Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is ∼99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

Coal ash poultice: an unusual cause of a chemical burn.

Burns from seemingly innocuous substances are rare, probably underrecognized and typically present late. We describe a case of a child who sustained a full-thickness burn after an application of a coal ash poultice for ankle pain. This case report highlights a rare cause of a chemical burn that may become more common with increasing use of traditional remedies worldwide.

Phase II trial of neoadjuvant nab-paclitaxel in high risk patients with prostate cancer undergoing radical prostatectomy.

PURPOSE: Taxane based chemotherapy has activity in advanced prostate cancer but previous studies of neoadjuvant docetaxel demonstrated a prostate specific antigen response with no obvious antitumor activity. The efficacy and safety of neoadjuvant albumin-bound paclitaxel (nab-paclitaxel, Abraxane), a novel nanoparticle based formulation, were assessed in patients with high risk, locally advanced prostate cancer. MATERIALS AND METHODS: Eligible patients had locally advanced prostatic adenocarcinoma, clinical stage cT2b or greater, Gleason score 8 or greater, or serum prostate specific antigen 15 ng/ml or greater without metastatic disease. Patients received 2 cycles of 150 mg/m(2) nab-paclitaxel weekly for 3 weeks during each 4-week cycle, followed by radical prostatectomy with bilateral lymphadenectomy. Efficacy assessments included pathological and prostate specific antigen response. RESULTS: A total of 19 patients completed neoadjuvant therapy and 18 underwent radical prostatectomy. Median pretreatment prostate specific antigen was 8.5 ng/ml and median Gleason score was 8. Despite the lack of complete pathological responses 5 of 18 patients (28%) had organ confined disease and 9 of 18 (50%) had specimen confined disease. Post-chemotherapy prostate specific antigen was decreased in 18 of 19 (95%) patients and median decrease was 2.9 ng/ml (35%, p <0.001). An initial prostate specific antigen after radical prostatectomy of 0.02 ng/ml or less was achieved in 17 of 18 (94%) patients. There were no significant perioperative complications. Cytoplasmic vacuolization (focal in 10 and extensive in 7) was evident in all but 1 patient (94%). Ten patients (56%) had grade 3 and 1 had grade 4 neutropenia with no febrile neutropenia. CONCLUSIONS: Neoadjuvant nab-paclitaxel was well tolerated. Similar to our experience with neoadjuvant docetaxel there were no pathological complete responses, although a possible histological antitumor effect was observed.

Patterns of contraction in human full thickness skin grafts.

It is taught that full thickness skin grafts contract minimally in humans. We aimed to examine this assumption. In a prospective study, a scale photograph of each of 54 human full thickness skin grafts was taken at operation once the graft had been inset, but before the application of any tie-over or other dressing. For 50 grafts, a subsequent scale photograph was taken at follow-up (mean 111 days post-operation). The photographs were digitised and the areas of the grafts recorded. Significant area reduction in human full thickness skin grafts was found (P< 0.01, mean area change -38%). Greater contraction was associated with infection than without (P = 0.02, mean area change with infection -48%, without infection -33%). Full thickness skin grafts applied to the peri-orbital area and nose contracted more than those applied to the scalp and temples (P = 0.002). No differences in contraction were found between donor sites, between methods of fixation, between males and females or between those taking no medication and those taking steroids or non-steroidal anti-inflammatory medication. Area change did not correlate with initial graft area, patient age or time to second photograph.

Technique of percutaneous anchoring suture placement.

We describe a technique to assist in the placement of percutaneous anchoring sutures when used in poorly accessible tunnels such as in rhinoplasty by using a sucker tube to guide retrieval and placement of the suture needle. This technique avoids unintended catching of the needle on soft tissue within the tunnel, which could prevent the structure from becoming anchored at other than in its intended location.

Methicillin-resistant Staphylococcus aureus in burns patients--why all the fuss?

Procedures designed to limit spread of methicillin-resistant Staphylococcus aureus (MRSA) in burns units demand time and resources. To assess the significance of MRSA in burns patients we performed a retrospective review of MRSA colonization in in-patients over a 41-month period at the North Trent Sub-regional Burns Unit. Patients were compared with MRSA free controls, matched for age and percentage body surface area (BSA) burn and admitted during the same time period. Length of stay, number of operations and deaths were outcome indicators. All patients managed non-operatively were excluded, leaving 40 MRSA patients and 46 controls. There was no statistical difference between the two groups with regard to number of operations (p= 0.07), duration of admission (p = 0.12) or mortality (p = 0.09). Of the control group, 83% had wound swabs positive for methicillin-sensitive Staphylococcus aureus (MSSA). there was no statistical difference in any outcome variables between this sub-group of controls and MRSA patients. Colonization with S. aureus (both MRSA and MSSA) was associated with larger burns (p<0.05), twice as many operative procedures (p<0.05) and prolonged admissions (p<0.01). Mortality was unaltered by staphylococcal colonization (p = 0.8). Although our study lacks power, we would suggest that methicillin resistance per se is not associated with increased morbidity or mortality in burns patients.

Human immunodeficiency virus infection of human bone derived cells.

Human immunodeficiency virus infection of a human bone derived cell line was initiated by either cell free virus or with a cell to cell transmission method. The human bone derived cells were examined for 8 weeks, and virus infection was not detected when assessed by microscopy, immunofluorescence, reverse transcriptase activity, or infection of cocultivated human T lymphoid cells susceptible to human immunodeficiency virus. Polymerase chain reaction analysis of human bone derived cells inoculated with the cell to cell infection format showed less than 0.1% infected cells. It is possible that the infected cells detected by polymerase chain reaction were lymphocytes used in the cell to cell infection format. Alternatively, latent infection may have been established in the bone derived cells with no apparent expression of the proviral genome. A large proportion of bone is represented by human bone derived cells, and it is unlikely that bone will contribute to a significant human immunodeficiency virus reservoir in vivo. The blood of bone allograft donors is likely to have a greater virus bioburden than is bone. Methods to sterilize bone should be assessed by their efficacy to inactivate the virus in blood contaminating the graft, and methods to detect human immunodeficiency virus deoxyribonucleic acid in a bone graft may be less sensitive than examining the donor's blood.

Initiation of reverse transcription during cell-to-cell transmission of human immunodeficiency virus infection uses pre-existing reverse transcriptase.

H3B cells, a laboratory clone of H9 cells persistently infected with the HTLV-IIIB strain of human immunodeficiency virus (HIV), contained significant levels of cell-associated reverse transcriptase (RT) activity measured by in vitro assays using either exogenous or endogenous templates. The cell-associated RT activity detected using exogenous template was almost wholly in a soluble (non-sedimentable) form whereas endogenous activity sedimented as a particulate structure associated with viral RNA. Despite this, H3B cells did not contain episomal HIV DNA detectable by Southern blot, indicating that in vivo reverse transcription was not occurring to any significant extent in these cells. However, when susceptible HUT 78 cells were infected by co-cultivation with H3B cells, dramatic synthesis of episomal HIV DNA occurred. Concurrently with this de novo initiation of reverse transcription, however, we found no detectable change in intracellular levels or cleavage profiles of immunoprecipitable RT polypeptides. Finally, actinomycin D pre-treatment of H3B cells to prevent de novo transcription from donor cell proviral DNA after co-cultivation did not affect the initiation of in vivo reverse transcription following cell-to-cell HIV infection. These results demonstrated that cells persistently infected with HIV contained significant fully cleaved cell-associated RT in a form that was active in vitro but not in vivo and that following cell-to-cell transmission of HIV infection to susceptible cells, de novo reverse transcription was initiated without detectable evidence of further synthesis or proteolytic processing of HIV RT. The nature of this initiation process requires further study.

Sterilization of HIV by gamma irradiation. A bone allograft model.

A human immuno-deficiency virus (HIV) infected bone allograft model has been created using HTLV-IIIB virus in a concentration simulating a massively HIV infected bone allograft donor [HTLV-III is the denomination initially given to the human immuno-deficiency by the american team of Prof. Gallo. It represent the virus HIV 1 of the present international nomenclature]. 5 x 10(4) tissue culture infective doses per ml. of virus were placed within the medullary cavity of bovine femora and tibiae with a radiation dosimeter, and the ends sealed with lead. The bone/virus model was maintained at -70 degrees C while being irradiated with 1 to 4 megarads of gamma irradiation in increments of 0.5 megarads. The study showed that the HTLV-IIIB virus is a relatively radio-resistant organism, a property common to most viruses. The results suggest that HTLV-IIIB can be inactivated in bone infected with a clinically significant viral load, as may be found in donors who are initially negative when screened for HIV. It is recommended that bone allografts which are secondarily sterilized by gamma irradiation receive at least 2.5 megarads. The amount of radiation absorbed by the bone cortex was minimal.

Double-stranded strong-stop DNA and the second template switch in human immunodeficiency virus (HIV) DNA synthesis.

Synthesis of unintegrated retroviral DNA via reverse transcription is thought to involve two separate template switches. Minus-strand strong-stop DNA, a major product of in vitro reactions using detergent-treated virions, is synthesized prior to the first template switch. Plus-strand strong-stop DNA, which is found base-paired to near full-length minus-strand DNA in infected cells, is believed to be synthesized before the second template switch. Using a synchronized, one-step HIV infection model, we report here the detection in acutely infected cells of a novel double-stranded strong-stop HIV DNA with a discrete length of approximately 650 base pairs, commencing at or near the left hand end of the right-hand U3 region of the HIV long terminal repeat. The plus-strand of this double-stranded strong-stop DNA possesses the primer binding site sequence and appears to be synthesized prior to the completion of the synthesis of its complementary minus-strand. In contrast, the minus-strand of the double-stranded strong-stop DNA lacks the primer binding site sequence after RNaseH digestion. We propose that a transient free plus-strand strong-stop DNA is released from its template by displacement synthesis and subsequently used as template for the synthesis of its complementary minus-strand. The proposed transient free plus-strand strong-stop DNA may also mediate the second template switch.

De novo reverse transcription is a crucial event in cell-to-cell transmission of human immunodeficiency virus.

The proposal that replication of human immunodeficiency virus type 1 (HIV-1), mediated by cell-to-cell transmission of the virus, might bypass de novo reverse transcription was tested by using one-step cell-to-cell and cell-free virus infection systems. Two well characterized reverse transcriptase (RT) inhibitors, azidothymidine at 20 microM and phosphonoformic acid at 100 micrograms/ml, blocked HIV replication completely following both cell-free virus and cell-to-cell transmission infection, as determined from the kinetics of unintegrated viral DNA synthesis and supernatant RT production after virus infection. Our results confirm that de novo reverse transcription is a crucial and mandatory event in HIV-1 replication following cell-to-cell transmission of the virus.