift basins that formed during Triassic – Jurassic rifting along western Africa. The petroleum system of the Atlas basins is fairly well documented, but certain aspects as hydrocarbon generation and migration stages are poorly understood. At the locality of Aït Moussa, hydrocarbon generation stage is recorded as fluorescent inclusions in dolomite crystals (dolomite-2 and -3) and starts in the Late Jurassic - Early Cretaceous (approx. 150 Ma). Hydrocarbon fluids remained normally pressured until the opening of late diagenetic fractures during Late Eocene tectonic compression. At the locality of Tunnel de la Légion, hydrocarbon generation stage begins with the opening of conjugate fractures during Late Cretaceous – Early Paleocene and continue until the begining of tectonic compression (Late Eocene). At the locality of Aït Athmane, hydrocarbon generation stage is synchronous to the opening of the second generation of fractures and continues after the begining of tectonic compression. The GC and GC-MS chromatograms of samples taken from the three location shows a very similar n-alkanes pattern with a maximum at n-C17 and n-C19. Biomarker analyses revealed that the origin of the organic matter in the localities of Aït Moussa and Tunnel de la Légion is marine (kerogene type II and I) and the small differences are related to thermal maturation and to migration. An exploration strategy should consider the begining of hydrocarbon migration stages and associated fractures relative to the rock reservoir formation.
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