Fatal acute cardiac vasculopathy during cisplatin-gemcitabine-bevacizumab (CGB) chemotherapy for advanced urothelial carcinoma.

BACKGROUND: Bladder cancer (BC) accounts for ∼14,680 deaths annually in the U.S. The prognosis of advanced disease remains dismal with current therapies. A phase III intergroup trial for metastatic BC adding bevacizumab to first-line cisplatin-gemcitabine chemotherapy (GCB regimen) is currently ongoing. We report the clinical-pathologic findings of a patient who developed fatal acute cardiac microvascular toxicity while receiving this regimen. CASE REPORT: A 66 year old man consulted for epigastric pain, nausea, intermittent diarrhea and lightheadedness two weeks after receiving the first cycle of GCB chemotherapy for metastatic BC. Physical evaluation, laboratory studies and electrocardiogram (EKG) were within normal limits except for marked thrombocytopenia that was attributed to his recent chemotherapy. The patient was admitted for observation, rehydrated and started on a proton pump inhibitor. The following day, however, he experienced sudden severe chest and right upper quadrant pain. EKG showed tachycardia, ST elevations in leads V2 and V3, laboratory analyses revealed marked elevation of cardiac troponin I, and an echocardiogram showed a markedly reduced ejection fraction of 10-20%, consistent with rapidly progressive cardiogenic shock. Emergent cardiac catheterization showed no significant coronary artery disease. Sepsis work-up was negative. He became progressively hypotensive, developed multi-organ failure, and died 48 h after admission. Postmortem examination showed diffuse microvasculopathy and changes due to global hypoperfusion of 12-48 h evolution. CONCLUSIONS: We present the first case of acute, fatal cardiac failure due to microvasculopathy most consistent with bevacizumab-associated toxicity. The findings are discussed in light of the existing literature.

An unusual case of Ewing sarcoma: a middle-aged woman with multiple recurrences over 36 years.

Ewing sarcoma (EWS) is a primary bone tumor that most often occurs in the long bones of young patients. EWS is typically an aggressive tumor that is highly sensitive to radiation therapy; recurrences often occur, usually within a year of treatment. We present a case of EWS that first presented in a patient at the age of 40 with extraosseous disease. The patient was treated initially with radiation and surgery. Over the following 36-year period, the tumor recurred once and metastasized twice. The morphologic, immunohistochemical, and cytogenetic features of this tumor were typical of EWS, and the tumor was highly responsive to radiation therapy. The unusually prolonged course in this patient demonstrates significant heterogeneity in the biological behavior of EWS, and the importance of randomized trials in cancer therapy.

Chemotherapy influences the pseudocapsule composition in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignant tumors. Standard treatment for soft tissue sarcoma of the extremity is surgical excision and adjuvant therapy; however, the role of neoadjuvant chemotherapy is controversial. QUESTIONS/PURPOSES: We sought to (1) define the histologic characteristics of the pseudocapsule in soft tissue sarcomas; (2) compare the appearance of this structure in chemotherapy-treated versus untreated soft tissue sarcomas; and (3) evaluate the effect of chemotherapy on the presence and viability of tumor cells at the host-sarcoma interface. METHODS: Twenty-eight patients with biopsy-proven, deep, high-grade extremity soft tissue sarcomas greater than 5 cm (AJCC stage III) treated with chemotherapy and surgical excision were compared histologically with 47 matched control subjects treated with surgery alone. RESULTS: A pseudocapsule was identifiable in the majority of tumors and consisted of two identifiable layers, each with specific histological characteristics suggesting the biologic processes occurring in these layers are different. The pseudocapsule was more frequently observed in the group treated with chemotherapy and it was more frequently continuous, thicker, and better developed in this group. Chemotherapy decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CONCLUSIONS: Neoadjuvant chemotherapy contributed to the development of a pseudocapsule and decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CLINICAL RELEVANCE: These findings may provide a histological explanation for the clinical effect of chemotherapy in soft tissue sarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells.

Common human malignancies acquire derangements of the translation initiation complex, eIF4F, but their functional significance is unknown. Hypophosphorylated 4E-BP proteins negatively regulate eIF4F assembly by sequestering its mRNA cap binding component eIF4E, whereas hyperphosphorylation abrogates this function. We found that breast carcinoma cells harbor increases in the eIF4F constituent eIF4GI and hyperphosphorylation of 4E-BP1 which are two alterations that activate eIF4F assembly. Ectopic expression of eIF4E in human mammary epithelial cells enabled clonal expansion and anchorage-independent growth. Transfer of 4E-BP1 phosphorylation site mutants into breast carcinoma cells suppressed their tumorigenicity, whereas loss of these 4E-BP1 phosphorylation site mutants accompanied spontaneous reversion to a malignant phenotype. Thus, eIF4F activation is an essential component of the malignant phenotype in breast carcinoma.

Renal angiomyoadenomatous tumor.

We report a case of a 40-year-old woman with renal angiomyoadenomatous tumor, a rare neoplasm with only 6 previous cases reported in the literature. Unlike our case, most tumors have been identified in middle-aged males; they present as well-circumscribed, encapsulated tan-brown masses with variably prominent cystic areas. Microscopically, the tumors have a variably thick leiomyomatous capsule, which invaginates into the tumor and intermixes with tubules or solid nests of clear epithelial cells. The epithelial cells have low-grade basally oriented nuclei, and their basement membranes are intimately linked to a labyrinthine network of capillaries and pericytes. Microscopically, these tumors can be confused with clear cell carcinoma, papillary carcinoma, mixed epithelial and stromal tumors, and angiomyolipoma. This is also the first case report correlating the radiographic and morphological findings of this rare entity. The differentiating features of these neoplasms and a review of literature of are herein presented.

A suspicious vulvar mass diagnosed as a subpubic cartilaginous cyst.

BACKGROUND: Subpubic cartilaginous cysts were initially described in 1996 with few reports to date. CASE: We describe a 62-year-old woman with a history of breast cancer who presented with a painful, fixed, vulvar mass. MRI revealed an 18 x 10 x 12 mm3 mass extending from the anterior portion of the symphysis pubis without bony involvement. Excision was performed. Histologically, the mass consisted of fibrocartilage with extensive degenerative changes, compatible with a subpubic cartilaginous cyst. Over 24 months later, there has been no recurrence. CONCLUSION: Subpubic cartilaginous cyst is a rare, benign lesion occurring on the vulva and should be considered in the differential diagnosis of a painful, superior vulvar mass.

Identification of heterogeneity among soft tissue sarcomas by gene expression profiles from different tumors.

The heterogeneity that soft tissue sarcomas (STS) exhibit in their clinical behavior, even within histological subtypes, complicates patient care. Histological appearance is determined by gene expression. Morphologic features are generally good predictors of biologic behavior, however, metastatic propensity, tumor growth, and response to chemotherapy may be determined by gene expression patterns that do not correlate well with morphology. One approach to identify heterogeneity is to search for genetic markers that correlate with differences in tumor behavior. Alternatively, subsets may be identified based on gene expression patterns alone, independent of knowledge of clinical outcome. We have reported gene expression patterns that distinguish two subgroups of clear cell renal carcinoma (ccRCC), and other gene expression patterns that distinguish heterogeneity of serous ovarian carcinoma (OVCA) and aggressive fibromatosis (AF). In this study, gene expression in 53 samples of STS and AF [including 16 malignant fibrous histiocytoma (MFH), 9 leiomyosarcoma, 12 liposarcoma, 4 synovial sarcoma, and 12 samples of AF] was determined at Gene Logic Inc. (Gaithersburg, MD) using Affymetrix GeneChip U_133 arrays containing approximately 40,000 genes/ESTs. Gene expression analysis was performed with the Gene Logic Genesis Enterprise System Software and Expressionist software. Hierarchical clustering of the STS using our three previously reported gene sets, each generated subgroups within the STS that for some subtypes correlated with histology, and also suggested the existence of subsets of MFH. All three gene sets also recognized the same two subsets of the fibromatosis samples that we had found in our earlier study of AF. These results suggest that these subgroups may have biological significance, and that these gene sets may be useful for sub-classification of STS. In addition, several genes that are targets of some anti-tumor drugs were found to be differentially expressed in particular subsets of STS.

Giant cell tumor of the uterus: case report and response to chemotherapy.

BACKGROUND: Giant cell tumor (GCT) is usually a benign but locally aggressive primary bone neoplasm in which monocytic macrophage/osteoclast precursor cells and multinucleated osteoclast-like giant cells infiltrate the tumor. The etiology of GCT is unknown, however the tumor cells of GCT have been reported to produce chemoattractants that can attract osteoclasts and osteoclast precursors. Rarely, GCT can originate at extraosseous sites. More rarely, GCT may exhibit a much more aggressive phenotype. The role of chemotherapy in metastatic GCT is not well defined. CASE PRESENTATION: We report a case of an aggressive GCT of the uterus with rapidly growing lung metastases, and its response to chemotherapy with pegylated-liposomal doxorubicin, ifosfamide, and bevacizumab, along with a review of the literature. CONCLUSION: Aggressive metastasizing GCT may arise in the uterus, and may respond to combination chemotherapy.

Thymic hyperplasia in a child treated with growth hormone.

OBJECTIVE: To report a case of thymic hyperplasia diagnosed three months after initiation of recombinant human growth hormone (GH) for the treatment of GH deficiency. DESIGN: Retrospective chart review was conducted to evaluate the temporal relationship between treatment with GH and thymic enlargement in a 7-year-old girl who had a history of embryonal rhabdomyosarcoma of the nasopharynx diagnosed at the age of 3 years. RESULTS: The diagnosis of GH deficiency was made based on clinical and auxological criteria, an insufficient response to clonidine-arginine stimulation testing (peak GH level of 4.8 microg/L) and low insulin-like growth factor 1 (IGF-1) level (30 ng/mL, -2.7 SD). The patient was started on GH at a dose of 0.3mg/kg/week. At the initiation of treatment with GH, the baseline growth velocity was 0.8 cm/year (-6.0 SD) and height was 112.5 cm (-1.7 SD). After three months of treatment with GH, her height increased by 4.2 cm (from -1.7 to -1.2 SD), and the IGF-1 level from -2.7 SD to -1.1 SD. A chest CT performed at that time for recurrence surveillance showed 89% increase in thymic volume relative to previous scan before treatment with growth hormone. A thoracoscopic biopsy of the thymus was performed and revealed hyperplasia with normal thymic architecture without evidence of malignancy. CONCLUSIONS: The timing of the development of thymic hyperplasia, along with data from in vitro and in vivo animal studies showing that GH and IGF-1 can directly stimulate growth of the thymus, suggests that GH contributed to the development of thymic hyperplasia in this patient.

Persistent, asymptomatic, microscopic hematuria in prospective kidney donors.

BACKGROUND: Asymptomatic, microscopic hematuria is seen in 8-21% of the general population, has a good prognosis, and is generally not an indication for kidney biopsy. But whether it should preclude kidney donation is unclear. METHODS: Of 512 consecutive prospective donors, 14 (2.7%) continued to have asymptomatic, microscopic hematuria over 1 month. If the medical history, physical examination, and computerized tomographic angiography were unremarkable, and if they still wished to donate, a kidney biopsy was performed. RESULTS: In two prospective donors, hematuria resolved after treatment for urinary tract infection; two others declined donation and were referred to their primary care provider. Kidney biopsy in the remaining 10 showed: two normal; four thin basement membrane nephropathy (TBMN); one nonhomogeneous basement membrane abnormalities; one IgA nephropathy, 5 of 16 glomeruli globally sclerotic; one in a patient with a family history of Schimke's Syndrome, 7 of 30 glomeruli globally sclerotic; and one TBMN and early hypertensive changes without systemic hypertension. Only 4 of the 10 who underwent kidney biopsy donated (two normal, two TBMN). CONCLUSIONS: Kidney abnormalities are common in young, otherwise healthy, prospective kidney donor candidates with persistent, asymptomatic, microscopic hematuria. A kidney biopsy is often abnormal and aids in the decision-making process.

Ki-67 immunoreactivity in the differential diagnosis of pulmonary neuroendocrine neoplasms in specimens with extensive crush artifact.

The aim of the present study was to evaluate the usefulness of immunohistochemical markers in the differential diagnosis of pulmonary neuroendocrine tumors with particular emphasis on the preservation of immunoreactivity in areas showing crush artifacts. Specimens from 9 carcinoid tumors (CTs) and 13 small cell carcinomas (SCCs) with crush artifact were stained with antibodies to Ki-67, chromogranin A, synaptophysin, and cytokeratin. The immunoreactivity was well preserved in the crushed areas. Ki-67 was expressed in the crushed areas of all SCCs. Reactivity was diffuse or at least present in 25% of the crushed areas. In contrast, the immunoreactive areas in CTs never exceeded 10%. Immunoreactivity for Ki-67, synaptophysin, chromogranin A, and cytokeratin is well preserved in tissue with crush artifacts and can be interpreted reliably. The diagnosis of SCC should be questioned if fewer than 25% of cells show reactivity for Ki-67.

Radiation treatment decreases bone cancer pain through direct effect on tumor cells.

The most used treatment for bone cancer pain is radiation; however, the mechanism responsible for analgesia after irradiation is unknown. The mechanistic influence of a single, localized 10-, 20- or 30-Gy dose of radiation on painful behaviors, osteolysis, histopathology and osteoclast number was evaluated in mice with painful femoral sarcomas. Dramatic reductions in pain behaviors (P < 0.05) and osteolysis (P < 0.0001) were seen in mice irradiated with 20 and 30 Gy. Irradiation reduced the tumor area by more than 75% (P < 0.05) but did not affect osteoclast frequency per mm2 tumor. Treatment with 20 Gy prior to tumor injection had no effect on tumor growth or pain behaviors, suggesting that radiation reduces osteolysis and pain through direct tumor effects. To demonstrate that tumor elimination was responsible for reduction in osteolysis and pain, sarcoma cells containing the suicide gene cytosine deaminase (CD) were inoculated into femora. After onset of bone cancer pain, mice were treated with the prodrug 5-fluorocytosine (5-FC). 5-FC treatment significantly reduced both osteolysis (P < 0.0005) and bone cancer pain (P < 0.05). The findings in this study demonstrate that one mechanism through which radiation decreases bone cancer pain is by direct effects on tumor cells.

Improving surgical wound healing with basic fibroblast growth factor after radiation.

OBJECTIVES/HYPOTHESIS: Delayed wound healing in surgical patients who have received previous irradiation continues to be a significant problem. We investigated whether radiation decreases basic fibroblast growth factor (bFGF) production in skin and whether supplemental bFGF can improve irradiated postsurgical soft tissue healing. STUDY DESIGN: Experimental study in the porcine skin flap model. METHODS: Pigs were subjected to orthovoltage radiation (1,300 cGy). To test whether radiation alters bFGF production in skin, semiquantitation of bFGF message was compared in irradiated and nonirradiated skin by reverse transcription-polymerase chain reaction (RT-PCR). To determine whether supplemental bFGF can improve postsurgical soft tissue healing after radiation, bFGF was given intravenously or intracuticularly preoperatively. To investigate whether additional oxygen tissue levels would modify the effects of supplemental bFGF, one test group received hyperbaric oxygen. Six weeks later, 108 skin flaps (random and arterial) were created in 27 pigs and monitored over 2 weeks. Tissues were analyzed for flap viability, vascularity, endothelial cell apoptosis by caspase-3 activation, and histologic analysis. RESULTS: Radiation statistically increased endothelial cell apoptosis in porcine skin by 650%. Radiation also significantly reduced bFGF message by 75% in porcine skin by RT-PCR analysis. Supplemental intravenous bFGF in irradiated tissue significantly increased skin flap viability by 25% compared with controls (P < .001). Intravenous bFGF also significantly reduced gastrointestinal side effects from irradiation by 50% compared with controls. BFGF treatment induced a trend to decrease endothelial cell apoptosis in irradiated skin, but this was not statistically significant. Histologically, the intravenous bFGF-treated flaps had similar cellularity, fibroblasts, and extracellular acid mucopolysaccharides as controls. When bFGF was administered by intracuticular injection with and without hyperbaric oxygen, skin flap survival and flap vascularity were similar to controls. CONCLUSIONS: Decreased local levels of bFGF in skin may play an important role in the delayed healing of irradiated wounds. Radiation appears to decrease bFGF production by significantly reducing bFGF message in irradiated tissue. Supplemental intravenous bFGF reduced irradiated soft tissue injury and improved random skin flap viability in this porcine model. More studies are needed to investigate the effects of bFGF in the surgical healing of irradiated wounds.

The mystery of the vanishing Reinke crystals.

Reinke crystals (RC) are pathognomonic of Leydig cells (LCs); they are thought to be rare in normal testes and to occur only in approximately one third of LC tumors. We noticed that crystals present in touch imprint and frozen sections of an LC tumor disappeared after tissue fixation. This phenomenon led us to hypothesize that their reported low frequency in normal and neoplastic LCs may be secondary to degradation/dissolution of the crystals after formalin fixation. Our review of the literature also led us to hypothesize that RC are better preserved after air-drying and alcohol fixation. We collected testicular samples from 21 autopsies including air-dried cytologic preparations and tissue samples that were fixed in alcohol or formalin. We found that RC are common in normal LC but dissolve rapidly in formalin and slowly and only partially in alcohol. The composition of RC is unknown; however, they have been reported to stain specifically for nestin, an intermediate filament expressed mainly in neural and muscle tissue. Because the crystals have only been described in androgen-producing cells, we hypothesized that the crystals may represent a crystallized form of androgenic hormones, hormone complexes, or enzymes involved in their synthesis. We performed immunostains for androgens and enzymes involved in androgenesis. We also performed nestin immunostain to confirm the previous study. The crystals stain specifically with antibodies anti-3ß-hydroxysteroid dehydrogenase and are negative for the remaining androgenic enzymes, androgenic hormones, and nestin.

eIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells.

Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased self-renewal, triggered DNA replication stress, and induced formation of premalignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biologic output in lactating mammary glands and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer.

The pattern of CD10 expression in selected pathologic entities of the prostate gland.

There is increasing evidence that neuropeptides, including bombesin, may influence growth, angiogenesis, invasiveness, and metastasis in prostate cancer. One of the molecules tightly involved in the regulation of neuropeptide activity is the integral membrane glycoprotein CD10, or neutral endopeptidase 24.11. The pattern of CD10 expression in hyperplastic and neoplastic conditions of the prostate gland has not been previously described. Immunohistochemical staining for CD10 and high-molecular-weight cytokeratin was performed on 92 cases of paraffin-embedded tissue from needle-core biopsy specimens and prostatectomy specimens. Normal and hyperplastic acini showed strong and distinct membrane (apical and intercellular) and cytoplasmic CD10 expression in basal and secretory cells. In contrast, no intercellular membrane or cytoplasmic staining of secretory cells was seen in any cases of adenocarcinoma with Gleason patterns 2 or 3. A subset of high-Gleason grade adenocarcinoma (patterns 4 and 5) displayed CD10 expression in the secretory cells; those cases shared a distinct morphological pattern. Prostatic intraepithelial neoplasia (PIN) showed consistent absence of intercellular membrane and cytoplasmic CD10 expression in the secretory cells, with preserved expression in basal cells. Interestingly, the basal cells in basal cell hyperplasia lacked CD10 expression, and no expression was noted in the secretory cells in all cases examined. Atrophic acini and those associated with acute and chronic inflammation retained CD10 expression. In conclusion, a consistent differential pattern of CD10 expression was seen in basal cell hyperplasia, PIN, and adenocarcinoma, suggesting a role for CD10 in the pathobiology of the prostate gland.

Pulmonary nodular lesions in bone marrow transplant recipients: impact of histologic diagnosis on patient management and prognosis.

Bone marrow transplantation is associated with numerous pulmonary complications, which may manifest as nodules. We studied 33 bone marrow transplant (BMT) recipients in whom pulmonary nodular lesions (PNLs) developed during a 5-year period and who underwent open lung biopsy (OLB) for diagnosis. Of 33 patients with PNL, 15 (45%) had pulmonary cytolytic thrombi (PCT), a recently described condition characterized histologically by occlusive vascular lesions and hemorrhagic infarcts and clinically by a favorable outcome. Clinical symptoms and radiologic abnormalities disappeared during a period of a few weeks. None of the patients died of PCT; 10 were alive at last contact. The second most common cause of PNL (8/33 [24%]) was Aspergillus infection, which was the cause of death in 6. OLB is an effective way of obtaining diagnostic tissue in BMT recipients with PNLs. Histologic examination is accurate in determining the cause of PNLs and identifying lesions that have a favorable outcome and those that require a change in treatment.

Promoting healing with recombinant human platelet-derived growth factor--BB in a previously irradiated problem wound.

OBJECTIVES/HYPOTHESIS: Persistent, poorly healing wounds are a significant clinical problem in patients who have had previous irradiation. Despite current treatments, refractory nonhealing soft tissue wounds persist. The study described one of the earliest reported uses of recombinant human platelet-derived growth factor-BB (rhPDGF) gel to improve the healing of a previously irradiated refractory dermal wound to the neck that had been present for 12 years. STUDY DESIGN: Case report and literature review. METHODS: Review of local healing management of previously irradiated wounds and review of patients chart one year after follow-up treatment. RESULTS: A 47-year-old man had a 12-year history of a persistent, painful, nonhealing full-thickness dermal wound on the left side of his neck after radiation therapy and chemotherapy for a T2N2bM0 nasopharyngeal carcinoma. He had been tumor free for 12 years. Despite multiple modalities of therapy over a 1-year period (including moist hydrogel dressings, topical and oral antibiotics, serial debridement, and hyperbaric oxygen), the wound did not heal. After 6 months of topical rhPDGF gel treatment, sufficient granulation tissue developed within the dermal wound that a split-thickness skin graft was successfully performed. Symptomatically, the patient's continuous pain at the neck resolved after rhPDGF treatment. Serial histological biopsy specimens before and after rhPDGF treatment confirmed the wound transformation from a chronic state to a short-term healing state. CONCLUSION: In previously irradiated tissue, rhPDGF can be useful in helping refractory wounds to heal by inducing further granulation formation. If such treatment is planned, the patient should be informed of the possible theoretical risks of its use when it is in proximity to a previously treated neoplastic site.