Frailty predicts outcome of partial nephrectomy and guides treatment decision towards active surveillance and tumor ablation.

PURPOSE: To examine frailty and comorbidity as predictors of outcome of nephron sparing surgery (NSS) and as decision tools for identifying candidates for active surveillance (AS) or tumor ablation (TA). METHODS: Frailty and comorbidity were assessed using the modified frailty index of the Canadian Study of Health and Aging (11-CSHA) and the age-adjusted Charlson-Comorbidity Index (aaCCI) as well as albumin and the radiological skeletal-muscle-index (SMI) in a cohort of n = 447 patients with localized renal masses. Renal tumor anatomy was classified according to the RENAL nephrometry system. Regression analyses were performed to assess predictors of surgical outcome of patients undergoing NSS as well as to identify possible influencing factors of patients undergoing alternative therapies (AS/TA). RESULTS: Overall 409 patient underwent NSS while 38 received AS or TA. Patients undergoing TA/AS were more likely to be frail or comorbid compared to patients undergoing NSS (aaCCI: p < 0.001, 11-CSHA: p < 0.001). Gender and tumor complexity did not vary between patients of different treatment approach. 11-CSHA and aaCCI were identified as independent predictors of major postoperative complications (11-CSHA ≥ 0.27: OR = 3.6, p = 0.001) and hospital re-admission (aaCCI ≥ 6: OR = 4.93, p = 0.003) in the NSS cohort. No impact was found for albumin levels and SMI. An aaCCI > 6 and/or 11-CSHA ≥ 0.27 (OR = 9.19, p < 0.001), a solitary kidney (OR = 5.43, p = 0.005) and hypoalbuminemia (OR = 4.6, p = 0.009), but not tumor complexity, were decisive factors to undergo AS or TA rather than NSS. CONCLUSION: In patients with localized renal masses, frailty and comorbidity indices can be useful to predict surgical outcome and support decision-making towards AS or TA.

B-MYB-p53-related relevant regulator for the progression of clear cell renal cell carcinoma.

PURPOSE: To investigate the mRNA expression of B-MYB and MDM2 together with their p53 relatedness in clear cell renal cell carcinoma (ccRCC). METHODS: Genes were screened for their mRNA expression from 529 patients in a publicly available ccRCC cohort (TCGA). A cohort of 101 patients with ccRCC served as validation by qRT-PCR mRNA tissue expression analysis. RESULTS: Expression: B-MYB expression was significantly higher in high-grade tumours (p < 0.0001 and p = 0.048) and in advanced stages (p = 0.005 and p = 0.037) in both cohorts. Correlation: p53-B-MYB as well as MDM2-B-MYB showed significant correlations in local and low-grade ccRCCs, but not in high grade tumours or advanced stages (r < 0.3 and/or p > 0.05). Survival: Multivariable Cox regression of the TCGA cohort revealed B-MYB upregulation and low MDM2 expression as predictors for an impaired overall survival (OS) (HR 1.97; p = 0.0003; HR 2.94, p < 0.0001) and progression-free survival (PFS) (HR 2.86; p = 0.0005; HR 1.58, p = 0.046). In the validation cohort, the results were confirmed for OS by univariable, but not multivariable regression: high B-MYB expression (HR = 3.05, p = 0.035) and low MDM2 expression (HR 3.81, p value 0.036). CONCLUSION: In ccRCC patients with high-grade tumours and advanced stages, high B-MYB expression is common and is associated with poorer OS and PFS. These patients show a loss of their physiological B-MYB-p53 network correlation, suggesting an additional, alternative regulatory, oncogenic mechanism. Assuming further characterization of its signalling pathways, B-MYB could be a potential therapy target for ccRCC.

The comprehensive complication index (CCI): proposal of a new reporting standard for complications in major urological surgery.

PURPOSE: The comprehensive complication index (CCI) is a new tool for reporting the cumulative burden of postoperative complications on a continuous scale. This study validates the CCI for urological surgery and its benefits over the Clavien-Dindo-Classification (Clavien). MATERIAL AND METHODS: Data from a prospectively maintained data base of all consecutive patients at a university care-center was analyzed. Complications after radical cystectomy (RC), radical prostatectomy (RP), and partial nephrectomy (PN) were classified using the CCI and Clavien system. Differences in complications between the CCI and the Clavien were assessed and correlation analyses performed. Sample size calculations for hypothetical clinical trials were compared between CCI and Clavien to evaluate whether the CCI would reduce the number of required patients in a clinical trial. RESULTS: 682 patients (172 RC, 297 RP, 213 PN) were analyzed. Overall, 9.4-46.6% of patients had > 1 complication cumulatively assessed with the CCI resulting in an upgrading in the Clavien classification for 2.4-32.4% of patients. Therefore, scores between the systems differed for RC: CCI (mean ± standard deviation) 26.3 ± 20.8 vs. Clavien 20.4 ± 16.7, p < 0.001; PN: CCI 8.4 ± 14.7 vs. Clavien 7.0 ± 11.8, p < 0.001 and RP: CCI 5.8 ± 11.7 vs. Clavien 5.3 ± 10.6, p = 0.102. The CCI was more accurate in predicting LOS after RC than Clavien (p < 0.001). Sample size calculations based in the CCI (for future hypothetical trials) resulted in a reduction of required patients for all procedures (- 25% RC, - 74% PN, - 80% RP). CONCLUSION: The CCI is more accurate to assess surgical complications and reduces required sample sizes that will facilitate the conduction of clinical trials.

Peroxiredoxin proteins protect MCF-7 breast cancer cells from doxorubicin-induced toxicity.

Peroxiredoxin (Prdx) proteins are thiol-specific antioxidants that protect cells from oxidative stress in many normal and disease states. There are six Prdx proteins expressed in mammals, each with a characteristic tissue expression, subcellular distribution and substrate specificity. Recent studies have revealed elevated Prdx levels in many cancers, suggesting a protective role for these proteins in cancer cell survival. The present study is the first to investigate the function of all six Prdx proteins in the MCF-7 breast cancer cell line. We show that these cells have both higher resistance to doxorubicin-induced toxicity and significantly elevated Prdx levels, compared to the non-cancer MCF-10A cells. Using transient siRNA transfections, we show that Prdx3 suppression leads to decreased MCF-7 cell survival in the absence of doxorubicin. We further demonstrate that individual suppression of four of six of the Prdx proteins leads to increased doxorubicin-induced toxicity by apoptosis. Finally, we show that clonal selection of a doxorubicin-resistant MCF-7 subline by 2-week culture in 0.1 µM doxorubicin resulted in a marked elevation in the expression of several Prdx proteins. Together, these data reveal a protective function for peroxiredoxins in MCF-7 cell survival, and suggest that Prdx overexpression in breast cancer may play a role in doxorubicin-resistance in these, and possibly other, breast cancer cells. This study is the first to investigate the function of the entire Prdx family in a breast cancer cell line.

Bubble hair.

An unusual hair dystrophy was studied by means of light and electron microscopy. Hair fibers demonstrated a boomerang deformity containing small and large "bubbles". Electron microscopy revealed a loss of cortical cells and medulla at these sites. Cross-section images showed either a single large cavity or a reticulated, "swiss cheese-like" loss of cells. These two cases represent the second and third reported cases of bubble hair deformity. We present the second light and electron microscopic study of this disorder, including new electron microscopic findings. The cause of bubble hair deformity remains obscure. The involved tufts of wiry hair resolved with gentle hair care. This suggests that trauma to the hair shaft may play a role. It is likely that additional cases of bubble hair remain unrecognized. Investigation of other patients with localized tufts of wiry hair is likely to reveal additional cases.

Studies on the cellular origin of neurothekeoma: clinical, light microscopic, immunohistochemical, and ultrastructural observations.

The clinical, histopathologic, and immunohistochemical features of 11 cases of neurothekeoma are reported. One case was examined by electron microscopy. The mean age of the patients was 27.1 years; the study comprised eight female and three male patients. Most lesions were nondescript papules and located on the upper part of the body, seven cases of neurothekeoma on the head. Eight cases were classified as cellular neurothekeoma on the basis of a striking fascicular pattern and three cases as myxomatous neurothekeoma because of prominent myxoid stromal change. All cellular neurothekeomas failed to express S-100 protein, whereas the three myxomatous types were strongly positive for this marker. Other than vimentin, there was no significant immunoreactivity with other immunohistochemical markers. Ultrastructural study of one case of cellular neurothekeoma was inconclusive for cell type although a perineurial origin could not be excluded. On the basis of these results, we conclude that cellular neurothekeoma differs from myxomatous neurothekeoma not only by clinical and histologic findings but also by immunoreactivity with S-100 protein. These findings also suggest the existence of two distinct subtypes of neurothekeoma and possible origin of the two variants of neurothekeoma from different cell types or at least variation in phenotypic expression of a common cell type. On the other hand, it cannot be excluded that these two variants are different stages in the natural history of neurothekeoma.

Iatrogenic left main coronary artery stenosis following aortic valve replacement.

A case of severe iatrogenic fibrous left main coronary artery stenosis following aortic valve replacement (Hall-Kaster prosthesis) is documented clinically, angiographically and histologically. Reported histological data of this rare complication of valve replacement are reviewed. The onset of ischaemic symptoms in the first six months after valve replacement is highly suggestive of iatrogenic coronary artery stenosis, and urgent coronary angiography is recommended.

Sporadic dysplastic nevus syndrome in a tyrosinase-positive oculocutaneous albino.

A case of dysplastic nevus syndrome in a 41-year-old tyrosinase-positive oculocutaneous albino man is presented. Clinically the patient exhibited multiple amelanotic lesions; histologic examination provided the diagnosis of dysplastic nevus syndrome. Fontana-Masson silver staining revealed the presence of melanin in the nevus cells. Hair bulbs incubated in tyrosine buffer produced melanin. This is the second reported case of dysplastic nevus syndrome in an oculocutaneous albino and the first case of dysplastic nevus syndrome in a tyrosinase-positive albino of which we are aware.

Epidermal antigen preservation with freezing.

Antigen preservation in human foreskin was evaluated after prolonged storage. Foreskin sections previously separated and stored were examined after 24 h, 6 days, 102 days, 364 days, and 493 days, using indirect immunofluorescence techniques. Each foreskin was evaluated with high-titer human antisera against bullous pemphigoid and pemphigus antigens, rabbit antiserum against laminin, and IgG murine monoclonal antibodies against OKT6, OKIa, AF-1, and Kab-3. Each section was studied and scored by three independent observers. Except for decreased fluorescent staining of pemphigus antigens, no decrease of the immunofluorescence titers was seen over the period of observation.

The spectrum of minimal deviation melanoma: a clinicopathologic study of 21 cases.

A retrospective study of 21 patients with the histopathologic diagnosis of minimal deviation melanoma (MDM; n = 18) and borderline melanoma (BM; n = 3) was undertaken to determine the prognosis for these patients compared with that for patients with other types of malignant melanoma. The findings indicate that the prognosis for these uncommon nevomelanocytic tumors is somewhat better than that for other malignant melanomas. Follow-up periods in this series ranged from 18 to 96 months (mean, 57 months). Primary lesions ranged in thickness from 1.6 to 10.4 mm. The histopathologic subtypes included the Spitz variant (nine patients), the spindle cell variant (six patients), the combined spindle and epithelioid cell type (three patients), and the small epithelioid cell type (three patients). Only two of the patients died of widespread metastatic disease. Comparison of the histologic and clinical prognostic indicators of mortality in patients who have malignant melanoma with the clinical and pathologic features seen in this series of 21 patients would appear to indicate a diminished tendency toward metastatic or recurrent disease in patients with MDM and BM.

Pre-Kaposi's sarcoma.

Clinically uninvolved skin in a homosexual patient with acquired immunodeficiency syndrome and Kaposi's sarcoma showed abnormal vascular proliferation (pre-Kaposi's sarcoma). The diagnostic and therapeutic implications of this finding are discussed.

Cat-scratch disease. Bacteria in skin at the primary inoculation site.

Cat-scratch disease is a zoonotic infection characterized by a skin papule at the site of the scratch followed by regional lymphadenitis. Recently, small gram-negative pleomorphic bacilli were demonstrated in sections of lymph node from patients with the disease. We now report identical bacteria in the primary inoculation site of three patients with cat-scratch disease. Lymph nodes from two of these patients also contained the same bacilli. Identical bacteria in both skin and lymph nodes from these patients are further evidence that the bacilli are the cause of cat-scratch disease. In early infections, biopsy of the primary site of inoculation and demonstration of bacilli may replace excision and histologic examination of lymph node in establishing the diagnosis of cat-scratch disease.

Papular polymorphous light eruption. Fibrin, complement, and immunoglobulin deposition.

Biopsy specimens of papules taken from eight patients with polymorphous light eruption ( PMLE ) were examined by a direct immunofluorescence technique. Extensive intervascular and focal perivascular deposits of fibrin were detected in each case. Slight vascular deposition of C3 and IgM were observed in five and two patients, respectively. The lupus band test was negative in all cases. The findings suggest that venular injury with activation of the clotting system is involved in the development of lesions in PMLE .

Immunopathology of pityriasis lichenoides acuta.

Eleven biopsy specimens (five papules and six dusky or crusted lesions) from four patients with pityriasis lichenoides et varioliformis acuta ( PLEVA ) were studied by direct immunofluorescence and immunoperoxidase technics. Slight vascular deposits of IgM and C3 were present in most lesions. Slight perivascular deposits of fibrin were observed in early lesions; more extensive perivascular and interstitial deposits of fibrin were detected in advanced lesions. Most of the infiltrating cells were T lymphocytes; cells with cytotoxic/suppressor phenotype (T8-positive) were generally more numerous than cells with helper/inducer phenotype (Leu-3a-positive, T4-positive). A marked increase in epidermal T8-positive cells over epidermal Leu-3a/T4-positive cells was found in late lesions. Moreover, a reduction of the ratio of circulating T4-positive to T8-positive cells was observed in most cases. The number of epidermal T6-positive (Langerhans/indeterminate) cells was decreased in the lower as compared with the upper stratum spinosum. About 5% of perivascular infiltrating cells were T6-positive. These results suggest that cell-mediated immune mechanisms are probably important in the pathogenesis of PLEVA .

Metastasis of solid tumors in extraocular muscles.

Three autopsy cases with discrete metastatic involvement of one or several extraocular orbital muscles by disseminated amelanotic melanoma (one case) and lobular mammary adenocarcinoma (two cases) associated with extensive meningeal involvement are reported. Clinical ocular symptoms including pain, exophthalamus, and diplopia occurred 6 months to almost 5 years after resection of the primary tumor; in two cases CT scan showed spindle-like enlargement of orbital muscles. Pathologic examination disclosed solid localized metastatic deposits in several extraocular muscles of one (breast carcinomas) or both orbits (melanoma), with diffuse invasion of striated muscle, but without necrosis, inflammation, or involvement of other orbital adnexa, eye ball, optic nerves, or orbital bone. Since no continuous invasion of orbital or intraocular structures by diffuse meningeal blastomatosis was histologically observed, rare metastatic involvement of extraocular muscles via hematogenic route is suggested.

Minimal deviation melanoma: a histologic variant of cutaneous malignant melanoma in its vertical growth phase.

Minimal deviation melanomas are uncommon nevomelanocytic tumors of indeterminate risk that appear as pigmented or nonpigmented skin nodules and are clinically diagnosed as Spitz nevi, hemangiomas, or malignant melanomas. They are characterized histologically by expansile growth in the papillary dermis with reticular dermal infiltration (minimal deviation type) or without reticular dermal invasion (borderline type). The tumors exhibit lesser cytologic atypia in their vertical growth phase (histologic variance) than observed in common forms of melanoma. A retrospective study of outcome in 21 patients with minimal deviation melanoma (mean tumor thickness by Breslow's measurement = 3.6 mm) disclosed recurrent disease in only 3 patients after a mean observation period of 57 months, supporting the impression that these tumors are not as biologically aggressive as common malignant melanomas. The histologic subtypes of minimal deviation melanoma are reviewed along with a discussion of the concept of histologic variance.

Multiple agminated spindle cell nevi: unique clinical presentation and review.

A boy with agminated spindle cell nevi is described. Present within the area of involvement were congenital nevocellular and composite spindle/nevocellular nevi. Other unusual features included a dynamic pattern of growth and regression of the lesions, with the presence of halo nevi and background café au lait pigmentation. This unique presentation of multiple nevi is discussed in the context of previous reports of agminated spindle cell nevi.

T6 is superior to Ia (HLA-DR) as a marker for Langerhans cells and indeterminate cells in normal epidermis: a monoclonal antibody study.

Previous studies in our laboratory using immunoelectron microscopy have shown that anti-T6 monoclonal antibody reacts with all epidermal Langerhans cells in normal skin. Comparison of the number of T6-positive (+) epidermal cells with Ia (HLA-DR) (+) cells, as defined by the monoclonal antibodies, anti-I1 and anti-I2, disclosed that these latter markers significantly underestimated Langerhans cell and indeterminate cell numbers (p less than 0.01 and p less than 0.001, respectively) when employed in a sensitive 4-step immunoperoxidase procedure. Thus, it appears that all epidermal Langerhans cells and indeterminate cells are not Ia-positive as defined in this system and that Ia(+)/T6(+) and Ia(-)/T6(+) subsets exist. These subsets may be analogous to the Ia(+) and IA(-) subsets of macrophages, in which the former are responsible for antigen interaction with T cells.