Impact of age, obesity, and renal impairment on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

INTRODUCTION: There remains a need to determine whether certain subgroups of newly diagnosed multiple myeloma (NDMM) derive the same benefit from high-dose chemotherapy-autologous stem cell transplant (HDT-ASCT). We describe our institutional experience highlighting the impact of age, obesity, and renal impairment on outcomes after HDT-ASCT for patients with NDMM in a real-world setting. METHODS: A total of 449 consecutive patients were included in this retrospective analysis. RESULTS: No difference in median progression free survival or overall survival was seen for patients with age > 65, body mass index (BMI) > 30 kg/m2, or estimated glomerular filtration rate < 60 mL/min/1.73 m2 when compared to those without these characteristics. From a safety standpoint, there were no differences in the incidence of transplant-related mortality or secondary malignancy among subgroups. CONCLUSION: For patients with NDMM undergoing HDT-ASCT, there is no difference in outcomes based on age, BMI, or renal function, and the presence of one or more of these factors should not preclude patients from HDT-ASCT.

Impact of race and ethnicity on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

Non-Hispanic Black patients are disproportionally affected by multiple myeloma (MM) and whether efficacy outcomes after autologous stem cell transplant (ASCT) differ by race and ethnicity remains an area of active investigation. This study included 449 patients enriched with a large proportion of non-Hispanic Black patients and sought to highlight the impact of race and ethnicity on outcomes after HDT-ASCT for patients with newly diagnosed MM. We found induction chemotherapy followed by high-dose therapy-ASCT and maintenance chemotherapy is associated with long-term PFS and OS, regardless of race or ethnicity.

Treatments and challenges in advanced prostate cancer.

PURPOSE OF REVIEW: This review is designed to highlight recent research examining treatment progress in advanced prostate cancer while identifying ongoing challenges to clinical outcomes. RECENT FINDINGS: Recent randomized trials suggest an overall survival advantage to treating some men with newly identified metastatic prostate cancer with a "triplet" of androgen deprivation therapy, docetaxel, and an androgen receptor axis-targeted agent. Questions remain about which men are best served by these combinations. Additional treatment success is being identified with prostate-specific membrane antigen positron emission tomography (PSMA)-radiopharmaceuticals, combinations involving targeted therapies, and novel manipulations of the androgen receptor axis. Challenges remain in selecting between available therapies, harnessing immune therapies, and treating tumors with emergent neuroendocrine differentiation. SUMMARY: An expanding number of therapeutics are becoming available for men with advanced prostate cancer improving outcomes but at the same time making treatment selection more demanding. Ongoing research will be required to continue to hone treatment paradigms.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

Background: High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. Methods: A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. Results: With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). Conclusions: In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Can Discord Domain-Containing Receptor 2 Mutation Act as a Disease Modifier for PRKAR1A Associated Melanotic Schwannoma?

Melanotic Schwannomas are rare neural sheath tumors with distinctive findings of both Schwann cells and melanocytic cells. Recognition of this entity has prompted the importance of distinction from similar tumor types such as melanomas. Early diagnosis facilitates removal of the mass with less risk of local invasion and metastasis. Although previously known as mostly benign lesions, malignant conversion and recurrence are recognized. This paper presents a patient with melanotic schwannoma, describes the distinctive features that will separate it from melanoma, and addresses the possibility of further guided therapy through next-generation sequencing.

Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction.

Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.

Leiomyosarcoma of the Inferior Vena Cava in an HIV-Positive Adult Patient: A Case Report and Review of the Literature.

BACKGROUND Leiomyosarcoma is the most common primary malignancy of the inferior vena cava (IVC), and represents approximately 10% of primary retroperitoneal sarcomas. Leiomyosarcoma presents with non-specific symptoms, including abdominal pain or back pain. There is an increased incidence in immunosuppressed individuals. CASE REPORT An unusual presentation of IVC leiomyosarcoma is reported in a 46-year-old female patient infected with human immunodeficiency virus (HIV) who was on highly active antiretroviral therapy (HAART) and who had a normal CD4 count of 934, who presented with back pain. Magnetic resonance imaging (MRI) of the lumbar spine showed a mass of the IVC. Initial computed tomography (CT)-guided biopsy of the IVC mass was non-diagnostic. An IVC filter was inserted, and the patient was discharged home, but 20 days later, she returned to the hospital with worsening right flank pain. Laboratory tests showed acute renal failure, and a repeat CT scan showed IVC thrombus extending 5 cm superiorly. When compared with the previous CT, there was an extension of thrombus into both renal veins. Histopathology of a transjugular needle core biopsy showed a moderately differentiated leiomyosarcoma. The patient was transferred to a multidisciplinary sarcoma center for surgical resection, chemotherapy, and radiation therapy. CONCLUSIONS This report is of a rare case of IVC leiomyosarcoma in a middle-aged HIV-positive woman with a normal CD4 count. Leiomyosarcoma of the IVC is extremely rare, is often detected when advanced, and has a poor prognosis. This case report describes the clinical, imaging, surgical and histopathological findings of leiomyosarcoma of the IVC.

Alpha-synuclein interacts with Glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases.

The presynaptic protein α-synuclein (α-syn), particularly in its amyloid form, is widely recognized for its involvement in Parkinson disease (PD). Recent genetic studies reveal that mutations in the gene GBA are the most widespread genetic risk factor for parkinsonism identified to date. GBA encodes for glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage disorder, Gaucher disease (GD). In this work, we investigated the possibility of a physical linkage between α-syn and GCase, examining both wild type and the GD-related N370S mutant enzyme. Using fluorescence and nuclear magnetic resonance spectroscopy, we determined that α-syn and GCase interact selectively under lysosomal solution conditions (pH 5.5) and mapped the interaction site to the α-syn C-terminal residues, 118-137. This α-syn-GCase complex does not form at pH 7.4 and is stabilized by electrostatics, with dissociation constants ranging from 1.2 to 22 µm in the presence of 25 to 100 mm NaCl. Intriguingly, the N370S mutant form of GCase has a reduced affinity for α-syn, as does the inhibitor conduritol-ß-epoxide-bound enzyme. Immunoprecipitation and immunofluorescence studies verified this interaction in human tissue and neuronal cell culture, respectively. Although our data do not preclude protein-protein interactions in other cellular milieux, we suggest that the α-syn-GCase association is favored in the lysosome, and that this noncovalent interaction provides the groundwork to explore molecular mechanisms linking PD with mutant GBA alleles.

Quantitative analysis of TEM-8 and CEA tumor markers indicating free tumor cells in the peripheral blood of colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) remains the third most common cancer in the world. Approximately in 50 percent of patients, metastatic disease is a major cause of death. Therefore, early diagnosis of CRC is crucial for a successful outcome. For the detection of circulating cancer cells, this study applied a sensitive method that employed specific tumor markers for early detection. METHODS: A total of 80 blood samples from 40 CRC patients and 40 age-matched healthy controls were collected for the study. The circulating mRNA levels of two CRC tumor markers, tumor endothelial marker 8 (TEM-8) and carcinoembryogenic antigen (CEA) were evaluated using an absolute quantitative real-time PCR assay in a Stratagene Mx-3000P real-time PCR system. GAPDH was used as the endogenous control. RESULTS: TEM-8 and CEA were primarily detected more in the CRC patients rather than in the controls: 22/40 vs 9/40, p=0.009 and 30/40 vs 11/40, p=0.00054, respectively. In the CRC patients, the mRNA level of these markers was significantly higher in comparison to the normal controls (p=0.018 and 0.01). The overall sensitivity of this panel was 65% with a specificity of 75%. Statistical analysis for demographic variants did not reach significant values. CONCLUSIONS: TEM-8 and CEA markers were detected more frequently and in significantly higher levels in the blood samples of patients compared with samples from age-matched healthy controls. The copy number of CEA and TEM-8 mRNA, as detected by a real-time quantitative PCR, appears to be a promising marker for evaluating the risk of tumor spread.

Differential diagnosis of cervical malignant lymphadenopathy among Iranian patients.

OBJECTIVE: To investigate the differential diagnosis in cases referred with neck lumps suspicious to malignant nodal masses and its relation to demographic variants. METHODS: Individuals who entered in this cross-sectional study conducted at the Department of Otolaryngology, Ghaem Medical Center, Mashdad, Iran from May 1995 to April 2005 were re-evaluated by history taking, physical examination and imaging studies. Fine needle aspiration was applied to obtain tissue sampling. Among the patients, 232 cases had malignant disease confirmed by pathology reports. Cases with unknown primary tumor underwent investigations including pan-endoscopy, and further imaging studies were carried out to determine the primary tumor site. Demographic data as gender, age, location, size, and pathology of tumor were considered. RESULTS: The results of this study showed that 50% of patients which were referred with neck masses had malignant neoplasm. The most common pathology in patients younger than 40 years were lymphoma (55%) and thyroid cancer (26%), whereas, in patients older than 40 years squamous cell carcinoma (67%) was more common. The most involved lymph nodes were jugulodigastric chain. Larynx and hypopharynx are the most common sources of aerodigestive tract metastatic. CONCLUSION: According to high incidence malignancy (50%) among neck lesions, an asymmetrical neck mass in adults should be considered malignant until proven otherwise. It seems that age is an important predictor of tumor pathology, and determination of further diagnostic investigations would be helpful.

Rare gross deletion in T-cell immune regulator-1 gene in Iranian family with infantile malignant osteopetrosis.

Infantile malignant osteopetrosis (arOP) is an autosomal recessive disorder. Mutations in the T-cell immune regulator 1 (TCIRG1) gene were found as the cause of arOP. We found the first Iranian patient with a rare gross deletion in this gene. The patient was a 5-year-old girl with macrocephaly, facial dysmorphism, blindness, mental retardation, hepatosplenomegaly, pancytopenia, and osteosclerotic changes in the skull and limb. Molecular analysis was performed using reverse transcriptase-polymerase chain reaction for exons 10-19 of the TCIRG1 gene followed by whole gene sequencing. She showed a 275 bp unexpected amplified segment. Sequencing revealed a gross deletion in exons 10-15 transcript region of TCIRG1 that affected codon 389 to 518. Various types of mutations in the TCIRG1 gene in arOP have been reported, however, gross deletions are reported rarely. This gross deletion is the first mutation reported among Iranian patients in this gene. This deletion is also the largest deletion of TCIRG1 gene reported to date.

Rapid DNA extraction protocol from stool, suitable for molecular genetic diagnosis of colon cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common forms of cancers in the world and is curable if diagnosed at the early stage. Analysis of DNA extracted from stool specimens is a recent advantage to cancer diagnostics. Many protocols have been recommended for DNA extraction from stool, and almost all of them are difficult and time consuming, dealing with high amount of toxic materials like phenol. Their results vary due to sample collection method and further purification treatment. In this study, an easy and rapid method was optimized for isolating the human DNA with reduced PCR inhibitors present in stool. METHODS: Fecal samples were collected from 10 colonoscopy-negative adult volunteers and 10 patients with CRC. Stool (1 g) was extracted using phenol/chloroform based protocol. The amplification of P53 exon 9 was examined to evaluate the extraction efficiency for human genomic targets and also compared its efficiency with Machiels et al. and Ito et al. protocols. RESULTS: The amplification of exon 9 of P53 from isolated fecal DNA was possible in most cases in 35 rounds of PCR using no additional purification procedure for elimination of the remaining inhibitors.inhibitors. CONCLUSION: A useful, rapid and easy protocol for routine extraction of DNA from stool was introduced and compared with two previous protocols.

Stool-based DNA testing, a new noninvasive method for colorectal cancer screening, the first report from Iran.

AIM: To detect tumor-associated DNA changes in stool samples among Iranian patients with colorectal cancer (CRC) compared to healthy individuals using BAT-26, p16 hypermethylation and long DNA markers. METHODS: Stool DNA was isolated from 45 subjects including 25 CRC patients and 20 healthy individuals using a new, fast and easy extraction method. Long DNA associated with tumor was detected using polymerase chain reaction method. Microsatellite studies were performed utilizing denaturating polyacrylamide gel to determine the instability of BAT-26. Methylation status of p16 promoter was analyzed using methylation-specific PCR (MSP). RESULTS: The results showed a significant difference in existence of long DNA (16 in patients vs 1 in controls, P < 0.001) and p16 (5 in patients vs none in controls, P = 0.043) in the stool samples of two groups. Long DNA was detected in 64% of CRC patients; whereas just one of the healthy individuals was positive for Long DNA. p16 methylation was found in 20% of patients and in none of healthy individuals. Instability of BAT-26 was not detected in any of stool samples. CONCLUSION: We could detect colorectal cancer related genetic alterations by analyzing stool DNA with a sensitivity of 64% and 20% and a specificity of 95% and 100% for Long DNA and p16 respectively. A non-invasive molecular stool-based DNA testing can provide a screening strategy in high-risk individuals. However, additional testing on more samples is necessary from Iranian subjects to determine the exact specificity and sensitivity of these markers.