Adjacent Lesions Research Articles

Thickening of Schneiderian membrane secondary to periapical lesions: A retrospective radiographic analysis.

ABSTRACTAim:The aim of this study was to investigate the possible correlation between adjacent periapical lesions of maxillary teeth and Schneiderian membrane thickness (SMT).Materials and Methods:An analytical study of case-control study design was conducted. From the archives, cone beam computed tomography (CBCT) images of 83 patients with periapical lesion in any of the maxillary posterior teeth were randomly selected as the case group. The normal, contralateral teeth in the same patient were considered in the control group. Eighty-eight teeth were considered in each group, comprising a total sample of 176. For each sample in case group, the distance from the border of the periapical lesion to the cortical bone of the bony floor of the maxillary sinus and SMT were measured. SMT on the contralateral side adjacent to the healthy (control) teeth was also measured. Data were presented in mean ± standard deviation and inferential statistics was performed using independent t test and analysis of variance (ANOVA). Later Pearson correlation and multiple linear logistic regression were carried out using Statistical Package for the Social Sciences software program, version 21.0 at 95% confidence interval.Results:Teeth with periapical lesion were found to have significantly (P < 0.001) increased SMT when compared with that of adjacent to healthy teeth. On the contrary, nonsignificant differences were found in SMT when genders and age groups were compared (P = 0.295 and 0.060, respectively). A strong negative correlation was observed between distance of the lesion to the sinus and SMT (P = 0.003).Conclusion:Neighboring periapical lesions of maxillary teeth are associated with SMT that is worsened when the lesion is close to the sinus.

A case of infantile digital fibromatosis with recurrent to adjacent lesion

A case of infantile digital fibromatosis with recurrent to adjacent lesion

Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis

ObjectiveFamilial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas...

Discordant Marker Expression Between Invasive Breast Carcinoma and Corresponding Synchronous and Preceding DCIS.

Ductal carcinoma in situ (DCIS) is considered a potential precursor of invasive breast carcinoma (IBC). Studies aiming to find markers involved in DCIS progression generally have compared characteristics of IBC lesions with those of adjacent synchronous DCIS lesions. The question remains whether synchronous DCIS and IBC comparisons are a good surrogate for primary DCIS and subsequent IBC. In this study, we compared both primary DCIS and synchronous DCIS with the associated IBC lesion, on the basis of immunohistochemical marker expression. Immunohistochemical analysis of ER, PR, HER2, p53, and cyclo-oxygenase 2 (COX-2) was performed for 143 primary DCIS and subsequent IBC lesions, including 81 IBC lesions with synchronous DCIS. Agreement between DCIS and IBC was assessed using kappa, and symmetry tests were performed to assess the pattern in marker conversion. The primary DCIS and subsequent IBC more often showed discordant marker expression than synchronous DCIS and IBC. Strikingly, 18 of 49 (36%) women with HER2-positive primary DCIS developed an HER2-negative IBC. Such a difference in HER2 expression was not observed when comparing synchronous DCIS and IBC. The frequency of discordant marker expression did not increase with longer time between primary DCIS and IBC. In conclusion, comparison of primary DCIS and subsequent IBC yields different results than a comparison of synchronous DCIS and IBC, in particular with regard to HER2 status. To gain more insight into the progression of DCIS to IBC, it is essential to focus on the relationship between primary DCIS and subsequent IBC, rather than comparing IBC with synchronous DCIS.

3073 Eosinophilic Gastroenteritis and Eosinophilic Proctocolitis With a Large Rectal Sessile Serrated Adenoma: A Rare Association

INTRODUCTION: Eosinophilic Gastrointestinal Disorders (EGID) are a group of rare disorders characterized by eosinophilic infiltration of the gastrointestinal tract. Eosinophilic gastroenteritis (EGE), eosinophilic colitis (EC) and eosinophilic proctitis (EP) are different types of EGID. We report a case of rare association of EGID and a large sessile serrated adenoma in a middle-aged Hispanic female. CASE DESCRIPTION/METHODS: A 49-year-old Hispanic female presented with epigastric discomfort, nausea and hematochezia. The symptoms were insidious in onset and evolved over the span of 3 years. Upper GI Endoscopy showed mild diffuse erythematous mucosa in the antrum and body of the stomach. Colonoscopy showed a few superficial ulcers in the terminal ileum, two polyps in the transverse colon and a large laterally spreading polypoid lesion in the rectum with adjacent multiple small polypoid lesions (Figures 1 and 2). Histological assessment of the gastric biopsy specimen revealed chronic active gastritis, numerous H. pylori, in addition to very high number of eosinophils in the lamina propria. Biopsies of ileum, colon and the rectum also revealed very high number of eosinophils in the lamina propria. Stool for ova and parasite examinations were negative and no peripheral eosinophilia was noted. Patient did not have any food or environmental allergies. Other disorders that could contribute to eosinophil infiltration of the GI tract were ruled out. Hematochezia was likely due to eosinophilic proctitis and rectal polypoid lesion. Although exact eosinophilic count in the biopsy specimen of the stomach, small bowel and the colon was not reported, the clinical presentation and histology was likely consistent with EGID. Patient was treated for H. Pylori infection. Endoscopic submucosal dissection of the rectal polypoid lesion was performed (Figure 3). Pathology revealed sessile serrated adenoma. DISCUSSION: Eosinophilic gastrointestinal disorders are a group of rare gastrointestinal diseases with non-specific symptoms and clinical presentation. Diagnosis of EGE, EC and EP involves evaluating for presence of gastrointestinal symptoms, histopathology finding of eosinophilic infiltration of the GI tract and ruling out secondary causes of eosinophilia. Endoscopic examination may reveal patchy erythema, loss of vascularity and lymphonodular hyperplasia mostly localized to the rectum. The authors report this rare case of possible association of EGID and sessile serrated adenoma.

Metástasis intraorbitárias de cáncer de mama

Objetivo: Describir un caso raro de una paciente previamente diagnosticada con cáncer de mama que evolucionó después de algunos años con metástasis intraorbitaria. Métodos: Relato del caso y revisión de literatura. Resultados: La correlación del diagnóstico previo de neoplasia de mama y la presencia de múltiples lesiones en la órbita y regiones adjacentes ha permitido concluir que la paciente presentaba enfermedad metastásica. Las metástasis se presentan como manifestaciones cada vez más frecuentes en enfermos oncológicos. La órbita y estruturas próximas constituyen topografías poco usuales de diseminación de células neoplásicas y manifestaciones iniciales pueden mimetizar otras condiciones, retrasando el diagnóstico. Como se trataban de pequeñas lesiones, se ha optado por radioterapia como tratamiento único. Después del término la paciente evolucionó con regresión de sintomatología. Conclusiones: Aunque infrecuentes, manifestaciones oculares pueden ocurrir en enfermos oncológicos y la investigación de enfermedad metastático de la órbita es esencial para el seguimiento adecuado.

Usefulness of immunohistochemistry for mismatch repair protein and microsatellite instability examination in adenocarcinoma and background endometrium of sporadic endometrial cancer cases.

Microsatellite instability (MSI), which reflects loss of DNA mismatch repair (MMR) activity, and immunohistochemistry (IHC) for MMR proteins are employed as screening examinations for Lynch syndrome (LS). Recent studies revealed that there is a population of MSI-high tumors in sporadic endometrial cancer (EC). However, MSI data for Japanese EC patients are scarce. Furthermore, sporadic estrogen-dependent EC (type I) is generally considered to arise from hyperplasia. Because LS is usually associated with type I EC, we hypothesized that MSI might be involved in the oncogenic process in some sporadic EC. We conducted MSI testing to reveal MSI status in sporadic Japanese EC. IHC for MMR proteins was also performed. Ninety-eight tissue samples of sporadic ECs from Japanese patients were used for IHC and MSI examinations. We also evaluated MMR protein expressions in the background normal endometrium. Microsatellite instability-high was observed in 10.2% of 98 cases with sporadic EC, a lower percentage than that in Western studies. Loss of some MMR proteins was observed in 23 cases (23.5%) and there was a significant correlation with MSI-high status (P < 0.001). Concerning the background endometrium, two cases showed partial loss of MLH1 and PMS2, corresponding to adjacent EC lesions, suggesting that MMR deficiency may already be present in the background endometrium. The MSI-high rate was low in our Japanese cohort. Our data confirmed the usefulness of MMR protein assessment for MSI screening in Japanese EC patients. Furthermore, IHC of the background endometrium might reveal the mechanism of MSI-high tumorigenesis.

Biomechanical Effects of Fixation of Different Segments of Goat Lumbar Spine on Adjacent Segmental Motion and Intradiscal Pressure Change.

BackgroundThe aim of this study was to investigate the biomechanical fixation effects of different segments of the goat spine on adjacent segmental motion and intradiscal pressure (IDP) change.Material/MethodsEighteen goat spine specimens were randomly divided into 3 groups: group A (single-segment fixation), group B (double-segment fixation), and group C (triple-segment fixation). The motion was tested on each specimen using a spinal motion simulation test system with rational pressure loading. The IDP was measured using a pinhole pressure sensor.ResultsRange of motion (ROM) and IDP of adjacent segments increased with increased external load. In comparison of the 3 groups, significant differences in ROM were found when the external force was more than 100 N (P<0.05). The differences in IDP of the adjacent segment were statistically significant (P<0.05) when external pressure was greater than or equal to 60 N. However, in comparison of group A with group B, no significant differences in ROM and IDP of the adjacent segments were noted for the motions of anterior flexion, posterior extension, and lateral bending (P>0.05). Moreover, upper adjacent segments had greater ROM than the lower adjacent segments (P<0.05). We found significant differences between IDPs of the upper adjacent segments and lower adjacent segments (P<0.05).ConclusionsAs the number of fixated lumbar segments increases, ROM and IDP of the adjacent segments increase. Multisegment fixation is most likely the main factor contributing to the development of adjacent segmental lesions after lumbar fixation.

Abstract 741: Clonal evolution of non-malignant proliferative lesions into breast cancers

Abstract [Introduction] Non-malignant proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of normal ducts, non-malignant proliferative lesions and cancers in the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from different proliferative lesions within the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] A total of 39 samples from 6 premenopausal females carrying estrogen receptor-positive cancers were analyzed, where the samples were obtained from normal ducts (N = 5), non-malignant proliferative lesions (N = 9), and non-invasive (N = 21) and invasive (N = 4) cancers. The number of somatic mutations per sample was ranging from 1 to 311 and increased with pathological disease progression. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining four unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7-33 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), a GATA3 mutation (UID: KU03 and KU06), a CBFB mutation (UID: KU06) and concurrent 1q gain and 16q loss (UID: KU02, KU03 and KU06), while harboring private mutations/CNAs of their own. The analysis of phylogenic trees based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Early breast cancer development is thought to be shaped by a simultaneous evolution of multiple precancerous clones. It may be multi-focally initiated by a germline mutation, frequently terminated in bilateral cancers. By contrast, in unilateral cases, cancer clones might be derived from a common ancestral clone, which has acquired a driver founder mutation long before the onset of cancer, and undergo independent evolution, giving rise to multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Kenichi Yoshida, Yukiko Kawata, Yasuhide Takeuchi, Nobuyuki Kakiuchi, Yusuke Shiozawa, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of non-malignant proliferative lesions into breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 741.

Abstract 5126: Genetic analysis of metachronous pancreatic cancers

Abstract [Introduction] Early detection of pancreatic cancer is a key to curable surgery, although many are diagnosed in advanced stage. However, even in those cases in which cancer was detected early enough for curative resection, metachronous pancreatic cancer may occur in residual pancreas, whose pathogenesis, including its relationship with primary cancer, has been poorly understood. In this study, we aimed to reveal the origin of metachronous pancreatic cancers using an unbiased detection of somatic mutations in primary and metachronous cancers as well as adjacent precursor lesions. [Methods] Samples were obtained from longitudinal sampling from above lesions using laser microdissection from formalin-fixed paraffin-embedded surgical specimens. DNA was extracted and analyzed for somatic mutations of each lesion by whole-exome sequencing with matched normal DNA. On the basis of shared and private mutations across different samples, we interrogated history of clonal evolution of these lesions. [Results] Four patients were enrolled who underwent curative surgery for early pancreatic cancer and subsequently for metachronous tumors in the residual pancreas. Pathology from surgery for primary cancer were margin-negative in all patients. The median interval between the initial and second surgery was 29.8 months (22.8 - 38.3 months). The number of precursor lesions analyzed was from 0 to 5 per patient. The median number of somatic mutations per sample was 78 (range: 41-92) in cancers and 20 (14-42) in precursor lesions. None of the patients have known pathogenic germline mutations. With a median of 78 and 20 mutations per sample, all samples had one or more driver mutations. In each case, all driver mutations that were detected in cancers were shared between primary and metachronous cancer. It indicated that metachronous cancer branched off from primary cancers at later stage of carcinogenesis. And negative margin at initial surgery suggested that metachronous cancer was formed by dissemination or metastasizing rather than Intraductal progression. By contrast, none of the mutations other than a hotspot KRAS mutations were shared between precursor lesions and cancers, suggesting multiple independent clonal growth of precancerous cells in the cancer bearing pancreas. [Conclusions] Our study shows that metachronous pancreatic cancers are derived from the same origin of initial cancer. Therefore, even in the case of early pancreatic cancer careful checkup for recurrence in the residual pancreas is important. Citation Format: Hirano Tomonori, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Yoshikage Inoue, Tomomi Nishimura, Yoichi Fujii, Akira Yokoyama, Hideki Makishima, Toshihiko Masui, Shinji Uemoto, Sachiko Minamiguchi, Hironori Haga, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Norimitsu Uza, Yuzo Kodama, Hiroshi Seno, Tsutomu Chiba, Seishi Ogawa. Genetic analysis of metachronous pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5126.

The role of rapid on-site evaluation on diagnostic accuracy of endoscopic ultrasound fine needle aspiration for pancreatic, submucosal upper gastrointestinal tract and adjacent lesions.

Our aim was to assess adequacy and diagnostic accuracy of endoscopic ultrasound-fine needle aspiration (EUS-FNA) specimens with or without rapid on-site evaluation (ROSE) from pancreatic, upper gastrointestinal tract (UGIT) and adjacent masses. A retrospective cohort study based on patients' files who underwent EUS-FNA in Galilee Medical Center in a 4years period. Number of needle passes, repeated EUS and ROSE effect on tissue adequacy and diagnostic accuracy were reported. One-hundred sixty-one patients were included. Ninety-three patients (57.7%) underwent EUS-FNA without ROSE (group A) compared to 68 patients (42.3%) with ROSE (group B). The most common location was in the pancreas (55% in group A vs 81% in group B). Addition of ROSE yielded a significantly higher specimen adequacy (65% in group A vs 92.6% in group B (Chi-Square<0.0001, OR 6.72, 95% CI 2.45-18.38). The matching rate (accuracy) between ROSE diagnosis and final histopathological diagnosis was noticed in 61 out of 68 patients (89.7%, 95% CI 0.7993-0.9576). The Kappa coefficient correlations of matching rate between ROSE and final histopathological diagnosis of all lesion and in pancreatic lesions were 0.7558, (95% CI 0.625-0.887) and 0.7814, (95% CI 0.639-0.924), respectively. EUS-FNA with ROSE significantly improve specimen adequacy and was associated with high diagnostic accuracy.

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma.

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.

Lateral rectus muscle biopsy as diagnosis of unknown metastatic breast cancer

The case concerns a 58 year-old female with no medical history of interest who consulted due to binocular diplopia of one week onset. It was associated with costal pain, dyspnoea, intense asthenia and weight loss of 2 months onset. In the blood analysis in the Emergency Department it showed hypercalcaemia, renal failure, and bicytopenia. The chest x-ray showed lytic bone lesions that initially lead to multiple myeloma with extra-osseous involvement. In addition to the corresponding study, in case of horizontal diplopia, a cranial CT scan without contrast was performed where an adjacent lesion to the lateral wall of the left orbit is observed. This was of soft tissue density, and included the external rectus muscle that exerts a mass effect on the optic nerve by displacing it medially. Many lytic bone diffuse lesions with salt and pepper pattern were found in the calotte. A rectus lateral muscle and bone biopsy of the sacral wing was performed, resulting in metastasis of carcinoma compatible with mammary origin. An atypical case is presented of horizontal diplopia in the context of a patient with a severe constitutional picture with no established diagnosis, in which the biopsy of the lateral rectum was key to the confirmation diagnosis.

Nonsurgical Endodontic Treatment of Necrotic Teeth Resolved Apical Lesions on Adjacent Implants with Retrograde/Apical Peri-implantitis: A Case Series with 2-year Follow-up

Retrograde (or apical/periapical) peri-implantitis (RPI) presents with radiographic signs of bone loss at the periapical area of endosteal implants and may also present with clinical signs of abscess formation or a sinus tract traceable to the implant periapex. The lesion may form days up to several years after the initial implant placement. In contrast to marginal peri-implantitis, which has a prevalence of 19.83%, RPI may be underreported because many clinicians are currently not aware of this type of lesion. The etiology, although not fully understood, may be attributed to endodontic infection of an adjacent tooth or residual microorganisms present after the extraction of an infected tooth at the implant site. There are several treatment modalities available for the management of RPI. Nonsurgical root canal treatment may be an option if the implant RPI etiology is suspected to be related to an adjacent endodontically involved tooth. In a previous report, surgical treatment modalities to correct RPI were described. This current case series presents 2 cases of RPI in which nonsurgical treatment of the necrotic adjacent teeth resulted in full radiographic and clinical resolution of the adjacent apical peri-implant lesions with 18-month and 2-year follow-ups, respectively. RPI may be prevented by evaluating the endodontic status of natural teeth adjacent to the implants and by addressing endodontic infections near the implant sites. Certain types of implant RPI may successfully be resolved nonsurgically by addressing adjacent endodontic infections as shown by this case series.

Etiology and clinical features of orbital cellulitis in adults

Objective To investigate the etiology and clinical features of orbital cellulitis in adults. Methods The data of 54 adults with orbital cellulitis from Jan. 2010 to Dec. 2017 were analyzed retrospectively. The clinical manifestations of patients infected by orbital and adjacent tissues were compared with those without these causese. Results There were 33 cases (61.11%) with orbital and adjacent tissue infection. The differences in subfascial effusion, extraocular muscle thickening, optic nerve involvement and severe complications were statistically significant between the two groups (P<0.05). Conclusion The spread of local and adjacent tissues is still the main infection channel of adult orbital cellulitis, dacryocystitis is the main cause. Severity of disease is more serious in those without local and adjacent tissue lesions. Key words: Cellulitis, orbital, adult; Etiology; Clinical features

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in a child with ataxia and diplopia

We report the case of a 15-year-old boy with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). He presented with diplopia and ataxia and his cerebrospinal fluid showed mild pleocytosis and elevated protein. MRI demonstrated a reversible splenial lesion in the corpus callosum. He did not receive any treatment and recovered quickly within two weeks. Results of neurological examination after 3 months were completely normal. MERS is relatively unknown in Europe. The majority of patients are reported in East Asia. This post-infectious encephalitis/encephalopathy arises soon after the onset of symptoms. The prognosis is excellent and most patients recover completely without neurological sequelae. MRI typically shows a reversible splenial lesion with diffusion restriction and without contrast enhancement, sometimes with adjacent symmetrical lesions extending into the subcortical white matter. The pathogenesis is still unknown. Recognition of the condition and its clinic-radiological discrimination from acute disseminated encephalomyelitis may prevent unnecessary treatment.

Abstract PD3-07: A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ

Abstract Background: Estrogen receptor (ER)-negative tumors and human epidermal growth factor 2-Neu (HER2) positive breast cancers are known to be more clinically aggressive subtypes of breast cancer and account for 30% of all breast cancers. Women with HER2 + breast cancers, whether ER+ or ER -, require cytotoxic chemotherapy with a HER2-targeting agent, and often have adverse outcomes. Thus, preventive agents are needed to reduce the incidence of these subtypes of aggressive breast cancer. Lapatinib, a dual tyrosine kinase inhibitor, inhibits epidermal growth factor receptors (EGFR) and HER2 kinases and has shown to decrease breast cell proliferation in invasive breast cancer and adjacent premalignant lesions. Therefore, we conducted a multi-institutional randomized Phase II clinical trial to study the effects of the signal transduction inhibitor lapatinib in women with HER2-positive or EGFR-positive ductal carcinoma in situ (DCIS). Methods: Randomized participants received either lapatinib (750mg, 1000mg, or 1500mg) or placebo daily for 2-6 weeks prior to their surgery. After minimal accrual, the trial was later amended to lapatinib 1000mg or placebo. Pre-treatment breast tissue was obtained from initial diagnostic core biopsy and post-treatment breast tissue was obtained from surgical excision specimen. Blood was obtained prior to surgery to assess serum lapatinib level. Participants kept a daily symptom assessment log and had a cardiac assessment at baseline and prior to surgery. Patients were instructed to take drug up to and including the day before surgery. The dual primary endpoint for this study was change in proliferation in pre- versus post-treatment biopsies between the two treatment arms, as measured by Ki67 as well as toxicity assessment. Secondary endpoints included incidence of DCIS at surgery and modulation of tissue biomarker expression in growth factor receptors (EGFR, ErbB2); phosphorylated growth factor receptor (phospho-ErbB2); signal transduction markers (MAPK, phospho-MAPK); hormone receptors (ER, PR); and p27. Results:Twenty-two women (mean age: 51; range: 32-66) with HER2+ or EGFR+ DCIS were treated with lapatinib (1,000 or 1,500 mg) or placebo for 2–6 weeks prior to surgical excision. Ki67 expression was significantly decreased in the lapatinib treatment arms compared to placebo (p=0.0122). Diarrhea, fatigue, and skin reactions were notable adverse events that occurred predominately in the lapatinib arm compared to placebo. No grade 3 or 4 events related to the study drug were noted during the study. No changes were noted in cardiac function. DCIS was present in all surgical specimens in both arms. Invasive breast cancer was noted in 1 patient on lapatinib 1000mg and 3 patients on placebo. No statistically significant changes were noted in signal transduction biomarkers Conclusion:These results demonstrate the effectiveness of lapatinib in reducing proliferation in women with EGFR+ or HER2+ DCIS. Even low-grade toxicities can deter use of an agent in the prevention setting. This and the lack of a risk model for HER2+ and triple negative breast cancer make the development of larger scale clinical prevention trials of lapatinib for the prevention a challenge. Citation Format: Thomas PS, Contreras A, Pruthi S, Krontiras H, Rimawi M, Garber J, Wang T, Hilsenbeck SG, Vornik LA, Gilmer T, Friedman R, Heckman-Stoddard BM, Dunn B, Kuerer H, Brown PH. A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-07.

Abstract P3-06-04: Clonal evolution of non-malignant proliferative lesions into breast cancers

Abstract [Introduction] Non-malignant proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles (with and without pathogenic germline mutations) of normal mammary ducts, non-malignant proliferative lesions, and cancer tissues from the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from different proliferative lesions within the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] We analyzed a total of 34 samples from 5 premenopausal females carrying estrogen receptor-positive cancers, where the samples were obtained from normal ducts (N = 6), non-atypical (N = 1) and atypical (N = 8) proliferative lesions, and non-invasive (N = 16) and invasive (N = 3) cancers. The number of somatic mutations per sample ranged from 1 to 276 and increased with disease progression, regardless of the germline mutation status. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining three unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7-25 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), concurrent 1q gain and 16q loss (der(1;16)) (UID: KU02), and a GATA3 mutation and der(1;16) (UID: KU03), while harboring private mutations and/or CNAs of their own. The phylogenetic analysis based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Our results suggest that early breast cancer development is shaped by the evolution of multiple precancerous clones. These clones are originated from a common ancestor that acquired a founder mutation long before the onset of cancer, followed by branching evolution of multiple clones that acquired additional driver mutations of their own, from which an invasive cancer ultimately develops. In hereditary cases, this process is thought to be substantially promoted multi-focally from within the entire breasts by a germline mutation shared by all mammary cells, frequently resulting in bilateral and/or multifocal breast cancers. Our findings provide unique insight into the early development of breast cancer. Citation Format: Nishimura T, Yoshida K, Kawata Y, Takeuchi Y, Kakiuchi N, Shiozawa Y, Aoki K, Hirata M, Kataoka TR, Sakurai T, Baba S, Shiraishi Y, Chiba K, Takeuchi K, Haga H, Miyano S, Toi M, Ogawa S. Clonal evolution of non-malignant proliferative lesions into breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-04.

A case report of delayed cortical infarction adjacent to sulcal clots after traumatic subarachnoid hemorrhage in the absence of proximal vasospasm

BackgroundCortical ischemic lesions represent the predominant pathomorphological pattern of focal lesions after aneurysmal subarachnoid hemorrhage (aSAH). Autopsy studies suggest that they occur adjacent to subarachnoid blood and are related to spasm of small cortical rather than proximal arteries. Recent clinical monitoring studies showed that cortical spreading depolarizations, which induce cortical arterial spasms, are involved in lesion development. If subarachnoid blood induces adjacent cortical lesions, it would be expected that (i) they also develop after traumatic subarachnoid hemorrhage (tSAH), and (ii) lesions after tSAH can occur in absence of angiographic vasospasm, as was found for aSAH.Case presentationAn 86-year-old woman was admitted to our hospital with fluctuating consciousness after hitting her head during a fall. The initial computed tomography (CT) was significant for tSAH in cortical sulci. On day 8, the patient experienced a secondary neurological deterioration with reduced consciousness and global aphasia. Whereas the CT scan on day 9 was still unremarkable, magnetic resonance imaging (MRI) on day 10 revealed new cortical laminar infarcts adjacent to sulcal blood clots. Proximal vasospasm was ruled out using MR and CT angiography and Doppler sonography. CT on day 14 confirmed the delayed infarcts.ConclusionsWe describe a case of delayed cortical infarcts around sulcal blood clots after tSAH in the absence of proximal vasospasm, similar to results found previously for aSAH. As for aSAH, this case suggests that assessment of angiographic vasospasm is not sufficient to screen for risk of delayed infarcts after tSAH. Electrocorticography is suggested as a complementary method to monitor the hypothesized mechanism of spreading depolarizations.

Biopsia del músculo recto lateral orbitario como diagnóstico de cáncer de mama metastásico no conocido

The case concerns a 58 year-old female with no medical history of interest who consulted due to binocular diplopia of one week onset. It was associated with costal pain, dyspnoea, intense asthenia and weight loss of 2 months onset. In the blood analysis in the Emergency Department it showed hypercalcaemia, renal failure, and bicytopenia. The chest x-ray showed lytic bone lesions that initially lead to multiple myeloma with extra-osseous involvement.In addition to the corresponding study, in case of horizontal diplopia, a cranial CT scan without contrast was performed where an adjacent lesion to the lateral wall of the left orbit is observed. This was of soft tissue density, and included the external rectus muscle that exerts a mass effect on the optic nerve by displacing it medially. Many lytic bone diffuse lesions with salt and pepper pattern were found in the calotte. A rectus lateral muscle and bone biopsy of the sacral wing was performed, resulting in metastasis of carcinoma compatible with mammary origin.An atypical case is presented of horizontal diplopia in the context of a patient with a severe constitutional picture with no established diagnosis, in which the biopsy of the lateral rectum was key to the confirmation diagnosis.