Paul Biddinger

Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1.

Lung cancer is still the leading cause of cancer-related deaths worldwide. Identifying new oncogenic drivers and developing efficient inhibitors through molecular targeting approaches are crucial for improving therapies. The aim of this study was to investigate whether targeting fibroblast growth factor receptor 1 (FGFR1) with ponatinib inhibits the cell growth in both established and primary lung cancer cells overexpressing FGFR1. Eighty-eight non-small cell lung cancer (NSCLC) and paired normal tissue specimens were analyzed by real-time RT-PCR for FGFR1 gene expression. We identified four cell lines and two newly established primary lung cancer cultures that showed high FGFR1 expression levels, and evaluated the effect of the novel FGFR1 inhibitor ponatinib on cell growth. Approximately 50% (30 out of 59) NSCLC specimens expressed FGFR1>2-fold compared with their adjacent normal counterparts using quantitative RT-PCR. Ponatinib treatment of established NSCLC cell lines expressing higher levels of FGFR1 resulted in marked cell growth inhibition and suppression of clonogenicity. This growth inhibition was associated with inactivation of FGFR1 and its downstream targets. FGFR1 knockdown by shRNA achieved similar results when compared to treatment with ponatinib. Furthermore, ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1.

Neutral sphingomyelinase 2 deficiency is associated with lung anomalies similar to emphysema

Neutral sphingomyelinase 2 (nSMase2) upregulation was recently demonstrated to serve as a molecular link between smoke inhalation and emphysematous changes in lungs. Here we report that nSMase2 deficit impairs lung development in mice. We have shown previously that fragilitas ossium (fro) mice carry a mutation in the Smpd3 gene, rendering nSMase2 catalytically inactive. Analysis of lung phenotype revealed that fro mice have abnormally enlarged alveoli and increased compliance of the respiratory system, similar to morphological and functional manifestations of emphysema. Analysis of sphingolipid content in fro lungs revealed a decreased level of C14:0 ceramide but no significant alterations in the levels of sphingosine or sphingosine-1-phosphate. Altogether, our data suggest that nSMase2 activity and ceramide level are critical for lung development and function. Based on our data, ceramide can no longer be viewed as a lipid solely detrimental to lung function.

IgG4-related leptomeningitis: A reversible cause of rapidly progressive cognitive decline

Immunoglobulin G4–related diseases (IgG4-RD) are a newly recognized category of diseases. CNS involvement in IgG4-RD includes hypophysitis1 and intracranial or spinal manifestations of hypertrophic pachymeningitis.2,3 We present a unique case of rapid cognitive decline due to IgG4-related leptomeningitis.

Molecularly confirmed primary malignant rhabdoid tumor of the urinary bladder: implications of accurate diagnosis

Malignant rhabdoid tumors (MRTs) are well recognized in the kidney and extrarenal sites such as soft tissues, retroperitoneum, and bladder but are classified as atypical teratoid/rhabdoid tumors in the central nervous system. The unifying features of both extracranial MRT and atypical teratoid/rhabdoid tumors are the exon deletions/mutations of the SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) gene in 22q11.23 and resulting loss of SMARCB1/INI1 (integrase interactor 1) protein expression by immunohistochemistry. We herein report a case of extrarenal rhabdoid tumor confined to the bladder in a 3-year-old child, diagnosed by histopathology and confirmed by immunohistochemical and molecular studies. This is only the fourth molecularly proven primary MRT of the bladder to be reported. The patients peripheral blood was negative for the deletions observed in the tumor, thereby confirming a sporadic origin for the tumor. Given the possible dismal outcome, urgency for definitive diagnosis to institute intensive multimodality therapy, histopathologic differential diagnosis with rhabdomyosarcoma and urothelial carcinoma with rhabdoid features, and lack of consensus management guidelines, oncologists, urologists, and pathologists must be aware of this entity. Evaluation for a germ line SMARCB1 alteration may greatly aid risk stratification and family planning.

A case of clear cell sarcoma of the kidney.

Clear cell renal sarcoma is a rare tumor and comprises 4% of primary pediatric malignant renal tumors. It is known as an aggressive tumor with poor prognosis. Clinically and radiographically, it resembles Wilms tumor. We present a case of a child with an abdominal mass that was diagnosed as clear cell sarcoma of her right kidney.

Giant, Metachronous Bilateral Dorsalis Pedis Artery True Aneurysms

This report is the first to describe the clinical, radiographic, operative, and pathologic findings associated with large, bilateral dorsalis pedis artery true aneurysms in a single patient. A 61-year-old African American woman complained of difficulty in wearing shoes. She had a moderately firm, nontender, pulsatile mass on the dorsum of her right foot. Computed tomography and angiography confirmed dorsalis pedis artery aneurysm with sufficient collateralization. She underwent resection without reconstruction. Pathologic analysis revealed a true aneurysm (8 × 5.3 × 4.1 cm(3)) containing intralumenal thrombus. Treatment for small symptomatic and large dorsalis pedis artery aneurysms remains resection with or without reconstruction.

IgG4-Related Disease Presenting as a Solitary Neck Mass

IgG4-related disease is a newly recognized entity associated with autoimmune conditions involving almost every organ system. It is characterized by elevated serum IgG4 as well as mass like tissue infiltration by IgG4-positive plasma cells. Imaging findings are nonspecific, vary depending on the site of disease, and include mass like enlargement of the salivary or lacrimal glands and enlarged lymph nodes. Radiographic findings often mimic malignancy, necessitating tissue sampling to confirm the diagnosis. Distinguishing IgG4-related disease from malignancy is important as IgG4 responds well to steroids and conservative management.

A soft-tissue coupling for wound closure

Wounds often cannot be successfully closed by conventional means of closure such as sutures or staples. Our group developed the FiberSecure™ device to close soft tissue wounds reliably, surpassing native tissue strength. We closed cross-fiber muscle incisions, to evaluate (1) four different configurations of FiberSecure™ for 30 days, then (2) the resulting preferred configuration for 180 days. The four treatment groups each placed 21,504 polyester (PET) 12-μm fibers (cross-sectional area 1% of muscle) traversing the incision, in the form of (A) Four large (No.7 suture) non-textured bundles, (B) Eight small (No.2 suture) non-textured, (C) Four large textured, or (D) Eight small textured. Four incisions were closed in the external oblique muscle of 16 Sinclair minipigs. At 30 days, specimens were removed for biomechanics, histology, and total collagen content. Group (B) was selected for 180-day evaluations in the same wound model in eight animals, four closures each (n = 32), again with biomechanics and histology. In strength testing, every specimen tore through muscle remotely, while the repair region remained intact. Maximum forces were (A) 37.8 ± 3.9 N, (B) 37.1 ± 4.7 N, (C) 39.0 ± 5.3 N, and (D) 32.4 ± 3.4 N at 30 days, and 37.2 ± 11.3 N at 180 days (mean ± SEM). No significant difference was observed among the groups or time points (p > 0.05).

Clear Cell Adenocarcinoma of the Prostate: A Rare Oncologic Entity in a 42-Year-Old African American Man

42-year-old African American man presented with a 6-month history of gross hematuria, marked abdominal pain, and urinary retention. His symptoms began 3 years earlier, when he experienced gross hematuria; work-up and treatment at an outside institution at that time included a computed tomography (CT) scan demonstrating a congenital solitary left kidney and a possible prostatic abscess. The patient underwent a transurethral resection of the prostate (TURP), but was subsequently lost to follow-up. His medical history included obesity and his only surgical procedure was the prior TURP. He had no family history of genitourinary malignancy; however, his uncle had end-stage renal disease, his mother had endometrial cancer, and his grandmother had breast cancer. He had a 10-pack-year history of smoking, and he had no history of international travel or occupational chemical exposure. On presentation to our institution, his vital signs were normal except for tachycardia (115 beats per minute), and his body mass index was 33.5 kg/m 2 . Physical examination revealed an abdomen that was distended and tender to palpation with guarding but no rebound. Additionally, there was a palpable mass in the suprapubic region. His genitourinary examination included a normal circumcised phallus and bilateral descended testis without masses. A digital rectal examination demonstrated normal rectal tone, and a firm, enlarged, mobile mass with mobile pelvic organs. Laboratory studies, including a comprehensive metabolic panel, complete blood count, and prostate-specific antigen level (0.18 ng/mL), were within normal limits; however, his c-reactive protein level (6.35 mg/dL) was elevated. Urinalysis revealed moderate blood and urine culture was negative.

Suppression of respiratory papillomatosis with malignant transformation by erlotinib in a kidney transplant recipient

A 52-year-old non-smoker and renal transplant recipient developed an incessant cough. A CT scan of the thorax revealed ill-defined hazy opacities in the right upper lung. He was diagnosed with non-tuberculosis Mycobacterium chelonae/abscessus infection based on sputum culture results. A trial of antibiotics initially resulted in some clinical improvement. A subsequent CT of the thorax documented worsening of the lesions in the right lung and new lesions on the left. An intratracheal growth was noted. Bronchoscopy with biopsy of the tracheal lesions documented respiratory papillomatosis with transformation to squamous cell cancer. Test for high-risk human papilloma virus was positive. Video-assisted thoracoscopic surgery biopsy with wedge resection of the left lower lobe revealed metastatic squamous cell lung cancer. He was treated with one ablation followed by four cycles of chemotherapy. He has been maintained on erlotinib ever since. There has been no recurrence of the cough or papillomas.