EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma.

The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.

A Machine Learning-Driven Comparison of Ion Images Obtained by MALDI and MALDI-2 Mass Spectrometry Imaging.

Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) enables label-free imaging of biomolecules in biological tissues. However, many species remain undetected due to their poor ionization efficiencies. MALDI-2 (laser-induced post-ionization) is the most widely used post-ionization method for improving analyte ionization efficiencies. Mass spectra acquired using MALDI-2 constitute a combination of ions generated by both MALDI and MALDI-2 processes. Until now, no studies have focused on a detailed comparison between the ion images (as opposed to the generated m/z values) produced by MALDI and MALDI-2 for mass spectrometry imaging (MSI) experiments. Herein, we investigated the ion images produced by both MALDI and MALDI-2 on the same tissue section using correlation analysis (to explore similarities in ion images for ions common to both MALDI and MALDI-2) and a deep learning approach. For the latter, we used an analytical workflow based on the Xception convolutional neural network, which was originally trained for human-like natural image classification but which we adapted to elucidate similarities and differences in ion images obtained using the two MSI techniques. Correlation analysis demonstrated that common ions yielded similar spatial distributions with low-correlation species explained by either poor signal intensity in MALDI or the generation of additional unresolved signals using MALDI-2. Using the Xception-based method, we identified many regions in the t-SNE space of spatially similar ion images containing MALDI and MALDI-2-related signals. More notably, the method revealed distinct regions containing only MALDI-2 ion images with unique spatial distributions that were not observed using MALDI. These data explicitly demonstrate the ability of MALDI-2 to reveal molecular features and patterns as well as histological regions of interest that are not visible when using conventional MALDI.

Sex as a Predictor of Response to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma.

Approximately 3-5% of patients with cutaneous squamous cell carcinoma (CSCC) develop advanced disease, accounting for roughly 1% of all cancer deaths in Australia. Immunotherapy has demonstrated significant clinical benefit in advanced CSCC in several key phase II studies; however, there are limited data for patients treated outside of clinical trials. This is particularly relevant in advanced CSCC, which is most often seen in elderly patients with significant comorbidities. Thus, we aim to describe our experience with immunotherapy in a cohort of patients with advanced CSCC in Australia. We retrospectively reviewed all advanced CSCC patients treated with immunotherapy within the Illawarra and Shoalhaven Local Health District. Among the 51 patients treated with immunotherapy, there was an objective response rate (ORR) of 53% and disease control rate (DCR) of 67%. Our most significant predictor of response was sex, with male patients more likely to have better responses compared to female patients (DCR 85% vs. 41%, p < 0.0001), as well as improved progression-free survival (HR 4.6, 95%CI 1.9-10.8, p = 0.0007) and overall survival (HR 3.0, 95%CI 1.3-7.1, p = 0.006). Differential expression analysis of 770 immune-related genes demonstrated an impaired CD8 T-cell response in female patients. Our observed ORR of 53% is similar to that described in current literature with durable responses seen in the majority of patients.

Primary Breast Lymphoma in a Woman: A Case Report and Review of the Literature.

BACKGROUND: Primary breast lymphoma (PBL) is an unusual clinical entity accounting for 0.4-0.5% of all breast neoplasms. The usual presentation includes a painless palpable mass similar to that of breast carcinoma. Diffuse large B-cell lymphoma (DLBCL) is the most common identifiable type of PBL based on the histopathological examination. CASE REPORT: We report an unusual case of a 43-year-old Indonesian woman who presented with a 7-month history of a painless mass in the left breast. A core needle biopsy revealed diffuse infiltration of large atypical lymphoid cells. The immuno-histochemical biomarkers confirmed the diagnosis of a DLBCL. A bone scan showed no evidence of bone metastasis. It was treated non-surgically, based on the decision of the breast multidisciplinary team (MDT). The patient was treated with 4 cycles of combination chemotherapy with R-CODOX/IVAC. A follow-up PET scan revealed non-significant mild F-18 fluorodeoxyglucose (FDG) uptake at the periphery of the residual left breast mass, indicating a radiologically favorable response. CONCLUSIONS: Early and accurate diagnosis of PBL is crucial for selecting the appropriate MDT treatment strategies to avert potentially harmful surgical interventions.

Neuroendocrine tumor of the gallbladder.

BACKGROUND: The primary neuroendocrine tumors of the gallbladder are very rare, representing 0.2% of all neuroendocrine tumors. The definite diagnosis is incidental in most cases. CASE REPORT: A 60-year-old male patient presented with a one-month history of epigastric pain and jaundice, itching, flushing, cough and wheezing. Ultrasound demonstrated the gallbladder containing multiple stones, with wall thickening and an adjacent liver lesion. Additionally, those structures showed noticeable contrast enhancement in CT and MRI. Histopathological examination revealed a primary gallbladder neuroendocrine tumor. CONCLUSIONS: Though a rare entity, primary neuroendocrine tumor should be considered in the differential diagnosis of gallbladder cancers.

Case report of complicated epidermoid cyst of the floor of the mouth: Radiology-histopathology correlation.

Epidermoid cysts, true dermoid cysts and teratoid cysts compose the spectrum of cystic teratomas, which are defined as neoplasms whose tissue are derivatives of more than one germ layer, foreign to that part of the body from which the tumor arises. Epidermoid cysts of the floor of the mouth are rare lesions and are much less common than dermoid cysts in the head and neck. This case reports a 43-year-old male patient who presented with a longstanding midline swelling in the submental region. Initial imaging was done using ultrasound followed by computed tomography (CT) scan. Biopsy was taken and revealed a cyst wall lined with epidermal squamous epithelium along with areas of focal ulceration suggesting chronic inflammatory changes of the wall of the epidermoid cyst. There are characteristic and even pathognomonic imaging features of epidermoid cysts at the floor of the mouth in ultrasound and CT scan. Imaging has an important role in the surgical management plan according to the size and location of the cyst in relation to geniohyoid and mylohyoid muscles.

Primary transitional cell carcinoma of the fallopian tube.

The fallopian tube is the least common site for origin of malignancy in the female genital tract. Most primary fallopian tube malignancies are adenocarcinomas. Primary transitional cell carcinoma (TCC) of the fallopian tube is an extremely rare tumor with a small number of cases reported in the literature. We present a 67-year-old woman who was found incidentally to have a left adnexal mass on a screening pelvic ultrasound. Subsequently the patient underwent laparoscopic left salpingo-oophorectomy and the specimen was submitted for intraoperative frozen section, which revealed a high-grade carcinoma; therefore, she underwent a laparotomy and total abdominal hysterectomy, right salpingo-oophorectomy and omentectomy. Histopathology revealed high-grade transitional cell carcinoma in the left fallopian tube. Post-surgery she was treated with four cycles of adjuvant chemotherapy with carboplatin and paclitaxel with no complications. Our patient had a family history of malignancy, so genetic testing for BRCA1 and BRCA2 mutations was undertaken and did not reveal any mutation or unclassified variants. Multiplex ligation-dependent probe amplification (MLPA) was normal.

A study of Helicobacter pylori-associated gastritis patterns in Iraq and their association with strain virulence.

BACKGROUND/AIM: Helicobacter pylori (H. pylori) infection causes peptic ulceration and gastric adenocarcinoma. In Iraq, gastric cancer is rare. We investigated whether infected adults had the antral-predominant pattern of H. pylori-associated gastritis, which does not predispose to cancer. MATERIALS AND METHODS: We evaluated histopathological changes by the Sydney scoring system in gastric biopsies taken from 30 H. pylori-infected adults and studied the correlation of these changes with the virulence factors. The Mann-Whitney test was used for the comparison of histopathological data. The presence or absence of each pathological index was evaluated with respect to the possession of virulence factors by the infecting H. pylori strain using the chi(2) test. RESULTS: Gastric lymphocyte infiltration was more prominent in the antrum (P = 0.01). Neutrophil infiltration was mild and gastric mucosal atrophy was rare. No relationship was found between virulence factors and histopathological changes. CONCLUSIONS: The mild pathology and antral-predominant gastritis help explain the low cancer rate in Iraq.