Therapy-Related Acute Promyelocytic Leukemia: A Case Report and a Review of Literature.

Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML), and while not a common form of cancer, it does make up a modest portion of acute leukemia. The genetic hallmark of APL is the t(15;17)(q24.1;q21.2) promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) protein. We present the case of a patient who had undergone prior therapy for stage IIIC squamous cell carcinoma of the anorectal region with 5-fluorouracil, mitomycin C, and radiation and developed therapy-related acute promyelocytic leukemia about 18 months later. We also review the clinical features and management of APL while also highlighting that therapy-related APL, although uncommon, can develop from chemoradiation. The specific diagnosis of therapy-related APL is its own distinct diagnosis, but its treatment remains the same as primary APL.

An Etiological Investigation of Paraneoplastic Cerebellar Degeneration in Ovarian Cancer Patients: A Systematic Review.

Paraneoplastic syndromes (PNS) are uncommon, distinct clinical complications of a primary tumor. Paraneoplastic cerebellar degeneration (PCD) is a PNS that is described as an autoimmune response targeting Purkinje cells in the cerebellum. Ovarian cancer (OC) is one of the most prevalent causes of cancer-related deaths in women. Anti-Yo is the most common onconeural antibody produced in the PCD immune response and is most typically found in ovarian and breast cancer patients. While the current literature highlights the predisposing genetic factors, diagnostic workflows, and treatment options, the pathophysiology of PCD, among other considerations, remains largely unestablished. This review aimed to systematically observe procedural solutions to facilitate an early diagnosis and improve the prognosis of patients with OC-associated PCD. To that end, we examined literature published from 01/01/2015-11/10/2022 indexed in PubMed by using the keywords "paraneoplastic, cerebellar degeneration" combined with "ovarian cancer." Inclusion criteria were met if PCD and OC diagnoses were made and if studies provided adequate patient information. After screening and assessing records for eligibility using the inclusion and exclusion criteria, 18 articles involving 102 patients were included. The typical patient observed in this sample was diagnosed with International Federation of Gynecology and Obstetrics (FIGO) Stage III, high-grade serous carcinoma. The diagnostic workup typically included a clinical evaluation for dysarthria (50%), ataxia (60%), and gait abnormalities (50%), along with multiple imaging modalities and serological findings (90%). Genetic screening for human leukocyte antigen (HLA) haplotype susceptibility for PCD and immune tolerance modulators regulation may also be recommended prior to starting treatment. Findings support the use of corticosteroids (35%) and intravenous immunoglobulin (IVIg) (40%) as viable treatment options for managing PCD in conjunction with systemic therapy for the primary malignancy. A diagnosis of PCD should be considered if a patient has had a malignancy in the past five years with the presence of explicit cerebellar symptoms. This clinical diagnosis can be further supplemented by serologic and radiologic findings. Recognizing PCD symptoms and scheduling genetic and proteomic testing may help with early diagnosis and better prognosis.

SMARCA4-Deficient Undifferentiated Tumor: A Rare Malignancy With Distinct Clinicopathological Characteristics.

Switch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4-deficient undifferentiated tumor (SMARCA4-dUT) is a rare malignancy due to inactivating mutations in the SMARCA4 gene of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. These are aggressive malignancies presenting predominantly in male smokers in their fifth and sixth decades of life with nonspecific respiratory symptoms. Most patients have metastatic disease on presentation. The pattern of metastasis is similar to carcinomas, and the most common metastatic sites are lymph nodes, bones, and adrenal glands. Histologically, these tumors can be either entirely sarcomatoid or with mixed features of sarcoma and carcinoma, with extensive necrosis and high mitotic activity. Immunohistochemistry demonstrates negative expression of keratin and claudin-4, and tumor cell nuclei characteristically lack expression of Brahma-related gene-1 (BRG1). No standard treatment guidelines have been established due to the relative rarity of these tumors, and systemic chemoimmunotherapy has demonstrated benefit in some cases. We report two cases of SMARCA4-dUT with their clinical course and management to provide a perspective on the behavior of these tumors in a Western population cohort.

Using Peritumor and Intratumor Vascularity on Preoperative Imaging to Predict Fuhrman Grade Histology of Renal Tumors.

Objective: To investigate if peritumor and/or intratumor vasculature is associated with high-grade tumor histology for renal cell carcinoma. Methods: A retrospective review at a tertiary care facility was performed of patients who underwent radical nephrectomy or partial nephrectomy for a renal tumor between January 2015 and December 2020. Data of tumor characteristics were collected from final pathology reports. A single radiologist specializing in genitourinary imaging reviewed all preoperative cross-sectional imaging for peritumor vessels and intratumor vessels. Single and multivariable logistic regression was utilized to identify variables associated with high-grade tumor histology. Results: The average tumor size on final pathology report was 6.4 cm (range 3.0-17.0 cm). Ninety-two patients (56.1%) had either an enlarged peritumor vessel (n = 72), an intratumor vessel (n = 3), or both a peritumor vessel and an intratumor vessel (n = 17). Of the 92 patients with either a peritumor vessel or both a peritumor vessel and intratumor vessel, 60.9% of these patients had high Fuhrman grade histology on final pathology report (60.9% vs 39.1%, p < 0.001). Pathologic stage T1a tumors with an enlarged peritumor vessel on preoperative imaging were associated with high Fuhrman grade histology (58.3% vs 41.7%, p = 0.015). Across all stages, the presence of an enlarged peritumor vessel was significantly associated with high Fuhrman grade (odds ratio: 2.37, 95% confidence interval 1.17-4.9, p = 0.01). Conclusion: Findings suggest that vessels surrounding small renal tumors and large renal tumors is associated with high tumor grade (Fuhrman grade >3). Further research is needed to support the association of peritumor vessels with high tumor grade.

"En-Bloc" Enucleation With Early Apical Release Compared to Standard Holmium Laser Enucleation of the Prostate: A Retrospective Pilot Study During the Initial Learning Curve of a Single Surgeon.

OBJECTIVE: To compare operative efficiency of Holmium laser enucleation of the prostate (HoLEP) using both the standard multi-incisional approach and en-bloc enucleation with early apical release during the initial learning curve. MATERIALS AND METHODS: We retrospectively reviewed the initial 95 consecutive men who underwent HoLEP between April 2019 and September 2020 by a single surgeon. We compared patient demographics, and pre-, intra-, and post-operative metrics between both groups. Differences between groups were evaluated with Mann-Whitney U and Kruskal-Wallis tests. RESULTS: Forty-nine patients underwent the standard HoLEP approach, and 46 patients underwent the en-bloc approach. Compared to a standard HoLEP, the en-bloc approach was associated with decreased operative time (131.11 minutes vs 153.59 minutes, P = .007) with similar weights of tissue removed. Operative efficiency, as measured by grams of prostate tissue removed per minute, was greater for the en-bloc approach (0.49 g/min vs 0.36 g/min, P = .005). There was no difference in length of stay (0.91 days vs 0.96 days, P = .383), laser efficiency (4.41 kJ/g vs 4.83 kJ/g, P = .200), or number of post-operative complications (10 vs 6, P = .236) between the groups. CONCLUSION: Utilization of the en-bloc technique during the initial learning curve allows for a faster, more efficient operation without any difference in functional outcomes or major complications compared to a standard HoLEP.

Metastatic BRAF V600E-Mutated Adenocarcinoma of the Lung Presenting as Extreme Neutrophilia and Eosinophilia.

Hematologic paraneoplastic syndromes with extreme neutrophilia and eosinophilia are very rarely associated with adenocarcinoma of the lung. We describe a case of a 57-year-old female who presented with neutrophil- and eosinophil-predominant hyperleukocytosis and hypoxic respiratory insufficiency. Bone marrow biopsy confirmed metastatic adenocarcinoma, similar to the biopsy-proven adenocarcinoma of the lung. She was administered one dose of cytotoxic chemotherapy with carboplatin and pemetrexed and started on leukoreductive therapy with hydroxyurea. Molecular testing revealed a BRAF V600E mutation and she was started on dabrafenib and trametinib with significant clinical improvement. This is the first reported case of metastatic BRAF V600E mutated non-small cell lung cancer presenting with extreme neutrophilia and eosinophilia treated with a combination BRAF and mitogen-activated extracellular kinase (MEK) inhibitor.

Diagnostic hepatic haemodynamic techniques: safety and radiation exposure.

BACKGROUND & AIMS: Hepatic venous pressure gradient (HVPG) and transjugular liver biopsy (TJLB) are increasingly used in the management of patients with liver disease. We aimed to describe the safety profile of these procedures, providing data on the intra- and periprocedure complications, radiation exposure and amount of iodinated contrast material used. METHODS: In 106 consecutive patients undergoing HVPG and TJLB data on fluoroscopy time (FT), absorbed radiation dose, equivalent effective dose (mSv) and volume of iodinated contrast material (ICM) were prospectively collected and reviewed, together with clinical and laboratory data. Incidence and severity of procedure-related complications were assessed. In 28 hospitalised patients, creatinine values after 72 hours of the procedure were reviewed to identify contrast-induced nephropathy (CIN). RESULTS: Median effective radiation dose was 5.4 mSv (IQR 10 mSv). A total 28.3% of patients exceeded an effective exposure of 10 mSv and 9.4% exceeded 20 mSv. Only age and BMI correlated with radiation dose (R = .327, P=.001 and R = .410, P<.0001 respectively), and only BMI remained independently associated with an exposure over 20 mSv. Procedure-related complications occurred in eight patients (7.5%), and were minor in six cases. Median ICM volume was 12.5 mL. 6/28 patients met the diagnostic criteria for CIN. CONCLUSIONS: Hepatic venous pressure gradient and Transjugular liver biopsy show a good safety profile and radiation exposure associated with these procedures is in most of the cases low. In hepatic haemodynamic procedures, efforts should be made to reduce the radiation dose in patients with overweight/obesity and to use the minimal possible ICM volume in patients with acute-on-chronic liver failure.

Assessment and management of advanced adrenocortical carcinoma using a precision oncology care model.

Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, cytotoxic chemotherapy and mitotane have been utilized with a very modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases using next-generation sequencing (NGS)-based genomic and other '-omic' profiling to guide the precision medicine approach and personalized use of targeted and novel therapies.

Practice innovation: the need for nimble data platforms to implement precision oncology care.

Given the drive toward personalized, value-based, and coordinated cancer care delivery, modern knowledge-based practice is being shaped within the context of an increasingly technology-driven healthcare landscape. The ultimate promise of 'precision medicine' is predicated on taking advantage of the range of new capabilities for integrating disease- and individual-specific data to define new taxonomies as part of a systems-based knowledge network. Specifically, with cancer being a constantly evolving complex disease process, proper care of an individual will require the ability to seamlessly integrate multi-dimensional 'omic' and clinical data. Importantly, however, the challenges of curating knowledge from multiple dynamic data sources and translating to practice at the point-of-care highlight parallel needs. As patients, caregivers, and their environments become more proactive in clinical care and management, practical success of precision medicine is equally dependent on the development of proper infrastructures for evolving data integration, platforms for knowledge representation in a clinically-relevant context, and implementation within a provider's work-life and workflow.

Synthetic α-(aminomethyl)-γ-butyrolactones and their anti-pancreatic cancer activities.

Aminated α-methylene-γ-butyrolactones, which are readily synthesized with facile control of the diastereoisomerism, provide an economical and commercially-viable alternative to the use of aminated natural products. These aminoloactones, which exhibit excellent activity against three pancreatic cancer cell lines when measured at 10 µM-Panc-1, MIA PaCa-2, and BxPC-3-and are comparable to or better than parthenolide and dimethylaminoparthenolide (DMAPT, LC-1). It has also been shown that there is an effect on the biological activity depending on the identity of the amine.

Tailored α-methylene-γ-butyrolactones and their effects on growth suppression in pancreatic carcinoma cells.

A selected series of racemic α-methylene-γ-butyrolactones (AMGBL) were synthesized via allylboration and screened against three human pancreatic cancer cell lines (Panc-1, MIA PaCa-2, and BxPC-3). This systematic study established a discernible relationship between the substitution pattern of AMGBL and their anti-proliferative activity. ß,γ-diaryl-AMGBLs, particularly those with a trans-relationship exhibited higher potency than parthenolide and LC-1 against all three cell lines.

Unstable hemiarthroplasty of the hip-treated with a simple technique of acetabular augmentation.

Hemiarthroplasty of the hip is one of the most frequently performed orthopedic procedures for trauma in the elderly. Dislocation is one of its well-recognized complications and ranges from 1% to 16% (Acta Orthop Scand. 2003;74:45-48) in different series. Often, dislocation can be recurrent when the morbidity is even higher. Suggested methods of treatment for this difficult problem range from closed/open reduction followed by conservative management to Girdlestone excision arthroplasty. We report a unique, simple, and effective method of managing this problem, particularly in those elderly patients who are medically unfit to undergo a total hip arthroplasty or a major revision hip surgery at a later date for a dislocated hemiarthroplasty. Nine patients have been treated with our technique, and none of these patients had a further dislocation over a 6-month to 9-year follow-up.

A mechanistic investigation of the enhanced cleavage at histidine in the gas-phase dissociation of protonated peptides.

Enhanced gas-phase cleavage of peptides adjacent to histidine was investigated. The peptides examined were angiotensins III (RVYIHPF) and IV (VYIHPF) as well as synthetic peptide analogues with altered key residues ((R)VYI-X-Z-F; X = F or H and Z = A, P, or Sar) or a fixed charge M3P(+)CH(2)C(O)-VYIHPF. While all singly protonated peptide ions containing both histidine and arginine fragment nonselectively, the doubly protonated peptide ions with arginine and histidine, and the singly protonated peptides containing histidine but not arginine, cleave in a selective manner. In particular, dominant complementary b+/y+ product ions resulting from cleavage between the HP amide bond are observed. For the fixed-charge derivative, selective cleavage occurs only if a proton is added to produce a doubly charged precursor. The results are consistent with involvement of a protonated histidine in the selective cleavage. The ratio of b+/y+ is determined by the identity of the residue C-terminal to histidine and by the ability of protonated histidine to transfer a proton to the C-terminal leaving fragment. This was probed further by systematically changing the residue C-terminal to histidine and by alkylating histidine. The results indicate that while b+/y+ complementary ion pairs dominate in doubly protonated RVYIHPF, b5(2+) and b6(2+) product ions dominate the spectra of doubly protonated RVYIHAF. Also, dominant b5(2+) product ions are observed when the histidine side chain is alkylated (H) in doubly protonated RVYIHPF. Based on all of the results, a selective fragmentation mechanism for enhanced cleavage at histidine involving an atypical b ion structure is proposed.

Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes.

The natural product quercetin is a flavonoid found in many fruits and vegetables. Previous research has shown that quercetin has antitumor, anti-inflammatory, antiallergic, and antiviral activities. In the present investigation we studied the effect of quercetin on the ability of prostate cancer cell lines with various degrees of aggressive potential to form colonies in vitro. Specifically, we examined the molecular mechanisms underlying this effect, including the expression of cell cycle and tumor suppressor genes as well as oncogenes. We observed that quercetin at concentrations of 25 and 50 micro M significantly inhibited the growth of the highly aggressive PC-3 prostate cancer cell line and the moderately aggressive DU-145 prostate cancer cell line, whereas it did not affect colony formation by the poorly aggressive LNCaP prostate cancer cell line or the normal fibroblast cell line BG-9. Using the gene array methodology, we found that quercetin significantly inhibited the expression of specific oncogenes and genes controlling G(1), S, G(2), and M phases of the cell cycle. Moreover, quercetin reciprocally up-regulated the expression of several tumor suppressor genes. In conclusion, our results demonstrate that the antitumor effects of quercetin directly correlate with the aggressive potential of prostate cancer cells and that the mechanism(s) of quercetin-mediated antitumor effects may involve up-regulation of tumor suppressor genes and reciprocal down-regulation of oncogenes and cell cycle genes. The results of these studies provide a scientific basis for the potential use of flavonoids as nutraceuticals in the chemoprevention of cancer.