Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 μm of ...formalin-fixed, paraffin-embedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 × and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0–10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0–7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.
Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive form of bladder cancer. We conducted genomic analyses next-generation sequencing (NGS) of MPUC and non-micropapillary urothelial ...bladder carcinomas (non-MPUC) to characterize the genomic landscape and identify targeted treatment options.
DNA was extracted from 40 μm of formalin-fixed paraffin-embedded sections from 15 MPUC and 64 non-MPUC tumors. Sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries to high coverage for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alteration.
Mutations in the extracellular domain of ERBB2 were identified in 6 of 15 (40%) of MPUC: S310F (four cases), S310Y (one case), and R157W (one case). All six cases of MPUC with ERBB2 mutation were negative for ERBB2 amplification and Erbb2 overexpression. In contrast, 6 of 64 (9.4%) non-MPUC harbored an ERBB2 alteration, including base substitution (three cases), amplification (two cases), and gene fusion (one case), which is higher than the 2 of 159 (1.3%) protein-changing ERBB2 mutations reported for urinary tract cancer in COSMIC. The enrichment of ERBB2 alterations in MPUC compared with non-MPUC is significant both between this series (P < 0.0084) and for all types of urinary tract cancer in COSMIC (P < 0.001).
NGS of MPUC revealed a high incidence of mutation in the extracellular domain of ERBB2, a gene for which there are five approved targeted therapies. NGS can identify genomic alteration, which inform treatment options for the majority of MPUC patients.
Purpose: Due to improved survival durations and enhanced surveillance modalities, metastases of systemic malignancies to the orbit are increasing. This review is intended to discuss the ...epidemiologic, clinical, and management features of orbital metastases.
Methods: A literature search for relevant publications on the topic was performed via PubMed, and the appropriate data were extracted from these manuscripts.
Results: While rare, metastases to the orbit are regularly encountered in clinical practice. The overwhelming majority of these lesions present in adult patients, and metastatic disease may emerge several years after the diagnosis of the initial cancer. Subjectively, these lesions tend to present with complaints of diplopia, blurred vision, and pain, and objective signs tended to include vision loss, limitation of extraocular motility, proptosis, the presence of a palpable mass, and ptosis. Different studies reported a variety of primary tumors, although breast and lung malignancies were generally among the most common. A sizeable portion of patients may not have a known primary malignancy. After detection, survival rates are generally short, and metastatic disease suggests a worrisome prognosis. Radiation therapy may alleviate symptoms.
Conclusions: Metastases of systemic disease present with specific subjective, clinical, and radiographic features. Furthermore, these lesions may present years after an initial diagnosis. Clinicians should be aware of the implications of this malady on patient survival and must consider interventions to improve quality of life.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
(1) Background: Acute myeloid leukemia (AML) accounts for up to one-third of more than 60,000 leukemia cases diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is ...associated with adverse prognosis and resistance to chemotherapies. A novel anticancer compound Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) interacts with high affinity (Ki 0.3 nM) and specificity with the thyrointegrin αvβ3. We evaluated P-bi-TAT activities in two different AML models representing monocytic and myelocytic forms of acute leukemia. (2) Methods and Results: The in vivo AML models were established prior to initiation of treatment protocols by grafting human leukemia cells in immunocompromised mice. IVIS imaging scans revealed that leukemic colonies were extensively established throughout the bone marrow, liver, and lung of the untreated animals. In animals treated with P-bi-TAT at daily doses ranging from 1–10 mg/kg, subcutaneously for 2–3 weeks, IVIS imaging scans revealed 95% reduction in bone marrow colonies and leukemic colonies in liver and lung. Also, the leukemic cells were not detected in bone marrow samples of P-bi-TAT-treated animals. The anti-neoplastic effect of P-bi-TAT administration on leukemic cells was associated with marked inhibition of NF-κB activity. We conclude that experimental P-bi-TAT therapy in vivo appears extraordinarily effective against the two forms of human AML models in mice. Because the P-bi-TAT molecular target, thyrointegrin αvβ3, is consistently expressed in many, if not all, clinical AML samples, P-bi-TAT-based therapy seems to have significant clinical potential in treating most AML sub-types. Hence, P-bi-TAT represents a promising targeted therapeutic agent for AML patients.
Inflammatory myofibroblastic tumors (IMT) of the urachus is a rare neoplastic condition characterized by proliferation of spindle cell, likely derived from myofibroblasts or fibroblasts, with acute ...and chronic inflammatory infiltrate. Urachal IMT present with abdominal/pelvic pain and urinary symptoms. These often manifest as abdominal mass involving adjacent structures. We describe a case of young female with urachal IMT that was excised with a wide margin to ensure complete removal of all adjacent affected tissue using robotic-assisted laparoscopic approach. Immunohistochemical evidence of ALK and ALK gene rearrangement were confirmed in this tumor which are diagnostic of IMT.
Background: The association between Merkel cell carcinoma (MCC) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) is well established in the literature. A majority of MCCs are ...known to be associated with Merkel cell carcinoma polyomavirus (MCPyV), which is postulated to be a possible causative agent linking these two entities. We aim to identify the presence of MCPyV in patients with concurrent adjacent MCC and CLL/SLL. Methods: Archived pathology materials of three cutaneous or surgical excisions with concurrent MCC and CLL/SLL were reviewed. Additional 12-µm sections from paraffin-embedded tissue of these resections were matched with original hematoxylin and eosin-stained slides and used to extract foci from each tumor separately. DNA was extracted from these tissues, and polymerase chain reaction (PCR), utilizing a primer set within a highly conserved “small T” viral DNA region, was done to detect MCPyV. Results: Out of 140 cases of cutaneous or surgical excisions with MCC identified in our electronic medical records (EMR), three had coexisting neighboring CLL/SLL in the same resection specimen. In one case out of three, MCPyV was detected in MCC but not in CLL/SLL. The remaining two cases showed no detection of MCPyV in either MCC or CLL/SLL. Conclusion: MCPyV was not concurrently associated with adjacent MCC and CLL/SLL, indicating that it is not driving simultaneous tumorigenesis, at least in a subset of these cases.
Spinal primary dural lymphoma (PDL) is uncommon with a total of 37 previous well‐documented cases reported, including one diagnosed in the authors' institution. More recently we encountered an ...additional case of spinal PDL that, similarly to our previous case, was grade 1–2 follicular B‐cell PDL. Our two cases were diagnosed over a 3‐year interval in a 72‐year‐old female and a 74‐year‐old male, respectively. An exhaustive literature review on PDL was performed consequently to reveal that: (i) spinal and cerebral sites of involvement by PDL are constantly mutually exclusive; and (ii) unlike cerebral PDL, which is usually of marginal zone B‐cell type, only two of the 38 cases of spinal PDL were diagnosed as such, diffuse large B‐cell lymphoma being the most commonly encountered type in the spine. This divergence infers that, in contrast to the prevailing concept that PDL is a unique disease group, PDL appears to be rather heterogeneous with a difference in predilection of lymphoma type for the anatomical site of dural involvement. Such a site‐specific lymphoma‐type predilection phenomenon, well‐recognized in other organ systems, has not been acknowledged in PDL. This report brings new insights into PDL, and may contribute to a better understanding of nervous system pathophysiology and lymphoma classification.
High grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) in the sextant biopsy had been associated with a high risk of prostate cancer. We determined ...whether the extended biopsy schemes used in the contemporary era have altered the prognostic value of these lesions at repeat biopsies.
From 1998 to 2003, 105 of 1,188 men had at least 1 repeat extended biopsy due to the presence of HGPIN (33 men) or ASAP (72 men) in a previous extended biopsy. Median biopsy interval for HGPIN and ASAP was 15 and 10 weeks (p <0.05), respectively. Differences in cancer detection rates were analyzed using the Pearson chi-square test.
In the HGPIN group only 1 of 22 (4.5%) men had cancer on 1st repeat biopsy and 0 of 11 men had cancer on 2nd repeat biopsy. In men with ASAP 19 of 53 (36%, p <0.005) had cancer on 1st repeat biopsy, and 3 of 19 (16%) had cancer on 2nd repeat biopsy. Cancer was confined to a single core in 16 of 22 (73%) men. Median Gleason score was 6. Patient age, digital rectal examination status, prostate specific antigen, free prostate specific antigen, number of cores and biopsy interval were not independent predictors of cancer in men with ASAP.
HGPIN found in the contemporary extended biopsy does not warrant repeat biopsy. ASAP continues to be associated with a high risk of cancer and requires at least 1 repeat biopsy using the extended biopsy scheme.
Objective: To present a case of an aggressive adrenocortical carcinoma producing both ectopic cortisol and androgens and to provide an extensive literature review of similar cases.Methods: A case ...presentation is provided that illustrates clinical, biochemical, radiologic, and pathologic findings. We also conducted a PubMed search for similar cases and summarize 15 other cases of malignant adrenal rest tissue.Results: A 50-year-old woman presented with symptoms of Cushing syndrome and virilization. Urine free cortisol and serum adrenal androgens were significantly elevated. Computed tomography of the abdomen revealed a 12-cm mass within the right kidney. Subsequently, the patient underwent right radical nephro-adrenalectomy. The tumor showed a high-grade neoplasm centered in the kidney with polymorphism, highly atypical nuclei, abundant mitotic activity, and necrosis. The Ki-67 proliferation index was 25 to 30%. Immunohistochemical staining of the neoplastic cells favored an adrenal origin. The native adrenal gland was atrophic and free of the tumor. Postoperatively, cortisol and adrenal androgen levels became undetectable. However, her disease unfortunately recurred 5 months later with innumerable peritoneal, mesenteric, omental, and serosal implants within the abdomen and pelvis. She was started on mitotane and mifepristone but unfortunately expired within a few days from a septic shock secondary to Pseudomonas aeruginosa pneumonia.Conclusion: We present an unusual case of a functional adrenocortical carcinoma arising in adrenal rest tissue in a kidney resulting in Cushing syndrome and virilization with very aggressive biology. To the best of our knowledge, no similar case has been reported thus far.Abbreviations: ACC = adrenocortical carcinoma; CT = computed tomography
PDF
