Evaluation of measurable residual disease in multiple myeloma by multiparametric flow cytometry: Current paradigm, guidelines, and future applications.

Multiple myeloma (MM) is a heterogeneous group of mature B-cell diseases that are typically characterized by the presence and accumulation of abnormal plasma cells (PCs), which results in the excess production of monoclonal immunoglobulin and/or light chain found in the serum and/or urine. Multiparametric flow cytometry (MFC) is an indispensable tool to supplement the diagnosis, classification and monitoring of the disease due to its high patient applicability, excellent sensitivity and encouraging results from various clinical trials. In this regard, minimal or, more appropriately, measurable residual disease (MRD) negativity by MFC has been recognized as a powerful predictor of favourable long-term outcomes. Before flow cytometry can be effectively implemented in the clinical setting for MM MRD testing, sample preparation, panel configuration, analysis and gating strategies must be optimized to ensure accurate results. This manuscript will discuss the current consensus guidelines for flow cytometric processing of samples and reporting of results for MM MRD testing. We also discuss alternative approaches to detect plasma cells in the presence of daratumumab treatment. Finally, there is a lack of information describing the subclonal distribution of myeloma cells based on their protein expression. The advent of high-dimensional analysis may assist in following the evolution of antigen expression patterns on abnormal plasma cells in patients with relapsed/refractory disease. This in turn can help identify clonal subtypes that are more aggressive for potential informed decision. An analysis using t-SNE to identify the emergence of PCs subclones by MFC, along with the analysis of their immunophenotypic profiles are presented as a future perspective.

dPCR application in liquid biopsies: divide and conquer.

Introduction: Precision medicine is already a reality in oncology, since biomarker-driven therapies have clearly improved patient survival. Furthermore, a new, minimally invasive strategy termed 'liquid biopsy' (LB) has revolutionized the field by allowing comprehensive cancer genomic profiling through the analysis of circulating tumor DNA (ctDNA). However, its detection requires extremely sensitive and efficient technologies. A powerful molecular tool based on the principle of 'divide and conquer' has emerged to solve this problem. Thus, digital PCR (dPCR) allows absolute and accurate quantification of target molecules.Areas covered: In this review we will discuss the fundamentals of dPCR and the most common approaches used for partition of samples and quantification. The advantages and limitations of dPCR will be mentioned in the context of LB in oncology.Expert opinion: In our opinion, dPCR has proven to be one of the most sensitive methods available for LB analysis, albeit some aspects such as its capacity of multiplexing and protocol standardization still require further improvements. Furthermore, the increasing sensitivities and lower costs of next generation sequencing (NGS) methods position dPCR as a confirmatory and complementary technique for NGS results which will likely prove to be very useful for treatment monitoring and assessing minimal residual disease.

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia.

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph- adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph- adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at www.clinicaltrials.gov as # NCT01540812.

Measuring the density of iodine depositions: Detecting an invisible residual tumor after conventional transarterial chemoembolization.

PURPOSE: The purpose of this study is to evaluate the use of density measurements in the diagnosis of an underlying residual tumor beyond iodine depositions after Lipiodol-based conventional transarterial chemoembolization (cTACE). METHOD AND MATERIALS: Thirty follow-up CT scans of 20 patients 6-12 weeks after Lipiodol-based cTACE, receiving a digital subtraction angiography at the same time, were analyzed. Reference for the detection of a residual tumor was the angiography, and a visible contrast enhancement was categorized as a residual tumor (n = 16 with residual tumor; n = 14 without residual tumor). The density of the iodine depositions was measured in all containing slices in non-contrast-, arterial- and portal venous-phase CT scans, with a slice thickness of 5.00 mm. The mean density of the iodine deposition during the portal venous phase was subtracted from the mean density of the arterial phase to calculate the density changes (a positive enhancement score represents washout in the portal venous phase). In addition, a quotient relating to the non-contrast measurement was evaluated. RESULTS: Patients with a residual tumor displayed significantly higher enhancement scores in favor of density reduction between the arterial and portal venous phases, compared to patients without a residual tumor (1.41 ± 3.59, n = 14 vs. -13.97 ± 2.88, n = 16; p-value < 0.01). Furthermore, 87.75% of patients with an enhancement score higher than -1.00 (n = 9) had a residual tumor, whereas 100.00% of patients with an enhancement score lower than -20.00 (n = 6) were shown to be tumor-free. The enhancement score quotient resulted in similar findings. CONCLUSION: After cTACE in patients with hepatocellular carcinoma (HCC), the presence of a viable tumor correlated with enhancement scores based on the density measurements of iodine depositions in different phases of the CT scan. Low enhancement scores were associated with completely treated tumors and can aid the decision process to avoid possibly unnecessary angiographies.

Photodegradable CuS SERS Probes for Intraoperative Residual Tumor Detection, Ablation, and Self-Clearance.

Surface-enhanced Raman scattering (SERS) probes have exhibited great potential in biomedical applications. However, currently reported SERS probes are mainly fabricated by nondegradable Au or Ag nanostructures, which are not favorably cleared from the imaged tissues. This bottleneck hinders their in vivo applications. We herein explore a degradable SERS probe consisting of hollow CuS nanoparticles (NPs) to circumvent the current limitation. We identify, for the first time, the Raman enhancement effects of hollow CuS NPs as a SERS probe for Raman imaging of residual tumor lesions. Uniquely, CuS SERS probes are degradable, which stems from laser-induced photothermal effects of CuS NPs, leading to their disintegration from shell structures into individual crystals, thus facilitating their self-clearance from imaged tissues. This novel CuS SERS probe with photodegradation characteristics opens avenues for applying Raman imaging toward a myriad of biomedical applications.

Sorafenib as a Salvage Therapy in FLT3-ITD Negative Relapse/ Refractory Acute Myeloid Leukemia.

BACKGROUND: Multi-kinase inhibitor sorafenib showed dramatic effects in acute myeloid leukemia (AML) cells harboring fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation. However, FLT3-ITD mutation only occurs in 25% of AML cases. The therapeutic effects of sorafenib in AML patients without FLT3-ITD are still in need of further investigation. METHODS: A young AML patient with central nervous system (CNS) relapse was treated with sorafenib combined with chemotherapy. Another patient with refractory AML arising form chronic myelomonocytic leukemia (CMML) was treated with sorafenib monotherapy. Spinal and cranial magnetic resonance imaging (MRI), minimal residual disease (MRD) and peripheral blood cell count were monitored to evaluate disease status. RESULTS: The patient with CNS relapse exhibited significant shrink of tumor volume. The other patient with refractory AML achieved hematological improvements. CONCLUSION: These two cases suggested that sorafenib might be utilized as a potent salvage therapy for some refractory/relapsed AML patients without the FLT3-ITD mutation.

Enfermedad Mínima Residual en leucemia: rompiendo el paradigma de remisión completa / Residual minimal disease: breaking the paradigm of complete remission

Las malignidades hematológicas constituyen un grupo heterogéneo de condiciones. La enfermedad mínima residual (EMR) hace referencia a la presencia de enfermedad maligna hematológica, en pacientes que se encuentran en remisión según análisis convencionales. La EMR ha mostrado tener importancia pronóstica en condiciones como: leucemia mieloide aguda, leucemia mieloide crónica, mieloma múltiple, y en leucemia linfoide aguda y crónica. La detección ultrasensible de este estado podría permitir una mejor estratificación del riesgo y de igual forma abrir oportunidades para intervenciones terapéuticas tempranas. En el siguiente artículo se realiza una breve revisión acerca de la importancia pronóstica de la EMR en diferentes malignidades hematológicas(AU)

Hematological malignancies constitute a heterogeneous group of conditions. Residual minimal disease (RMS) refers to the presence of haematological malignancy in patients who are in remission if conventional pathological analyzes are used. RMS has been shown to have prognostic significance in conditions such as: acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, and acute and chronic lymphoblastic leukemia. Ultrasensitive detection of this condition could allow a better risk stratification and open opportunities for early therapeutic interventions. In the following article there will be a brief review about the prognostic importance of RMS in different hematologic malignancies(AU)

Barking up the right tree: advancing our understanding and treatment of lymphoma with a spontaneous canine model.

PURPOSE OF REVIEW: Spontaneous lymphoma in pet dogs is increasingly recognized as an ideal model for studying the disease in humans and for developing new targeted therapeutics for patients. Increasing interest by funding agencies, the private sector, and multidisciplinary academic collaborations between different disciplines and sectors now enables large knowledge gaps to be addressed and provides additional proof-of-concept examples to showcase the significance of the canine model. RECENT FINDINGS: The current review addresses the rationale for a canine lymphoma model including the valuable role it can play in drug development, serving as a link between mouse xenograft models and human clinical trials and the infrastructure that is now in place to facilitate these studies. Research in this field has focused on filling in the gaps to make the canine lymphoma model more robust. These advances have included work on biomarkers, detection of minimal residual disease, expansion of genomic and proteomic data, and immunotherapy. SUMMARY: Incorporating pet dogs into the drug development pipeline can improve the efficiency and predictability of preclinical models and decrease the time and cost required for a therapeutic target to be translated into clinical benefit.

Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: prognostic factors and clinical outcomes.

This study investigated the prognostic factors and clinical outcomes of preemptive chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion (Chemo-DLI) according to minimal residual disease (MRD) status in patients with acute leukemia and myelodysplastic syndromes who received allogeneic hematopoietic stem cell transplantation (HSCT) (n = 101). Patients received immunosuppressive drugs to prevent graft-vs.-host disease (GVHD) after Chemo-DLI. The 3-yr cumulative incidences of relapse, non-relapse mortality, and disease-free survival (DFS) after HSCT were 39.5%, 9.6%, and 51.7%, respectively. The cumulative incidences of relapse and DFS were significantly poorer in patients who exhibited early-onset MRD. Forty-four patients turned MRD negative 1 month after Chemo-DLI; their cumulative incidences of relapse and DFS were significantly better than those with persistent MRD 1 month after preemptive Chemo-DLI (relapse: 19.8% vs. 46.8%, P = 0.001; DFS: 69.6% vs. 46.4%, P = 0.004). The cumulative incidences of relapse and DFS after HSCT were significantly better in patients with chronic GVHD (cGVHD) than those without cGVHD (relapse: 19.6% vs. 63.7%, P < 0.001; DFS: 74.4% vs. 23.8%, P < 0.001). Early-onset MRD, persistent MRD after Chemo-DLI, and non-cGVHD after Chemo-DLI, which were associated with increased relapse and impaired DFS, suggest unsatisfactory response to preemptive Chemo-DLI.

11C-colina PET/TAC y RM multiparamétrica en la recidiva bioquímica del cáncer de próstata / 11C-choline PET/CT and multiparametric MRI in patients with biochemical relapse of prostate cancer

Problema clínico con casuística: Comparar la utilidad diagnóstica de la PET/TC con 11C-colina y la RM multiparamétrica en la detección de la recidiva del cáncer de próstata a nivel pélvico. Hemos estudiado retrospectivamente 21 pacientes con antecedente de cáncer de próstata, tratados inicialmente con cirugía (n = 12) o radioterapia (n = 9), que presentaban elevación del PSA (poscirugía 0,3-3,6 ng/ml; posradioterapia 2,4-8,8 ng/ml). A todos ellos, en un periodo de tiempo inferior a 15 días, se les realizó: estudio PET/TC «doble fase» de cuerpo completo, inmediatamente tras la administración de11C-colina (296 ± 29 MBq) y RM prostática multiparamétrica, empleando secuencias anatómicas, estudio de difusión y estudio dinámico tras la administración de contraste intravenoso paramagnético. A partir de nuestros resultados, a todos ellos se les realizó estudio diagnóstico dirigido y/o seguimiento clínico, analítico y de imagen. En 15 pacientes (71,4%) ambas exploraciones fueron concordantes, 4 negativas y 11 positivas: 7 recidivas locales, 3 adenopatías pélvicas únicas (2 infracentimétricas), una recidiva local y una M1 ósea única. En 6 pacientes (28,6%) ambas exploraciones fueron discordantes: 3 recidivas locales identificadas en la RM y sin significación en la PET, una recidiva local identificada en la PET sin significación en la RM y 2 M1 óseas identificadas en la PET fuera del campo de RM. Comentario: La PET/TC con 11C-colina y la RM multiparamétrica tienen un papel complementario para la detección de recidiva local del cáncer de próstata, con sensibilidad similar para la detección de inflitración ganglionar. La PET/TC con 11C-colina, como técnica de cuerpo completo, permite la estadificación ósea

Clinic problem and case series: To assess the diagnostic usefulness of 11C-choline PET/CT vs. multi-parametric MRI in the prostate cancer relapse. A retrospective study of 21 patients with prostate cancer treated initially with surgery (n = 12), radiotherapy (n = 9). PSA levels were increased (post-surgery: .3-3.6 ng/ml; post-radiotherapy: 2.4-8.8 ng/ml). In an interval of time of 15 days all patients were underwent to: whole-body-dual-modality PET-CT carried out early after 11C-choline (296 ± 29 MBq) injection, and multiparametric prostate MRI with paramagnetic intravenous contrast (using anatomical imaging sequences, diffusion-weighted imaging and dynamic contrast-enhanced imaging). On the basis of our results, all patients were underwent to directed diagnosis and/or clinical, analytic and imaging follow-up. In 15 patients (71.4%) both procedures showed concordant results: 4 negative and 11 positive cases [7 local recurrences, 3 isolated pelvic lymph nodes (2 infracentimetric), 1 local relapse and only one M1 bone metastases]. The results were discordant in 6 patients (28.6%): 3 local relapses in MRI with no PET significance, 1 local relapse in PET with no MRI significance. 2 bone metastases were identified with PET (out of the field-of-view of MRI). Coment 11C-choline PET/CT and multi-parametric MRI play a complementary role in the detection of local relapse in prostate cancer patients, with similar sensitivity for the detection of lymph involvement. Whole-body 11C-choline PET/CT technique is also useful for bone staging

Indication and limitations of endoscopic extended transsphenoidal surgery for craniopharyngioma.

The transsphenoidal approach has been utilized in intrasellar craniopharyngioma surgeries. However, the advent of endoscopic extended transsphenoidal approach (EETSA) has expanded its indication to suprasellar craniopharyngiomas. We compared the indication and limitations of EETSA to those of unilateral basal interhemispheric approach (UBIHA), which presents similar indications for surgery. We analyzed 30 patients with tumors located below the foramen of Monro and the lateral boundary extending slightly beyond the internal carotid artery (UBIHA: N = 18; EETSA: N = 12). Postoperative magnetic resonance imaging (MRI) revealed gross total resection in 10 patients in the EETSA group (83.3%) and 12 in the UBIHA group (66.7%). Postoperative MRI in the EETSA group revealed residual tumor at the cavernous sinus in one patient, at the prepontine in one; in the UBIHA group, residual tumors were located in the retrochiasmatic area in two patients, infundibulum-hypothalamus in one, on the stalk in one, and in the intrasellar region in two. No intergroup differences were observed in the preservation of pituitary function and postoperative improvement of visual function. The extent of resection was better with EETSA than with UBIHA. EETSA is considered the first-line therapy because the distance between the optic chiasm and the superior border of the pituitary is large; the lateral extension does not go beyond the internal carotid artery; and the tumor does not extend inferiorly beyond the posterior clinoid process. However, in patients showing poorly developed sphenoid sinuses or pituitary stalks anterior to the tumor, surgery is difficult regardless of the selection criteria.

Prognostic nomograms to predict oncological outcome of thyroid cancers.

CONTEXT: Thyroid cancers represent a conglomerate of diverse histological types with equally variable prognosis. There is no reliable prognostic model to predict the risks of relapse and death for different types of thyroid cancers. OBJECTIVE: The purpose of this study was to build prognostic nomograms to predict individualized risks of relapse and death of thyroid cancer within 10 years of diagnosis based on patients' prognostic factors. DESIGN: Competing risk subhazard models were used to develop prognostic nomograms based on the information on individual patients in a population-based thyroid cancer cohort followed up for a median period of 126 months. Analyses were conducted using R version 2.13.2. The R packages cmprsk10, Design, and QHScrnomo were used for modeling, developing, and validating the nomograms for prediction of patients' individualized risks of relapse and death of thyroid cancer. SETTING: This study was performed at CancerCare Manitoba, the sole comprehensive cancer center for a population of 1.2 million. PATIENTS: Participants were a population-based cohort of 2306 consecutive thyroid cancers observed in 2296 patients in the province of Manitoba, Canada, during 1970 to 2010. MAIN OUTCOME MEASURES: Outcomes were discrimination (concordance index) and calibration curves of nomograms. RESULTS: Our cohort of 570 men and 1726 women included 2155 (93.4%) differentiated thyroid cancers. On multivariable analysis, patient's age, sex, tumor histology, T, N, and M stages, and clinically or radiologically detectable posttreatment gross residual disease were independent determinants of risk of relapse and/or death. The individualized 10-year risks of relapse and death of thyroid cancer in the nomogram were predicted by the total of the weighted scores of these determinants. The concordance indices for prediction of thyroid cancer-related deaths and relapses were 0.92 and 0.76, respectively. The calibration curves were very close to the diagonals. CONCLUSIONS: We have successfully developed prognostic nomograms for thyroid cancer with excellent discrimination (concordance indices) and calibration.

Adjuvant chemoradiotherapy after curative resection for extrahepatic bile duct cancer: a long-term single center experience.

OBJECTIVES: To analyze the outcome of adjuvant chemoradiotherapy for patients with extrahepatic bile duct (EHBD) cancer, and to identify the prognostic factors for these patients. METHODS: Between January 1995 and December 2002, 86 patients with adenocarcinoma of EHBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 59 male and 27 female patients, and median age was 59 years (range, 34 to 73 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/d) was given on day 1 to 3 of each split course. The median follow-up period was 83 months for survivors. RESULTS: Forty-eight patients failed the treatment: locoregional recurrence in 20, distant metastasis in 38, and both locoregional and distant relapses in 10 patients. Five-year locoregional relapse-free survival rate was 70.3%. On multivariate analysis, resection margin status was the only significant prognosticator (P=0.0299). Five-year distant metastasis-free survival rate was 53.6%. Three or more involved lymph nodes had an adverse impact on distant metastasis-free survival (P=0.0334). Five-year overall survival rate was 44.7%, and poorly differentiated tumor was associated with inferior overall survival (P=0.0297). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival in patients with EHBD cancer. Resection margin status, number of involved lymph nodes, and histologic differentiation are associated with locoregional relapse, distant metastasis, and overall survival, respectively. Distant metastasis was the major pattern of failure, possibly due to the increased locoregional control by use of adjuvant chemoradiotherapy. Intensification of systemic treatment is warranted.

Is a nadir bone marrow required and, if so, what to do with residual disease?

Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) treatment state that bone marrow biopsies should be completed 7-10 days after completion of chemotherapy. Treatment decisions change based on cellularity of that biopsy. Several studies show that bone marrow aspirates at nadir can be used to predict complete remission (CR) and overall survival. Many groups have attempted to modify induction regimens based on results of bone marrow biopsies with mixed results. This paper will review the current literature on using bone marrow biopsy to prognosticate and guide treatment for AML patients.

Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study.

PURPOSE: In 10-24% of patients with rectal cancer who are treated with neoadjuvant chemoradiation, no residual tumor is found after surgery (ypT0). When accurately selected, these complete responders might be considered for less invasive treatments instead of standard surgery. So far, no imaging method has proven reliable. This study was designed to assess the accuracy of diffusion-weighted MRI (DWI) in addition to standard rectal MRI for selection of complete responders after chemoradiation. METHODS: A total of 120 patients with locally advanced rectal cancer from three university hospitals underwent chemoradiation followed by a restaging MRI (1.5T), consisting of standard T2W-MRI and DWI (b0-1000). Three independent readers first scored the standard MRI only for the likelihood of a complete response using a 5-point confidence score, after which the DWI images were added and the scoring was repeated. Histology (ypT0 vs. ypT1-4) was the standard reference. Diagnostic performance for selection of complete responders and interobserver agreement were compared for the two readings. RESULTS: Twenty-five of 120 patients had a complete response (ypT0). Areas under the ROC-curve for the three readers improved from 0.76, 0.68, and 0.58, using only standard MRI, to 0.8, 0.8, and 0.78 after addition of DWI (P = 0.39, 0.02, and 0.002). Sensitivity for selection of complete responders ranged from 0-40% on standard MRI versus 52-64% after addition of DWI. Specificity was equally high (89-98%) for both reading sessions. Interobserver agreement improved from κ 0.2-0.32 on standard MRI to 0.51-0.55 after addition of DWI. CONCLUSIONS: Addition of DWI to standard rectal MRI improves the selection of complete responders after chemoradiation.

CD34+ immunoselection of autologous grafts for the treatment of high-risk neuroblastoma.

BACKGROUND: Graft contamination has been blamed for causing relapse in children with high-risk neuroblastoma (HRNB) after autologous hematopoietic stem cell transplantation (HSCT). PROCEDURE: We report the long-term results of hematopoietic reconstitution, post-transplant complications, and clinical outcome of 44 children with HRNB treated with busulfan/melphalan high-dose chemotherapy followed by transplantation of purged CD34+ immunoselected autologous peripheral HSCT. Minimal residual disease (MRD) of grafts was evaluated by anti-GD2 immunofluorescence or tyrosine hydroxylase reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Contaminating neuroblasts were found in 19/38 grafts (50%) before CD34+ positive selection, and none after (technique sensitivity of one cell in 10(5)). A median of 6.5 × 10(6) CD34+ cells/kg (range 0.8-23.7) were transplanted with only 2% of TRM. Neutrophils and platelet recovery occurred within a median of 12 days (range 9-47) and 44 days (range 12-259), respectively, without any secondary graft failure. Twenty-three percents of patients experienced a sepsis (10/44) and 14% a pyelonephritis (6/44). Recurrence of varicella zoster virus occurred in 21% of patients (9/44). Negative RT-PCR MRD within the leukapheresis product and cis-retinoic acid therapy were significantly and independently associated to a better survival (P < 0.05). Overall and event-free survivals at 5 years post-transplant were at 59.3% and 48.3% respectively. CONCLUSIONS: Besides high rates of manageable infections due to late immune recovery, transplantation with CD34+ immunoselected grafts in HRNB children was feasible and did not affect long-term hematopoiesis.

αvß3 imaging can accurately distinguish between mature teratoma and necrosis in 18F-FDG-negative residual masses after treatment of non-seminomatous testicular cancer: a preclinical study.

PURPOSE: We assessed whether imaging α(v)ß(3) integrin could distinguish mature teratoma from necrosis in human non-seminomatous germ cell tumour (NSGCT) post-chemotherapy residual masses. METHODS: Human embryonal carcinoma xenografts (six/rat) were untreated (controls) or treated to form mature teratomas with low-dose cisplatin and all-trans retinoic acid (ATRA) over a period of 8 weeks. In another group, necrosis was induced in xenografts with high-dose cisplatin plus etoposide (two cycles). (18)F-Fluorodeoxyglucose ((18)F-FDG) small animal positron emission tomography (SA PET) imaging was performed in three rats (one control and two treated for 4 and 8 weeks with cisplatin+ATRA). Imaging of α(v)ß(3) expression was performed in six rats bearing mature teratomas and two rats with necrotic lesions on a microSPECT/CT device after injection of the tracer [(99m)Tc]HYNIC-RGD [6-hydrazinonicotinic acid conjugated to cyclo(Arg-Gly-Asp-D-Phe-Lys)]. Correlative immunohistochemistry studies of human and mouse α(v)ß(3) expression were performed. RESULTS: Cisplatin+ATRA induced differentiation of the xenografts. After 8 weeks, some glandular structures and mesenchymal cells were visible; in contrast, control tumours showed undifferentiated tissues. SA PET imaging showed that mature teratoma had very low avidity for (18)F-FDG [mean standardised uptake value (SUV(mean)) = 0.48 ± 0.05] compared to untreated embryonal carcinoma (SUV(mean) = 0.92 ± 0.13) (p = 0.005). α(v)ß(3) imaging accurately distinguished mature teratoma (tumour to muscle ratio = 4.29 ± 1.57) from necrosis (tumour to muscle ratio = 1.3 ± 0.26) (p = 0.0002). Immunohistochemistry studies showed that α(v)ß(3) integrin expression was strong in the glandular structures of mature teratoma lesions and negative in host stroma. CONCLUSION: Imaging α(v)ß(3) integrin accurately distinguished mature teratoma from necrosis following cisplatin-based treatment in human NSGCT xenografts.

Significance of operative parameters on outcomes after transurethral resection of the prostate.

OBJECTIVE. The aim of this prospective study was to establish the influence of operative parameters on outcomes after transurethral resection of the prostate. MATERIALS AND METHODS. In this prospective case series study, 89 patients underwent transurethral resection of the prostate. The standardized protocol was used to investigate the impact of operative parameters (resected tissue weight, residual prostate weight, and residual prostatic weight ratio [total prostate volume - resected tissue weight / total prostate volume]) on outcomes after six months following transurethral resection of the prostate. The evaluation of treatment efficacy was done using the criteria of the Second International Consultation on Benign Prostatic Hyperplasia. All postoperative results were categorized as excellent, good, fair, or none. Treatment was considered effective when the postoperative results were excellent and good, and ineffective when results were fair and none. RESULTS. Treatment was effective for 85.4% and ineffective for 14.6% of the patients. The univariate analysis of operative parameters detected the residual prostatic weight ratio (cutoff value, 0.71; P<0.001; sensitivity, 0.62; specificity, 0.96; OR, 39.47) as the strongest independent predictor of ineffective outcome. Logistic regression analysis revealed two important parameters of unfavorable outcomes: residual prostatic weight ratio (cutoff value, 0.71; P<0.001; OR, 62.16) and residual prostate weight (cutoff value, 26.6 mL; P=0.013; OR, 9.98). When the values of both these parameters were lower than their cutoff values, the probability of an ineffective outcome was reduced to 3%; however, when they were higher, the probability of an unfavorable outcome was increased to 95%. CONCLUSIONS. Residual prostatic weight ratio and residual prostatic weight are significant operative parameters for the prediction of outcomes after transurethral resection of the prostate.

Identification of residual breast tumour localization after neo-adjuvant chemotherapy using a radioactive 125 Iodine seed.

INTRODUCTION: The use of neo-adjuvant chemotherapy has increased in the treatment of loco-regionally advanced primarily operable breast cancer. As a result of improved neo-adjuvant chemotherapy regimes the number of clinical as well as radiological responses have increased. In case of a complete response it is difficult to identify residual disease and to perform an adequate radical breast-conserving surgery. Therefore localization of the original tumour bed is mandatory. In this study we propose a novel technique with a seed containing radioactive 125 Iodine ((125)I). The (125)I has a half-time of 60 days and is therefore still recognisable with a gamma probe after admittance of several courses of neo-adjuvant chemotherapy. MATERIAL AND METHODS: In the period from July 2003 and November 2008, 47 consecutive patients had successful (125)I seed localization of a breast tumour before starting neo-adjuvant chemotherapy. RESULTS: The overall clinical response rate to neo-adjuvant chemotherapy was 100%. Complete clinical response occurred in 34 patients, partial clinical response occurred in 13 patients. Complete radiological response occurred in 18 patients, partial radiological response occurred in 29 patients. The initial surgical treatment consisted of breast-conserving surgery for all 47 patients, after a mean of 170 days (range: 70-220) after (125)I seed localization. In 19 patients pathology revealed no residual tumour, 23 patients showed a partial response. Only 3 lumpectomies were irradical. CONCLUSION: This study has shown that (125)I seed localization is a novel and highly successful technique in localizing the tumour bed in patients who receive neo-adjuvant chemotherapy for breast cancer leading to a high percentage of radical margins in case of breast-conserving surgery.

The effects of recombinant human TSH on bone turnover in patients after thyroidectomy.

Thyrotropin receptors are expressed in several extrathyroidal tissues including bone. We investigated whether the increase of thyroid-stimulating hormone (TSH) levels, under stable thyroid hormone levels, affects the bone markers. Thirty-two postmenopausal women, with papillary thyroid carcinoma, previously treated with near-total thyroidectomy and I131 remnant ablation underwent routine evaluation for residual disease by using injections of recombinant human TSH (rhTSH) without withdrawal from thyroxine therapy. Changes in TSH levels and various serum and urine markers of bone metabolism were followed before and 1, 2, 5, and 7 days after the rhTSH injections. A transient, significant decrease in serum calcium and urinary excretion of C- and N-terminal telopeptides of type I collagen was observed after the injections of rhTSH. Serum parathyroid hormone (PTH) started to rise along with TSH, but a significant increase of PTH was only reached on Day 5 when the TSH concentration had fallen more than 80% of the peak value. Bone alkaline phosphatase and osteocalcin did not show any significant change over time. There was no significant correlation between TSH concentration and the various parameters we measured. The study provides evidence that rhTSH produces a transient inhibition of bone resorption, as well as an attenuation of osteoblast response in spite of the PTH activation. Additional studies are needed to resolve the mechanisms by which TSH alters the response of the bone cells.