Gastrointestinal Stromal Tumors (GIST): A Population-Based Study Using the SEER Database, including Management and Recent Advances in Targeted Therapy.

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal (GI) system. Most GISTs originate from the interstitial cells of Cajal (ICC), the pacemaker cell situated between the circular and longitudinal layers of the muscularis propria along the GI tract. In this population-based study using the SEER database, we sought to identify demographic, clinical, and pathologic factors that affect the prognosis and survival of patients with this neoplasm. Molecular genetic advances, current management guidelines, and advances in targeted therapy are discussed. Methods: Demographic and clinical data from GIST patients were retrieved from the SEER research plus database for the period 2000−2018. Statistical analysis was performed with IBM SPSS® v20.2 software using the Chi-square test, paired t-test, multivariate analysis, and Kaplan−Meier functions. Results: A total of 10,833 patients with GIST were identified. Most patients were between 60−74 years of age: 40%, Caucasian: 68%, and the male to female ratio was 1.1:1. The most common primary tumor sites were stomach: 63%, small intestine: 30%, rectum: 3%, and esophagus: 0.7%. When reported, the grade of differentiation was well: 38%, moderately: 32%, undifferentiated: 19%, poorly: 12%. The size of most tumors ranged between 6−10 cm: 36% and they were treated by surgical intervention: 82% and/or chemotherapy/targeted therapy: 39%. The stage was localized: 66%, advanced: 19%, and regional: 15%. The 5-year survival was 74% (95% confidence interval (95% CI) = 72.6−74.7), and the 5-year cause-specific survival 82% (95% CI = 80.7−82.6). The 5-year cause-specific survival by treatment included surgery at 86% (95% CI = 85.4−87.3), chemotherapy/targeted therapy with or without surgery at 77% (95% CI = 75.7−78.9), and radiation at 75% (95% CI = 74.5−80). On multivariable analysis tumor size > 5 cm, poorly and undifferentiated grade, age > 60, and distant metastases at presentation were associated with worse overall survival. Conclusion: GISTs comprise 1−2% of malignancies of the GI tract, usually affect male Caucasians between the ages of 60 and 74 years, most tumors occur in the stomach and small intestine, and are usually >5 cm, but still localized, at the time of diagnosis. Most tumors receive multimodality surgical and chemotherapy/targeted therapy treatment, with a 5-year overall survival of 74% and cause-specific survival of 82%. GIST patients would benefit from enrollment in large clinical trials to establish better therapy guidelines for unresectable, treatment-refractory, and recurrent tumors.

Prolonged Response of Metastatic Programmed Death-Ligand 1 (PD-L1) Negative Basaloid Squamous Cell Carcinoma of the Lung to Maintenance Immunotherapy.

Basaloid squamous cell carcinoma (BSCC) is a variant of squamous cell carcinoma that is most often seen as a variety of primary head and neck cancers. BSCC of the lung is rare primary lung cancer and an uncommon histological subtype of non-small cell lung carcinoma. Due to its rarity, there is little published information and research available to direct disease-specific management of BSCC of the lung. Most published cases of basaloid carcinoma of the lung report on surgical management of eligible patients and even less information can be found for metastatic cases. We report a case of a 74-year-old male with stage four (IV) BSCC of the lung who experienced a complete metabolic with partial anatomic response to combined chemotherapy and immunotherapy with carboplatin/nab-paclitaxel/pembrolizumab and has continued to be in partial remission on maintenance immunotherapy with pembrolizumab despite PD-L1-negative status.

Primary Neurosarcoidosis Mimicking Gallbladder Pathology.

A 40-year-old African American male with long standing headaches and unintentional weight loss presented with nausea, vomiting, and blurry vision. Laboratory findings include hyponatremia and mildly raised liver enzymes. He underwent cholecystectomy six months prior for unexplained nausea and vomiting, which in hindsight was likely neurologic-induced vomiting from neurosarcoidosis. Brain imaging revealed diffuse, leptomeningeal, nodular enhancement involving the brain, brainstem, and upper cervical spinal cord. Further work up showed extensive lymphadenopathy above and below the diaphragm, solitary liver lesion, and multiple lytic lesions involving bones. Iliac spine biopsy revealed ill-defined, non-caseating granulomas with giant cell reaction infiltrating bone fragments. Acid-fast bacilli and fungal stains were negative. Patient was treated with steroids. Diagnosis of neurosarcoidosis is challenging in the absence of physical signs and symptoms. However, radiological and pathological correlation in clinical suspicion of sarcoidosis is helpful in more accurate diagnosis and timely management of the patient.

Atypical central neurocytoma with sarcomatous differentiation.

We report a case of an intraventricular tumor with features of atypical central neurocytoma with a sarcomatous component in a 44-year-old woman who presented with headaches and vomiting. Magnetic resonance imaging revealed a 3.4-cm lobulated enhancing mass in the occipital horn of the left lateral ventricle, and the patient subsequently underwent a left occipital-parietal craniotomy for debulking. The tumor contained 2 cell populations: round cells with perinuclear halos in a fibrillary background, and spindle cells with oval nuclei arranged in interlacing fascicles with focal necrosis. The round cells had diffuse synaptophysin immunopositivity, while the spindle cells were diffusely immunopositive for vimentin and had intercellular reticulin. The mitotic activity (8 mitotic figures per 10 high-power fields) and the high Ki-67 proliferation index (15.0%) were consistent with atypical central neurocytoma with a sarcomatous component. Although different histologic variants have been described, this is the first reported case, to our knowledge, of central neurocytoma with spindle cell sarcomatous features.

Gynecomastia presenting as a neck mass.

The differential diagnoses of neck mass may include a wide spectrum of lesions ranging from cysts, inflammatory processes, benign and malignant tumors arising from skin, soft tissue, lymph nodes, endocrine glands, salivary glands to metastatic tumors. In adults, malignant non-thyroid neck masses are often metastatic squamous cell carcinoma. Gynecomastia, presenting as a mass or enlargement in its typical subareolar location is usually a straightforward diagnosis. Enlargement due to gynecomastia in locations other than subareola can pose diagnostic challenge. We describe a unique case of gynecomastia presenting as a neck mass in a patient who was diagnosed and treated for squamous cell carcinoma of the floor of the mouth.

Unusual presentation of benign cystic brenner tumor with exuberant psammomatous calcifications.

Transitional cell tumors of the ovary comprise about 1% to 2% of all ovarian neoplasms. Most of these tumors are benign Brenner tumors and account for about 5% of benign surface epithelial-stromal tumors. Spicules of calcifications are found in the stroma of about 50% of benign Brenner tumors. Although diagnostic challenges might occur more frequently with either of the borderline or malignant Brenner tumors, this problem is not that common when diagnosing a benign Brenner tumor. This study reports a case of benign Brenner tumor with exuberant dystrophic calcifications that obscured most of the epithelium and posed a diagnostic challenge in differentiating it from the more common malignant counterparts such as serous carcinoma and specifically psammocarcinoma.

Suppression of cyclic GMP-specific phosphodiesterase 5 promotes apoptosis and inhibits growth in HT29 cells.

Phosphodiesterase 5 (PDE5) is a major isoform of cGMP phosphodiesterase in a variety of human tumor cell lines and plays a key role in regulating intracellular cGMP concentrations ([cGMP]i). Here, we demonstrate that suppression of PDE5 gene expression by antisense pZeoSV2/ASP5 plasmid transfection results in a sustained increase in [cGMP]i, growth inhibition, and apoptosis in human colon tumor HT29 cells. With stable transfection, antisense transcripts exhibited a specific suppression in PDE5 activity, mRNA levels, and a 93 kDa hPDE5A1 protein. In cloned antisense cells, prolongation of the cell growth doubling times correlate positively with suppressed PDE5 activity and increased [cGMP]i. The growth inhibition in PDE5 antisense clones is due to an increased apoptotic rate and delayed cell-cycle progression. These results corroborate previous findings with the PDE5 inhibitor exisulind and its derivatives showing that sustained [cGMP]i induces apoptosis and growth inhibition in tumor cells. Furthermore, an inducible mitotic inhibitor p21WAF1/CIP1 has been found to account for the delay of cell-cycle progression in PDE5 antisense clones at G2/M phase. A proteolytic cleavage of p21WAF1/CIP1 in the antisense clones is also increased at the later stage of serum stimulation. The protein kinase G (PKG) inhibitor, KT5823, can prevent the cleavage of p21(WAF1/CIP). These data substantiate a pivotal role for PDE5 as a modulator of apoptosis and cell-cycle progression for human carcinoma via a mechanism involving the activation of [cGMP]i/PKG signaling pathways.

Activation and induction of cyclic AMP phosphodiesterase (PDE4) in rat pulmonary microvascular endothelial cells.

Regulation of the rolipram-sensitive cAMP-specific phosphodiesterase 4 (PDE4) gene family was studied in rat pulmonary microvascular endothelial cells (RPMVECs). Total PDE4 hydrolysis was increased within 10 min after addition of forskolin (10 microM), reached a maximum at 20-40 min, and then gradually declined in the cells. A similar activation of PDE4 activity was observed using a protein kinase A (PKA) activator, N(6)-monobutyryl cAMP. Both the forskolin and the N(6)-monobutyryl cAMP activated PDE4 activities were blocked by the PKA-specific inhibitor, H89. This forskolin-stimulated and PKA-mediated short-term activation of PDE4 activity was further confirmed by in vitro phosphorylation of 87kDa PDE4A6 and 83kDa PDE4B3 polypeptides using exogenous PKA Calpha. Increased immunoreactivity of phosphorylated PDE4A6 in situ was detected in Western blots by a PDE4A-phospho antibody specific to the putative PKA phosphorylation sites. Following long-term treatment of RPMVECs with rolipram and forskolin medium (RFM) for more than 60 days, PDE4 activity reached ten-fold higher values than control RPMVECS with twenty-fold increases detected in intracellular cAMP content. The RFM cells showed increased immunoreactivities of the constitutive 4A6 and 4B3 isoforms plus two novel splice variants at 101kDa (4B1) and 71kDa (4B2). Treatment with H89 did not inhibit the PDE4 elevation in RFM cells. In addition to the increased levels of PDE4 in RFM cells, immunofluorescence showed a translocation of PDE4A and 4B to a nuclear region, which was normally not observed in RPMVECs. The PDE4 activity in RFM cells decayed rapidly with an even faster decline of intracellular cAMP content when forskolin/rolipram were removed from the medium. These results suggest that both the activation (short-term) and induction (long-term) of PDE4A/4B isoforms in RPMVECs are closely modulated by the intracellular cAMP content via both post-translational and synthetic mechanisms.