Metastatic Breast Adenocarcinoma Research Articles

Phenanthroline and phenyl carboxylate mixed ligand copper complexes in developing drugs to treat cancer

The success of a classic inorganic coordination compound, Cisplatin, cis-[Pt(NH3)2Cl2], as the first anticancer metallodrug started a field of research dedicated to discovering coordination compounds with antitumor activity, encompassing various metals. Among these, copper complexes have emerged as interesting candidates to develop drugs to treat cancer. In this work, mixed ligand complexes of Cu(II) with diimines (phenanthroline or 4-methylphenanthroline) and 3-(4-hydroxyphenyl)propanoate, phenylcarboxylate or phenylacetate were synthesized. They were characterized in the solid state, including a new crystal structure of [Cu2(3-(4-hydroxyphenyl)propanoate)3(phenanthroline)2]Cl·H2O. The obtained complexes presented a variety of stoichiometries. In solution, complexes were partially dissociated in the corresponding Cu-diimine complex. The complexes bound to the DNA by partial intercalation and groove binding, as assessed by Circular Dichroism, relative viscosity change and UV–Vis titration. The cytotoxicity of the complexes was determined in vitro on MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (breast nontumoral), A549 (human lung epithelial carcinoma), and MRC-5 (human nontumoral lung epithelial cells), finding an activity higher than that of Cisplatin, although with less selectivity.

Characterization of PIK3CA mutation testing in metastatic breast adenocarcinomas: a multi-site, single institution study

Abstract Introduction Detection of somatic mutations in advanced breast cancer may inform prognosis and therapy for patients. In ER+ breast cancer, nearly 40% of tumors have activating mutations in PI3 kinase (PIK3CA) for which targeted PI3 kinase inhibitors are available. At our institution, reflex ordered testing of PIK3CA in ER-positive, HER2-negative advanced breast cancers was implemented in 2017 to standardize the molecular biomarker testing in these tumors. Methods We analyzed 219 cases of advanced breast carcinoma diagnosed from 1/1/2017 to 12/31/2022 across the Houston Methodist system. With IRB approval, records were collated through full-text searching of interpretation, comment, and tumor synoptic fields in the anatomic pathology (AP) reports for “breast” and keywords for molecular oncologic testing, including “PIK3CA” and “MOLECULAR DIAGNOSTICS”, and then manually reviewed to exclude indeterminate/undifferentiated carcinomas and carcinomas of non-breast sites. Only molecular tests performed within this timeframe were considered. PIK3CA testing, both single-gene and targeted panels, was performed in 179 cases. Turnaround time (TAT) statistics, defined as days from AP report signout to molecular signout, were available for 102 cases. Cases with TATs greater than 60 days and referral laboratory testing were excluded. Data extraction, transformation, and loading was performed in Microsoft SQL Server (SSMS 18.0) and VS Code (Python 3.6). Analysis was performed using R-4.2.1 and Microsoft Excel. Results PIK3CA mutation testing was performed in 179 of 219 (82%) cases of all specimen types. The most common reasons for lack of reflex ordered molecular testing included insufficient tissue quantity and specimen decalcification. At least one PIK3CA genomic alteration was detected in 57 of 179 (32%) of cases. The most common alterations included p.H1047R (23/179, 13%), p.E545K (18/179, 10%), and p.E542K (8/179, 4%). One case had PIK3CA amplification, and one case had co-mutations of PIK3CA (p.G106V, p.H1047R). 217/219 (99%) of patients were female; no PIK3CA alterations were identified in the 2 male patients. PIK3CA frequency was not associated with age (mean age 65.4 for PIK3CA alteration detected and 63.8 for not detected, p=0.41). Mean TAT was 16.4 days (n=102), and 56% (57/102) of cases were resulted within 2 weeks of AP reporting. 22% (40/179) of cases had PIK3CA performed at a referral laboratory, largely occurring during the COVID-19 pandemic. Conclusion A reflex ordered strategy for PIK3CA mutations in advanced breast cancers led to the prompt availability of appropriate molecular results for most patients. PIK3CA alterations were present in 32% of cases, with the most common mutations being p.H1047R, p.E545K, and p.E542K. No significant differences in PIK3CA alterations by patient age was observed. Some cases had extended TATs for molecular results, which may be due to ordering practices, the specific PIK3CA testing procedure, and test send-out. Further studies will investigate the association of PIK3CA mutations and clinical staging.

Synthesis, Characterization, DNA Binding and Cytotoxicity of Copper(II) Phenylcarboxylate Complexes

Coordination compounds of copper exhibit cytotoxic activity and are suitable for the search for novel drug candidates for cancer treatment. In this work, we synthesized three copper(II) carboxylate complexes, [Cu2(3-(4-hydroxyphenyl)propanoate)4(H2O)2]·2H2O (C1), [Cu2(phenylpropanoate)4(H2O)2] (C2) and [Cu2(phenylacetate)4] (C3), and characterized them by elemental analysis and spectroscopic methods. Single-crystal X-ray diffraction of C1 showed the dinuclear paddle-wheel arrangement typical of Cu–carboxylate complexes in the crystal structure. In an aqueous solution, the complexes remain as dimeric units, as studied by UV-visible spectroscopy. The lipophilicity (partition coefficient) and the DNA binding (UV visible and viscosity) studies evidence that the complexes bind the DNA with low Kb constants. In vitro cytotoxicity studies on human cancer cell lines of metastatic breast adenocarcinoma (MDA-MB-231, MCF-7), lung epithelial carcinoma (A549) and cisplatin-resistant ovarian carcinoma (A2780cis), as well as a nontumoral lung cell line (MRC-5), indicate that the complexes are cytotoxic in cisplatin-resistant cells.

Supraclavicular lymph nodes: An easily accessible site for diagnosis and molecular profiling of malignancies in the era of precision medicine.

The supraclavicular lymph node (SCN) is a common metastatic site for malignancies of supra and infra-diaphragmatic origin and is easily accessible for small biopsy and fine needle aspiration (FNA). In this study, the utility of SCN biopsies was analyzed for diagnosis and ancillary studies. The electronic pathology archive was searched for cases of FNA of SCNs accompanied by small core biopsies (1/2016-12/2018). The patients' demographics, diagnosis, and ancillary studies were recorded. Eighty-eight cases were reviewed (49 females and 39 males), with patients' ages ranging from 23 to 84 years (mean = 52.85 years). Fifty-four (61.4%) specimens were from the left SCN and thirty-four (38.6%) from the right. All FNA cases were performed by a radiologist under ultrasound guidance and rapid on-site evaltion (ROSE) was performed by a cytologist. Nineteen cases (21.6%) were benign and sixty-nine cases were malignant (78.4%). Carcinoma was the most common malignant neoplasm (52.3%) including 38.2% (13/34) of the right SCN and 61.1% (33/54) of the left SCN cases. Metastatic lung and breast adenocarcinomas (9.1% each) were the most common carcinomas overall. Lymphoma was the second most common malignancy (17.0%) including 17.6% (6/34) of the right SCN and 16.7% (9/54) of the left SCN cases. The majority of cases were accomponied by ancillary studies for diagnosis and prognostic markers. Ancillary studies included immunostains (63 cases, 71.6%), PD-L1 testing (21 cases, 23.9%), FISH testing (7 cases, 8.0%), flow cytometry (20 cases, 22.7%) and NGS studies (8 cases, 9.1%). Supraclavicular lymph nodes are easily accessible and diagnostically useful sites for detection of malignancies and molecular alterations responsive to targeted or immune therapy.

EUS-guided choledochoduodenostomy using a lumen-apposing metal stent in a patient with preexisting duodenal stent and ascites.

Video 1EUS-guided choledochoduodenostomy using a lumen-apposing metal stent in a patient with preexisting duodenal stent and ascites.

Metastatic triple negative breast adenocarcinoma presenting as a fungating chest wall mass

A 60-year-old female with no previous medical history presented with progressive left sided weakness. Examination demonstrated a large, fungating chest wall mass with mucopurulent drainage and necrotic odor. The patient stated this lesion was worsening for multiple years and was associated with a 90-pound weight loss; however, she was hesitant to seek medical care until the onset of weakness. Comprehensive imaging, biopsy, and tissue analysis revealed the wound was consistent with fungating triple-negative breast adenocarcinoma with lung and frontal lobe metastasis (Figure 1).

Tetramethyl-phenanthroline copper complexes in the development of drugs to treat cancer: synthesis, characterization and cytotoxicity studies of a series of copper(II)-L-dipeptide-3,4,7,8-tetramethyl-phenanthroline complexes.

New compounds to fight cancer are needed due to cancer high incidence and lack of curative treatments for several classes of this disease. Metal-based coordination compounds offer a variety of molecules that can turn into drugs. Among them, coordination copper complexes are emerging as an attractive class of compounds for cancer treatment. A series of [Cu(L-dipeptide)(tmp)] (tmp = 3,4,7,8-tetramethyl-1,10-phenanthroline) complexes were synthesized and characterized in the solid state, including the determination of the crystalline structure of [Cu(Gly-Gly)(tmp)]·3.5 H2O and [Cu2Cl4(tmp)2]. The complexes were studied in solution, where the major species are also ternary ones. The lipophilicity of the complexes was determined and the binding to the DNA was evaluated, suggesting that it occurs in the DNA's major groove. The cytotoxicity of the complexes was evaluated on different cancer cell lines: human metastatic breast adenocarcinoma MDA-MB-231 (triple negative, ATCC: HTB-26), MCF-7 (ATCC: HTB-22),SK-BR-3 (ATCC: HTB-30),human lung epithelial carcinomaA549(ATCC: CCL-185),cisplatin resistant-human ovarian carcinomaA2780cis (SIGMA)and nontumoral cell lines: MRC-5 (lung; ATCC: CCL-171) and MCF-10A (breast, ATCC: CRL-10317). [Cu(L-dipeptide)(tmp)] complexes are highly cytotoxic as compared to [Cu(L-dipeptide)(phenanthroline)] and cisplatin. Therefore, [Cu(L-dipeptide)(tmp)] complexes are promising candidates to have their in vivo activity further studied toward new treatments for triple negative breast cancer and other aggressive tumors for which there is no curative pharmacological treatment to the date.

Antitumor Activity of Tubulin-Binding Agent MPC-6827 on Different Types of Cancer Cell Lines.

In this study, the antitumor effects of tubulin-binding agent MPC-6827 on HeLa, MCF-7 and A549 cell lines originated from cervix carcinoma, metastatic breast adenocarcinoma and adenocarcinomic human alveolar basal epithelial cells respectively were determined. Cell index, BrdU labelling index, mitotic index and apoptotic index were evaluated in experiments. In cell index experiment 2 nM, 4 nM, 6 nM, 8 nM, 10 nM MPC-6827 applied to three cell lines. These parameters showed that 4 nM was the optimum concentration for HeLa and A549 cells, while 2 nM was the optimum concentration for MCF-7 cells. The use of optimum concentrations for each cell line has shown that while there was a significant decrease in mitotic index, BrdU labelling index, there was a significant increase in apoptotic index.

Abstract P2-13-34: A phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer

Abstract Background: Targeted agents against HER2 have been a cornerstone of the treatment armamentarium for HER2 positive breast cancer since the approval of trastuzumab by the FDA in 1998 for metastatic HER2 positive breast cancer. However, many patients will develop resistance to HER2 targeted therapies and succumb to their disease. Novel therapeutic combinations are needed to overcome resistance to currently available therapies and improve patient outcomes. Activation of the mTOR pathway via pTEN loss or PI3K mutation has been identified in vitro as a mechanism of trastuzumab resistance, and preclinical studies have shown that mTOR inhibition enhances the efficacy of trastuzumab by reversing trastuzumab resistance mediated by PTEN loss. Moreover, two phase I trials evaluating the addition of the mTOR inhibitor everolimus to trastuzumab and chemotherapy reversed trastuzumab resistance in patients with heavily pretreated metastatic HER2 positive breast cancer, providing rationale for continued exploration of this combination in phase II trials.Methods: We report the results of a single arm, open-label phase II pilot study for patients with histologically or cytologically confirmed HER2 positive locally advanced or metastatic breast adenocarcinoma that had progressed on at least one prior HER2 targeted therapy. Enrolled patients received everolimus 5 mg PO daily and lapatinib 1000 mg PO daily until disease progression or unacceptable toxicity. Radiographic tumor assessment was performed at trial entry and every 8 weeks thereafter. Primary endpoint was 6-month overall response rate (ORR). Secondary endpoints included 6-month progression free survival (PFS), 6-month clinical benefit rate (CBR), and safety and tolerability of the combination. NCI CTCAE version 4.0 was used for toxicity and serious event reporting. The primary endpoint of 6-month ORR was computed using the point estimate and the 1-sided 97.5% confidence interval by the exact binomial method and compared to the previously reported 7% response rate of lapatinib monotherapy in this setting.Results: A total of 23 patients were enrolled. The median age at enrollment was 48, and the median number of prior lines of therapy was 4 (range 1-9). 13 patients had previously been treated with lapatinib, and CNS disease on trial entry was present in 7 (30.4%) patients. 6-month ORR was 0% (0-14.8%, 97.5% 1-sided CI) and 6-month CBR was 13% (2.8 - 33.6%, 95% CI). Median progression free survival was 112 days (109-115 days, 95% CI). 6-month PFS rate was 13% (2.8-33.6%, 95% CI). No CNS responses were observed. 17 serious adverse events (SAE) of grade 3 or greater were reported. The most common grade 3 or greater SAEs were dyspnea (4 patients - 17%), pleural effusion (3 patients - 13%), abdominal pain and ileal obstruction (2 patients each - 8.7%).Conclusion: The combination of lapatinib and everolimus was not found to be an active regimen in patients who had previously progressed on at least one line of prior HER2 targeted therapy. We would not recommend further exploration of this combination in phase II or phase III trials in this patient population. Citation Format: Anthony Rooney, Priyanka Sharma, Anne P O'Dea, Lauren Nye, Manana Elia, Jianghua He, Carol Fabian, Qamar Khan. A phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-34.

Clinical Reasoning: A 72-Year-Old Woman With Rapidly Progressive Bilateral Hearing Loss

A 72-year-old woman presented with rapidly progressive hearing loss and neuropsychiatric symptoms without other focal neurologic symptoms. Progressive sequential sensorineural hearing loss (SNHL) was demonstrated on serial audiology. A diagnostic approach to SNHL is reviewed. Lumbar puncture revealed elevated protein, low glucose, and pleocytosis with poorly differentiated cells, and a differential diagnosis is discussed. MRI of the brain revealed gadolinium enhancement within the internal auditory canals bilaterally as well as the left cochlea. Zic4 antibodies were present in serum and CSF. A malignancy workup revealed right axillary lymphadenopathy. Biopsy revealed poorly differentiated breast adenocarcinoma, with identical cells to those in the CSF. The patient was treated with intrathecal methotrexate with no effect on the patient's hearing. In this case, rapidly progressive SNHL was the presenting feature of widely metastatic breast adenocarcinoma with leptomeningeal carcinomatosis, highlighting the need to search for a central cause for this presentation.

Characterisation and Bioactivity Analysis of Peridinin-Chlorophyll a-Protein (PCP) Isolated from Symbiodinium tridacnidorum CS-73

Peridinin-Chlorophyll a-Proteins (PCP) are the major light harvesting proteins in photosynthetic dinoflagellates. PCP shows great variation in protein length, pigment ratio, sequence, and spectroscopic properties. PCP conjugates (PerCP) are widely used as fluorescent probes for cellular and tissue analysis in the biomedical field. PCP consists of a peridinin carotenoid; thereby, it can potentially be used as a bioactive compound in pharmaceutical applications. However, the biological activities of PCP are yet to be explored. In this study, we extracted, purified, and partially characterised the PCP from Symbiodinium tridacnidorum (CS-73) and explored its antioxidant, anti-cancer and anti-inflammation bioactivities. The PCP was purified using an ÄKTA™ PURE system and predicted to be of 17.3 kDa molecular weight (confirmed as a single band on SDS-PAGE) with an isoelectric point (pI) 5.6. LC-MS/MS and bioinformatic analysis of purified PCP digested with trypsin indicated it was 164 amino acids long with >90% sequence similarity to PCP of SymA3.s6014_g3 (belonging to clade A of Symbiodinium sp.) confirmed with 59 peptide combinations matched across its protein sequence. The spectroscopic properties of purified PCP showed a slight shift in absorption and emission spectra to previously documented analysis in Symbiodinium species possibly due to variation in amino acid sequences that interact with chl a and peridinin. Purified PCP consisted of a 19-amino-acid-long signal peptide at its N terminal and nine helixes in its secondary structure, with several protein binding sites and no DNA/RNA binding site. Furthermore, purified PCP exhibited antioxidant and in vitro anti-inflammation bioactivities, and anti-cancer activities against human metastatic breast adenocarcinoma (MDA-MB-231) and human colorectal (HTC-15) cancer cell lines. Together, all these findings present PCP as a promising candidate for continued investigations for pharmaceutical applications to cure chronic diseases, apart from its existing application as a fluorescent-probe.

Abstract 1311: PET-MRI microdosing can determine the delivery of the experimental cancer therapeutic, MN-anti-miR10b, to metastatic lesions in a murine model of breast cancer

Abstract Conventional therapies, which are effective against primary cancer, oftentimes are not successful at treating metastatic cancer. In our earlier work, we identified miRNA-10b as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR-10b inhibitor, termed MN-anti-miR10b, capable of delivery to metastatic sites via intravenous injection. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b, when combined with a low-dose cytostatic, caused lifelong complete regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases. Towards that goal, we developed a method to radiolabel MN-anti-miR10b with Cu-64, inject a microdose of the radiolabeled MN-anti-miR10b into murine models of metastatic breast cancer, and determine the uptake of the therapeutic by the metastatic lesions using positron emission tomography-magnetic resonance imaging (PET-MRI). Specifically, we injected a microdose of 64Cu-MN-anti-miR10b into mice bearing luciferase-expressing metastatic breast adenocarcinoma and performed in vivo bioluminescence (BLI) and PET-MRI to assess uptake by the metastatic lesions. The lesions were identified by BLI, based on their luciferase expression. PET-MRI clearly demonstrated uptake of 64Cu-MN-anti-miR10b, measurable at a microdose. Ex vivo PET-MRI confirmed that the activity was associated with the metastatic lesions, as identified at necropsy. Uptake by metastatic organs was also demonstrated by scintigraphy and shown to be significantly higher than in the same organs devoid of BLI-detectable metastatic lesions. Finally, 64Cu-MN-anti-miR10b injected as a non-carrier added microdose had comparable biodistribution to that injected at a standard therapeutic dose. The value of the current study is in setting the stage for clinical PET-MRI microdosing, which would be able to answer a key question on the path to drug development without the associated cost to do a full clinical trial – the question of delivery to the target organ sites. Since the PET technique is sensitive enough to determine the concentration of radiolabeled drug with sensitivity approaching the sub-picomolar range, as little as a microgram of the radiolabeled drug is sufficient to perform a PET-MRI study in humans. In addition to proving delivery, the microdosing studies will reveal the pharmacokinetic behavior of MN-anti-miR10b which will allow one to establish dosing during therapy. Finally, in clinical trials, one can use microdosing PET-MRI to select patients for treatment, based on which patients' metastases accumulate the therapeutic. Citation Format: Marianne Le Fur, Byunghee Yoo, Nicholas Rotile, Pamela Pantazopoulos, Alana Ross, Iris Zhou, Peter Caravan, Zdravka Medarova. PET-MRI microdosing can determine the delivery of the experimental cancer therapeutic, MN-anti-miR10b, to metastatic lesions in a murine model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1311.

Disruption of the Microtubule Network and Inhibition of VEGFR2 Phosphorylation by Cytotoxic N,O-Coordinated Pt(II) and Ru(II) Complexes of Trimethoxy Aniline-Based Schiff Bases.

Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes (1-5) of three N,O and N,N donor-based trimethoxyanilines containing Schiff bases with the general formula [PtII(L)(DMSO)Cl], [RuII(L)(p-cymene)Cl], [RuII(L)(p-cymene)Cl]+, and [PtII(L)Cl2]. All of the complexes are characterized by different analytical techniques. 1H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the N,O-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to N,N causes the Ru complexes to be more inert to aquation. The N,O-coordinating complexes show superiority over N,N-coordinating complexes by displaying excellent in vitro antiproliferative activity against different aggressive cancer cells, viz., triple-negative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. In vitro cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex 3 is 10-15 times more toxic than the clinical drugs cisplatin and oxaliplatin against MDA-MB-231 cells. Cellular studies show that all of the N,O-coordinated complexes (1-3) initiate disruption of the microtubule network in MDA-MB-231 cells in a dose-dependent manner within 6 h of incubation and finally lead to the arrest of the cell cycle in the G2/M phase and render apoptotic cell death. The disruption of the microtubule network affects the agility of the cytoskeleton rendering inhibition of tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a key step in angiogenesis. Complexes 1 and 2 inhibit VEGFR2 phosphorylation in a dose-dependent fashion. Among the Pt(II) and Ru(II) complexes, the former displays higher cytotoxicity, a stronger effect on the cytoskeleton, better VEGFR2 inhibition, and strong interaction with the model nucleobase 9-ethylguanine (9-EtG).

Mir-193a-5p Replacement Can Alter Metastasis Gene Expression in Breast Adenocarcinoma Cells In Vitro

Background: Recent evidence presented the significant role of the microRNA-193 (miR-193) family in biological processes by the contribution of specific targeting, which mainly display as a tumor suppressor in various cancers. In the present study, we evaluated the effect of miR-193a-5p replacement on some metastasis gene expression in metastatic breast cancer (BC) cells. Methods: For this purpose, firstly, the quantitative real-time polymerase chain reaction (qRTPCR) was used to detect the miR-193a-5p expression in the MDA-MB-231 BC cell line. Subsequently, miR-193a-5p was transfected into the cells, and the expression levels of ROCK1 (Rho‑associated, coiled‑coil containing protein kinase 1), CXCR4 (Chemokine Receptor-4), CD44, and vimentin genes were evaluated by qRT-PCR. Results: The expression level of miR-193a-5p strongly reduced in MDA-MB-231 cells. Interestingly, the ROCK1 (P < 0. 001), CD44 (P < 0.0001), CXCR4 (P < 0. 001) and vimentin (P < 0. 001) expression levels significantly decreased following miR-193a-5p transfection in MDA-MB-231 BC cells. Conclusion: To conclude, it seems that miR-193a-5p restoration can attenuate the metastatic behavior of BC cells in vitro through decreased expression level of metastasis-related genes and may constitute an effective novel therapeutic strategy in miRNA-replacement therapy and treatment of metastatic breast adenocarcinoma in the future.

Alopecia neoplastica: An uncommon presentation of metastatic breast carcinoma

<p>Cutaneous metastasis may correspond to the initial clinical presentation of hidden internal malignancies. In patients presenting said neoplasia, clinical manifestations of breast cancer reaches 23.9%. Considering that neoplastic alopecia appears as an unusual pattern of the said metastasis, this report describes a case of such uncommon neoplastic alopecia which presents itself as a cutaneous metastasis of rapid progression in a patient with prior breast cancer history. We present a 47-year-old female patient reporting lesions at the scalp, and who was asymptomatic with a 1-year evolution. The patient reported prior breast cancer history and presence of lung metastasis, and was undergoing chemotherapy at the time of consultation. A dermatological evaluation showed only a nodular lesion with erythematous surface and a diameter measuring about 4 cm, firm in consistency, and immovable. She was routed to the Department of Dermatological Surgery, and the results from histopathology were consistent with a diagnosis of metastatic breast adenocarcinoma. Neoplastic alopecia appears as an unusual form of cutaneous metastasis which is predominantly described in association with breast cancer. The lesion’s clinical features play a crucial role at the differential diagnosis, as the presence of erythema could distinguish neoplastic alopecia from alopecia areata. The existence of cutaneous metastasis leads to unfavorable outcomes. As a conclusion, cutaneous evaluation of patients is essential for treating visceral metastases, since the forms of cutaneous metastasis are diverse and can also affect the scalp.</p>

Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2 Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

Facial palsy caused by an intrameatal metastatic disease - Reconstruction with an autologous sural nerve graft

Dysfunction of the facial nerve is frequently attributed to inflammation, followed by traumatic injury. Knowledge of the complex anatomical course of the facial nerve is critical to localize the site of pathology and for successful management. The multiplicity of etiologies and its complex anatomy often make facial paralysis a diagnostic challenge. Neoplasms are a fairly rare cause of peripheral facial palsy, and are frequently overlooked in search of the more frequent traumatic or inflammatory etiologies of facial paralysis. Isolated metastatic lesions to the cerebellopontine angle (CPA) and internal auditory canal (IAC) are extremely rare. Their accurate diagnosis is difficult, since they share common clinical and radiological characteristics with vestibular schwannomas. We report a case of a 63-year-old female with a rapidly progressive left-sided hearing loss and complete facial palsy. Magnetic resonance imaging revealed a left intrameatal lesion. A provisional diagnosis of intracanalicular schwannoma or meningioma was made, although the possibility of metastasis due to her rapid neurological deterioration was considered. The patient underwent a translabyrinthine complete removal of the tumor followed by facial nerve reconstruction. The final histopathological findings revealed a metastatic breast adenocarcinoma. To our knowledge only seven prior cases of an isolated metastatic CPA lesion have been reported. In patients without a known malignancy, a rapid progression of hearing loss, disequilibrium, and facial palsy might be the first sign of a metastatic CPA lesion.

Dihydroquinoline derivative as a potential anticancer agent: synthesis, crystal structure, and molecular modeling studies.

Cancer is one of the leading causes of death worldwide and requires intense and growing research investments from the public and private sectors. This is expected to lead to the development of new medicines. A determining factor in this process is the structural understanding of molecules with potential anticancer properties. Since the major compounds used in cancer therapies fail to encompass every spectrum of this disease, there is a clear need to research new molecules for this purpose. As it follows, we have studied the class of quinolinones that seem effective for such therapy. This paper describes the structural elucidation of a novel dihydroquinoline by single-crystal X-ray diffraction and spectroscopy characterization. Topology studies were carried through Hirshfeld surfaces analysis and molecular electrostatic potential map; electronic stability was evaluated from the calculated energy of frontier molecular orbitals. Additionally, in silico studies by molecular docking indicated that this dihydroquinoline could act as an anticancer agent due to their higher binding affinity with human aldehyde dehydrogenase 1A1 (ALDH 1A1). Tests in vitro were performed for VERO (normal human skin keratinocytes), B16F10 (mouse melanoma), and MDA-MB-231 (metastatic breast adenocarcinoma), and the results certified that compound as a potential anticancer agent. A Dihydroquinoline derivative was tested against three cancer cell lines and the results attest that compound as potential anticancer agent.

Nest of Evil

Abstract An 83 year-old patient was referred to the neuro-ophthalmology service with symptoms of headaches and vision loss. She had been diagnosed with stable size meningioma one year prior to presentation. She had a history of breast cancer treated by lumpectomy and radiation 20 years ago. MRI of the orbit showed encasement of the optic nerve on the right orbital apex. Craniotomy was performed and the specimen was diagnosed as a meningioma. After resection, the tumor grew rapidly. When it was resected for the second time, the diagnosis was metastatic breast adenocarcinoma.

Cytotoxicity and reactivity of a redox active 1,4-quinone-pyrazole compound and its Ru(II)-p-cymene complex

Quinone based compounds display activation in hypoxia, an environment prevalent in tumours. We have synthesized a bis(pyrazole) based 1,4-quinone compound suitable for metal chelation. The quinone (L2) converted to hydroquinone (H2L1) during the complex synthesis leading to [RuII(η6-p-cym)(H2L1)Cl](PF6) (1). We found from 1H NMR studies that in the methanolic solution L2 stoichiometrically converted to H2L1 while oxidizing the methanol to formaldehyde. L2 crystallized in monoclinic space group I2/a while complex 1 crystallizes in P21/c. Cyclic voltammetry of the redox non-innocent L2 showed quasi-reversible (ΔEp = 67 mV) redox behaviour with E1/2 at 0.12 V w.r.t. NHE. Complex 1 is stable at pH 7.4 in presence of 4 mM chloride and does not hydrolyse even up to 24 h. L2 showed IC50 values of 155 and 123 µM against metastatic breast adenocarcinoma (MDA-MB-231) and pancreatic carcinoma (MIA PaCa-2) respectively. L2 gets activated by ca. 2.7-fold in hypoxia against MIA PaCa-2 cells. The mechanistic studies showed ROS accumulation and oxidation of NADH to NAD+, which may be responsible for the cytotoxicity. The reactivity studies showed that conversion to hydroquinone by reaction with NADH or glutathione is irreversible. Complex 1 is not cytotoxic up to 100 µM in normoxia or hypoxia. Complex 1 displays irreversible redox behavior in cyclic voltammetry displaying two overlapping oxidation peaks at 1.00 and 1.57 V w.r.t. NHE, which may be assigned to the conversion of hydroquinone to quinone and RuII → RuIII respectively.