The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo

Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [111In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [177Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [177Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [177Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [177Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [177Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [177Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation.

Case Report: Partial Response Following Nivolumab Plus Docetaxel in a Patient With EGFR Exon 20 Deletion/Insertion (p.N771delinsGF) Mutant Lung Adenocarcinoma Transdifferentiated From Squamous Cell Carcinoma

The histological transformation from lung squamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) and p. N771delinsGF mutations in EGFR exon 20 (ex20) are exceedingly rare in non–small cell lung carcinoma (NSCLC). EGFR ex20 mutations are insensitive to EGFR tyrosine kinase inhibitors in NSCLC. Here, we present a 76-year-old male smoker harboring LUAD with a novel p. N771delinsGF deletion/insertion mutation in EGFR ex20 transdifferentiating from advanced LUSC after chemoradiotherapy. The patient presented reduced hydrothorax and relieved tightness with the treatment of nivolumab plus docetaxel and carboplatin after the failure of second-line chemotherapy. The case highlights the importance of rebiopsy and molecular retesting after the progression of lung cancer and supports the idea that the combination of immune checkpoint blockade and chemotherapy may be an attractive option for patients with EGFR ex20 mutations associated with LUSC–LUAD transformation.

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. In the current study, we show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracts FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induces robust MYC(N) degradation and inhibits tumor cell growth in MYC(N) driven neuroblastoma and small cell lung carcinoma. Here, we demonstrate the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.

Evaluation of P40 and Napsin A in the Differential Diagnosis of Non Small Cell Bronchogenic Carcinoma on Small Lung Biopsies

BACKGROUND :- Lung cancer is the leading cause of cancer-related mortality over word wide, Although the pathological diagnosis of lung carcinoma is limited as only small specimen available for diagnosis.the availability of targeted therapies has created a need for precise subtyping of non-small cell lung carcinoma . Several recent studies have demonstrated that the use of Immunohistochemical markers can be helpful in differentiating lung squamous cell carcinoma (LSCC) from lung adenocarcinoma (LAC) not on surgically resected material but also on small biopsy samples and cytology. AIM (1) To classify the non small cell lung carcinoma into major categories like squamous cell carcinoma (LSCC) and adenocarcinoma (LAC) and other categories by applying immunohistochemicalmarker like p40 (truncated p63) and Napsin A (2) To analyse the sensitivity and specificity of p40 and Napsin A in light of histomorphology and/or other relevant immunohistochemical markers available, using appropriate statistical tests. Material and methods:- This study was a one and half year (18 months) prospective study from Jan 2017 to June 2018, conducted in department of pathology on patients attending the outpatient and inpatient department of TB and respiratory disease, a total of 210 bronchoscopic guided biopsies / transthoracic (CT/MRI /guided) small tissue biopsies from the patients suspected of lung malignancy were incorporated in the study. 20 corresponding resection specimens (wedge resection and lobectomy) were also included in the study for correlation of morphology and immunohistochemical findings on small biopsies. RESULTS:-In our study IHC for both p40 and napsin –A aided in subtyping of 71.9% cases of non small cell lung carcinoma and this diagnostic accuracy was found to be statistically significant with p-value < 0.05.,on statistical analysis we found that napsin-A had a sensitivity of 90% and specificity of 80%. Also, positive predictive value and negative predictive value were seen to be 88.0% and 81.8% respectively.

Usefulness of Liquid Biopsy for Intraocular Malignancies

Retinoblastoma (RB) is the most common primary intraocular malignancy in children, whereas Uveal melanoma (UM) is the most common intraocular malignancy in adults [1,2]. Tissue biopsy is the standard gold technique for diagnosing the malignant neoplasm but an incisional tissue biopsy or fine needle aspiration biopsy (FNAB) is contraindicated for the intraocular malignancy [3]. Clinical diagnosis and imaging study are the only way to diagnose the intraocular malignancy due to the risk and fear of extraocular spread [4]. Recently, liquid biopsy has gained in popularity in the ophthalmic field. Liquid biopsy allows retinoblastoma diagnosis and a better understanding of the metastatic spread of uveal melanoma. Recently, the USA Food and Drug Administration (FDA) approved the make use of liquid biopsy (LB) as an appropriate diagnosis, prognosis, and also for monitoring tool in non-small cell lung carcinoma to keep away from invasive tissue biopsy in designated cases [5-7]. Liquid biopsy (LB) utilizes biofluid to evaluate for tumor-derived cells or cell-free DNA. LB is a relatively non-invasive technique rather than a tissue biopsy. In LB, material collected from multiple body fluids such as aqueous humor (AH), blood, cerebrospinal fluid, urine, and saliva for molecular diagnosis [8] and detecting of cancer biomarkers such as circulating tumor cells (CTC), tumor derived cell free DNA (ct-DNA), circulating tumor RNA (ct-RNA), microRNA (miRNA), tumorrelated exosomes (TREs), and extracellular vescicles (EVs) [7]. Aqueous humor samples for RB (Ocular LB) and Venous blood samples for UM (systemic LB) are utilizing for analyzing the molecular characteristics [8]. In others ophthalmic malignancies like conjunctival melanoma or squamous cell carcinoma, the role of LB is still not studied because tissue biopsy is routinely done for confirming the diagnosis and also for mutational status [9-11].

PD-1/PD-L1-negative tracheal mucoepidermoid carcinoma: A case report and systematic review of the literature

Background: Tracheal mucoepidermoid carcinoma is a rare form of non-small cell lung carcinoma and is defined as a tumor characterized by a combination of squamous, mucus-secreting, and intermediate cell types. This carcinoma is usually located in the lobar or segmental bronchus. Currently, surgery is the preferred treatment for this disease, which includes pneumonectomy, lobectomy, and sleeve lobectomy. Case presentation: A 50-year-old Chinese male presented with cough, shortness of breath and hemoptysis, and the effect of antibiotic therapy was not good. Subsequently, the airway occupied lesion was found by chest CT, and he was transferred to our hospital for surgical resection. Histologically, the tumor contained squamous epidermal cells, mucoepidermoid cells and intermediate cells. Immunohistochemistrically, the tumor cells were positive for p63, CK5/6, CK7 and Ki67. However, the tumor is generally negative for TTF-1 and neuroendocrine markers. The patient had no recurrence 15 months after the surgery. Conclusions: We report a rare case of mucoepidermoid carcinoma in the distal trachea in which the surgery was difficult and could not be performed like a traditional pulmonary resection. We first provide a comprehensive description of airway management and anesthesia intubation. After surgery, we reviewed the literature and found that PD-1/PD-L1 detection had never been reported in tracheal mucoepidermoid carcinoma. Therefore, we studied the PD-1/PD-L1 pathway in this patient, and the results were negative, which may indicate that potential adjuvant therapy with immune checkpoint inhibitors (ICIs) is not useful in this case.