Hyperfractionated Cyclophosphamide and Dexamethasone Alone or in Combination with Daratumumab and/or Carfilzomib for the Treatment of Relapsed or Refractory Multiple Myeloma: A Single-Center Retrospective Analysis.

BACKGROUND: Hyperfractionated cyclophosphamide and dexamethasone (HyperCd) alone, or with carfilzomib(K) and/or daratumumab(D), represents a potential treatment option when rapid disease control is needed for patients with aggressive presentations of relapsed/refractory multiple myeloma (RRMM). PATIENTS AND METHODS: This is a single-center, retrospective analysis of adult patients with RRMM who received HyperCd with or without K and/or D between May 1, 2016 and August 1, 2019 at the University of Texas MD Anderson Cancer Center. We here report treatment response and safety outcomes. RESULTS: Data from 97 patients, 12 with plasma cell leukemia (PCL), were reviewed in this analysis. Patients had had a median of 5 prior lines of therapy and received a median of 1 consecutive cycle of hyperCd-based therapy. The overall response rate (ORR) of all patients was 71.8% (HyperCd 75%, HyperCdK 64.3%, D-HyperCd 73.3%, and D-HyperCdK 76.9%). Median progression-free survival and overall survival among all patients was 4.3 months (HyperCd 3.1 months, HyperCdK 4.5 months, D-HyperCd 3.3 months, and D-HyperCdK 6 months) and 9.0 months (HyperCd 7.4 months, HyperCdK 9.0 months, D-HyperCd 7.5 months, and D-HyperCdK 15.2 months), respectively. Grade 3/4 hematologic toxicities were common, thrombocytopenia being the most frequent at 76%. Notably, 29-41% of patients per treatment group had existing grade 3/4 cytopenias at initiation of hyperCd-based therapy. CONCLUSION: HyperCd-based regimens provided rapid disease control among MM patients, even when heavily pre-treated and with few remaining treatment options. Grade 3/4 hematologic toxicities were frequent, but manageable with aggressive supportive care.

[Scaphoid fractures in childhood]. / Skaphoidfrakturen im Kindesalter.

This article reviews current knowledge about scaphoid fractures in children and adolescents, including the development of the scaphoid, its injuries and age-specific treatment for acute and late presenting fractures. The following recommendations are based on the literature, although scientific evidence to support treatment strategies is scarce. The diagnosis of scaphoid fractures is often missed on initial X-rays. Therefore all suspected fractures should be treated with a thumb spica cast for 2 weeks, followed by clinical examination and repeat X-ray if symptoms persist. In cases of negative X-ray findings an MRI or alternatively a CT scan are indicated. None or minimally displaced paediatric scaphoid fractures should be treated in a spica cast for at least 7 weeks until union is documented. Unlike in adults, evidence has not been provided for a benefit of routine surgical therapy. Late presenting non-unions that have not yet been treated adequately warrant a trial of conservative therapy, because healing can be expected under prolonged immobilisation. Surgical treatment should be reserved for dislocated fractures, established pseudarthroses that have not united under adequate conservative treatment or for patients to whom prolonged immobilisation does not appear to be acceptable.

Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma.

Several clinical trials have shown the superiority of autologous stem cell transplantation over conventional dose therapy for patients with multiple myeloma. This treatment, however, is limited to younger patients (<65 years) owing to concerns about toxicity and treatment-related mortality (TRM) in older patients. We treated 26 elderly myeloma patients (>70 years), who received a preparative regimen of melphalan 200 mg/m2 (19 patients), melphalan 180 mg/m2 (six patients) or melphalan 140 mg/m2 (one patient). Twenty-two of the 26 patients were alive after a median follow-up of 25 months (range=8-74). Responses (complete+partial response) were seen in 20 patients (77%), five (19%) of which were complete responses. Median PFS was 24 months, whereas median OS has not been reached. Cumulative incidence of 100-day TRM was 0%. Three-year PFS and OS were 39% (range=16-61) and 65% (range=35-83), respectively. A low serum albumin (<3.5 g/dl) was associated with a shorter PFS (P=0.02). Patients with relapsed disease at transplant, and an interval of >12 months between diagnosis and autotransplant, had a shorter OS (P=0.0004 and 0.04). HDT and autologous transplant is safe and feasible in elderly myeloma patients.

[The psychosocial/-sexual development of boys with hypospadias]. / Die psychosoziale/-sexuelle Entwicklung von Knaben mit einer Hypospadie.

Boys with hypospadias can suffer from specific psychological stress as a result of genital surgery and a cosmetically and/or functionally impaired penis. During recent decades intensive efforts have been made to improve the surgical techniques; yet the psychosocial and psychosexual development of children and adolescents after hypospadias surgery has only rarely been investigated. While the results of the few studies are altogether very contradictory, they also indicate that hypospadias patients suffer from specific problems like a negative perception of genital appearance. Therefore, they should be offered long-term follow-ups and psychosocial support until they reach young adulthood. For future research, it is necessary to systematically investigate the boys' quality of life and development in methodologically sound studies.

Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial.

The safety and efficacy of siltuximab (CNTO 328) was tested in combination with lenalidomide, bortezomib and dexamethasone (RVD) in patients with newly-diagnosed, previously untreated symptomatic multiple myeloma. Fourteen patients were enrolled in the study, eleven of whom qualified to receive therapy. A majority of patients (81.8%) completed the minimal number or more of the four required cycles, while two patients completed only three cycles. The maximum tolerated dose (MTD) of siltuximab with RVD was dose level -1 (siltuximab: 8.3 mg/kg; bortezomib: 1.3 mg/m(2); lenalidomide: 25 mg; dexamethasone: 20 mg). Serious adverse events were grade 3 pneumonia and grade 4 thrombocytopenia, and no deaths occurred during the study or with follow-up (median follow-up 28.1 months). An overall response rate, after 3-4 cycles of therapy, of 90.9% (95% confidence interval (CI): 58.7%, 99.8%) (9.1% complete response (95% CI: 0.2%, 41.3%), 45.5% very good partial response (95% CI: 16.7%, 76.6%) and 36.4% partial response (95% CI: 10.9%, 69.2%)) was seen. Two patients withdrew consent, and nine patients (81.8%) opted for autologous stem cell transplantation.

Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma.

PURPOSE: To assess the prognostic significance of magnetic resonance (MR) imaging in patients with newly diagnosed asymptomatic multiple myeloma. PATIENTS AND METHODS: Thirty-eight consecutive patients with asymptomatic myeloma of low tumor mass and negative skeletal surveys underwent MR imaging of the thoracic and lumbosacral spine. The presence and patterns of marrow involvement were correlated with standard laboratory parameters and time to disease progression. RESULTS: Nineteen patients (50%) had evidence of marrow involvement at spinal MR imaging. MR patterns of marrow involvement were classified as diffuse (five patients), variegated (nine), and focal (five). Patients with abnormal MR imaging studies required therapy after a median of 16 months, versus 43 months for those with normal MR studies (P < .01). CONCLUSION: Abnormal marrow patterns were present in half of patients with asymptomatic myeloma. An abnormal MR study of the spine identified asymptomatic patients who were likely to require treatment earlier than those with a normal MR study. A normal MR pattern provided additional justification to defer institution of chemotherapy. However, MR imaging remains an investigational tool to stage patients with multiple myeloma until more data are accumulated.

Quantitative nuclear morphometry by image analysis for prediction of recurrence of ductal carcinoma in situ of the breast.

Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence. Tissue sections of archival breast tissue of 29 women with recurrent and 73 matched women with nonrecurrent DCIS were stained for DNA, and nuclei in the DCIS lesions were evaluated by image analysis. A clear correlation between mean fractal2_area (FA2) and nuclear grade was observed (P < 0.001), allowing an objective determination of nuclear grade. Several nuclear morphometric features, including mean and variance of variation of radius, mean area, mean and variance of frequency of high boundary harmonics (FQH), and variance in sphericity, were found to be useful in discriminating recurrent from nonrecurrent DCIS subjects. However, the nuclear features associated with recurrence differed between high- and low-grade lesions. For lesions with high FA2 (nuclear grade 3), mean variation of radius, mean FQH, and mean area alone yielded recurrence odds ratios of 4.55 [95% confidence interval (CI) 0.45-45.96], 3.86 (95% CI, 0.88-16.98), 2.90 (95% CI, 0.31-27.2), respectively. Using a summed feature model, high-FA2 lesions showing three poor prognostic features had an odds ratio of 15.63 (95% CI, 1.22-200), compared with those with zero or one poor prognostic feature. Lesions with low mean FA2 (nuclear grade 1 or 2) showing high variances in sphericity and FQH had an odds ratio of 7.71 (95% CI, 1.77-33.60). Addition of other features did not enhance the odds ratio or its significance. These results suggest that nuclear image analysis of DCIS lesions may provide an adjunctive tool to conventional pathological analysis, both for the objective assessment of nuclear grade and for the identification of features that predict patient outcome.

Geometric quantitative coronary arteriography. A comparison of unsubtracted and dual energy-subtracted images.

The application of dual energy (DE) subtraction techniques to quantitative coronary arteriography (QCA) has the advantage of removing the tissue signal surrounding the vessel profile. We have compared the performance of two geometric QCA algorithms on DE-subtracted and -unsubtracted images to determine, for each, if DE subtraction is advantageous. The two algorithms under study were an edge detection algorithm and a Fourier analysis-based algorithm. For each algorithm, linear regression analysis was performed of measured cross-sectional area (CSA) versus actual CSA of coronary vessel phantoms. The edge detection algorithm was found to have improved precision (P less than .05) when applied to the DE-subtracted images. The Fourier analysis algorithm, however, was not effected by the DE subtraction. Among the unsubtracted image results, the Fourier measurements were more accurate (P less than .05) than the edge detection measurements. We conclude that the benefits to edge detection QCA of DE tissue subtraction outweigh the disadvantages of increased image noise and possible misregistration artifacts. However, the Fourier algorithm is relatively insensitive to tissue signal variations.

Quantitative dual-energy coronary arteriography.

Subtraction techniques for digital cardiac imaging have been hampered by misregistration artifacts. The use of dual-energy imaging is being evaluated as a means for reducing these artifacts. Results reported previously indicate that the dual-energy technique may be useful for applications such as exercise ventriculography and general quantification tasks. The purpose of the current study is to investigate the use of dual-energy subtraction imaging for quantitative coronary arteriography. In vivo coronary vessel phantoms (0.2 to 7 mm2 in cross-sectional area) were used to study the potential advantages of tissue suppressed energy subtracted images over unsubtracted images for quantification of absolute vessel cross-sectional area when cardiac motion is present. Estimates of lumen cross-sectional area (N = 20) were determined using videodensitometric analysis of selected energy subtracted and unsubtracted images. Linear regression analysis of measured and actual cross-sectional area showed energy subtracted image data (slope = 1.06, intercept = 0.48 mm2, r = 0.99) to have improved accuracy (P less than .05) and precision (P less than .05) over unsubtracted image data (slope = 1.24, intercept = 1.07 mm2, r = 0.95).

Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course.

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

Intensive sequential therapy for VAD-resistant multiple myeloma.

Few effective regimens are available for patients with advanced multiple myeloma resistant to alkylating agents and VAD. We treated 65 patients with advanced and refractory multiple myeloma with the combination of cyclophosphamide (3.0 gm/m2) and etoposide (900 mg/m2) followed by GM-CSF at a daily dose of 0.125 mg/m2. Thirty-five percent of patients responded with a 6% mortality rate. After a median of 2 months, 16 patients received myeloablative treatment supported by autologous bone marrow or blood stem cells. Four of ten previously resistant patients responded so that the overall response rate was 42%. The median survival for all patients was 10 months and the median remission was 8 months. The median survival for patients with both low serum lactate dehydrogenase and B2 microglobulin, or for those who received myeloablative treatment, was projected at 18 months. Our combination of cyclophosphamide and etoposide provided an effective rescue treatment for many patients with advanced multiple myeloma resistant to conventional therapies. This program allowed early blood stem cell collection in support of subsequent myeloablative therapy for selected patients.

Absolute diameter measurements of coronary arteries based on the first zero crossing of the Fourier spectrum.

Current edge detection methods used to determine coronary artery dimensions from digital (DSA) images suffer a strong dependence on the system's modulation transfer function (MTF). The videodensitometric algorithms are less sensitive to MTF blurring, yet still result in an overestimation of the vessel size of 10% to 25% for blurring aperture sizes of 50% to 80% of the vessel diameter. We propose a new algorithm to measure the absolute diameter of a vessel which has a lower sensitivity to the system MTF for blurring aperture sizes up to 80% of the vessel diameter. A consequence of the similarity theorem of Fourier transform pairs is that the "width" of the Fourier transform, as characterized by the first zero crossing in frequency space, is inversely proportional to the width of the vessel profile. For an ideal (unblurred) vessel image, the width of the vessel profile is equal to the diameter of the vessel. For a blurred image this is not true. In frequency space, however, the transform of the blurred profile is simply the product of the transformed ideal profile and the system MTF. Thus, if the blurring aperture of the system is below some critical value, the first zero of the unblurred profile will still dominate the transform of the blurred profile. For vessels of circular cross section and a rectangular blurring aperture, this critical aperture size is approximately 80% of the vessel diameter. A more detailed explanation of the theory and calculations involved in this measurement, along with measurements of computer simulated and phantom vessels is presented.

Effects of helium pneumoperitoneum in pregnant ewes.

BACKGROUND: Previous animal studies have demonstrated that a carbon dioxide (CO(2)) pneumoperitoneum in pregnant ewes causes maternal and fetal acidosis, decreased uterine blood flow (UtBF), and fetal hypertension. This study was undertaken to determine whether helium (He) produces these same effects when used as an insufflating gas. METHODS: Six gravid ewes, at 116 to 120 days gestation, underwent catheterization of the maternal femoral artery and vein and the fetal hindlimb artery and vein, as well as insertion of a uterine artery flow probe. After a 6-day recovery period, the animals were anesthetized; a Hasson trocar was placed; and an He pneumoperitoneum was established (10 mmHg for 30 min followed by 15 mmHg for 30 min). The following parameters were recorded at baseline and at preset time points: maternal and fetal heart rate (HR), blood pressure (BP), arterial blood gasses, maternal end-tidal CO(2) (EtCO2), and UtBF. The percentage of change over time was determined for each variable. The results were compared with results previously obtained in control animals and in animals undergoing CO(2) pneumoperitoneum. Statistical significance was determined by repeated measures analysis of variance (ANOVA). RESULTS: The following statistically significant changes were found. CONCLUSIONS: Like CO(2), He used for pneumoperitoneum resulted in decreased UtBF and fetal hypertension because of increased intra-abdominal pressure. Unlike a CO(2), He used for pneumoperitoneum does not cause maternal or fetal acidosis, indicating that the metabolic effects seen with CO(2) are the result of the specific gas used. Therefore, He may be a safer gas than CO(2) to use for laparoscopic procedures in pregnant patients.

Laparoscopic cholecystectomy.

BACKGROUND: This study was undertaken to determine if patients undergoing laparoscopic cholecystectomy may be discharged home 4 h postoperatively with similar outcomes as patients admitted overnight. METHODS: Patients were randomized to an outpatient group (OP), consisting of patients who were discharged after a 4-h stay in the Post Anesthesia Care Unit (PACU), or to an inpatient group. Variables compared between the two groups included patient demographics; degree of postoperative pain, nausea, vomiting, and patient satisfaction; amount of pain and nausea medication taken; and number of phone calls, readmissions, or complications. Statistical analysis was performed with students t-test, Fisher's exact test, and Wilcoxon's signed rank and rank sums tests as appropriate. RESULTS: Eighty patients were initially enrolled. Two were converted and 4 required admission after being randomized to the OP group. Patients in the OP group received more oral pain medication prior to PACU discharge. Degree of pain, number of phone calls, readmission and complication rates, and patient satisfaction were similar between both groups. Of the 4 unexpected admissions, all were identified within the 4-h PACU stay. CONCLUSIONS: Patients undergoing laparoscopic cholecystectomy who are discharged home 4 h postoperatively will experience the same satisfaction with no increase in complications as patients admitted overnight.

Quadratic Gabor filters for object detection.

We present a new class of quadratic filters that are capable of creating spherical, elliptical, hyperbolic and linear decision surfaces which result in better detection and classification capabilities than the linear decision surfaces obtained from correlation filters. Each filter comprises of a number of separately designed linear basis filters. These filters are linearly combined into several macro filters; the output from these macro filters are passed through a magnitude square operation and are then linearly combined using real weights to achieve the quadratic decision surface. For detection, the creation of macro filters (linear combinations of multiple single filters) allows for a substantial computational saving by reducing the number of correlation operations required. In this work, we consider the use of Gabor basis filters; the Gabor filter parameters are separately optimized. The fusion parameters to combine the Gabor filter outputs are optimized using an extended piecewise quadratic neural network (E-PQNN). We demonstrate methods for selecting the number of macro Gabor filters, the filter parameters and the linear and nonlinear combination coefficients. We present preliminary results obtained for an infrared (IR) vehicle detection problem.

Duodenojejunal atresia with apple peel configuration of the ileum and absent superior mesenteric artery: observations on pathogenesis.

A child with loss of the third and fourth part of the duodenum and of the proximal jejunum was found to have an apple peel configuration of the remaining small bowel. The complete absence of branches from the superior mesenteric artery impaired the blood supply of the distal duodenum. An annular pancreas was found in this patient with Down's syndrome. This anomaly may have impaired the flow through the pancreaticoduodenal arcade, which would normally compensate for the distal vascular occlusion. According to current understanding, duodenal atresia is a primary malformation. The current case suggests, however, that in rare circumstances vascular accidents may be the underlying cause for duodenal atresia.

Absorbable sutures help minimise patient discomfort and reduce cost in syndactyly release.

Many surgeons hesitate to use absorbable suture material to correct syndactylies because they fear that it may induce hypertrophic scarring and compromise the outcome functionally and aesthetically. In a series of 25 syndactylies all sutures were carried out using an absorbable, multifilament polyglactin suture material (Vicryl Rapid, Ethicon). A good result with no functional impairment and a natural looking commissure was achieved in 20 syndactylies. 4 syndactylies had a fair result with no functional impairment but with certain aesthetic deficits such as a slightly hypertrophic scar in 2 and a hyperpigmentation of the skin graft in 2. One patient had a poor result with hypertrophic scars that were responsible for temporary flexion contractures. No patient needed to be reoperated. This case series demonstrates that good results can be achieved using absorbable sutures for syndactyly release. Children and parents appreciated the fact that no stitches had to be removed. Secondary anaesthesia for suture removal with its inherent risks and cost was not necessary.

Color Doppler sonography in the diagnosis of acute scrotum in boys.

Evaluation of acute painful scrotum is difficult and imaging studies have been reported to be unreliable in detecting testicular torsion. In order to assess the value of color Doppler sonography in acute scrotal disease, the authors reviewed 65 consecutive boys, ranging in age from 1 to 16 years. The study demonstrated absent or diminished flow signals in 11 patients. All of them had a surgical intervention, and in 8 of them, a testicular torsion was confirmed. 54 boys had a symmetrical or increased flow signal on the affected side. Just 5 boys among this group underwent surgical exploration. On follow up, none of the 54 patients with good flow signals proved to have a testicular torsion. Sonography and color Doppler sonography helped to differentiate epididymitis and torsion of a testicular appendage as a basis for further investigations and correct conservative therapy. In detecting a testicular torsion, color Doppler sonography yielded a positive predictive value of 73%, a sensitivity of 100% and a negative predictive value of 100%. We therefore conclude, that Doppler sonography can reliably rule out testicular torsion so that routine scrotal exploration in cases of acute scrotum is no longer necessary. By reducing the number of emergency operations and hospitalization days, color Doppler sonography can cut down the total cost of managing acute painful scrotum in boys.

Periumbilical necrotizing fasciitis in the newborn.

Periumbilical necrotizing fasciitis (PNF) in the newborn is an invasive bacterial infection of the abdominal wall with a fulminant course and a high mortality rate. Little is known about the etiology, risk factors and microbiology of the disease. 18 patients with periumbilical necrotizing fasciitis were included in this retrospective study and were compared with 50 patients with omphalitis over a 6-year period, between 1992 and 1998. This represents the largest reported study. The children with periumbilical necrotizing fasciitis presented at a younger age compared to the omphalitis group (8.4 days vs. 9.1 days) and had a shorter clinical history (1.9 days vs. 2.8 days), suggesting that PNF is not a mere sequela of omphalitis but has distinctive underlying causes. None of our patients in the omphalitis group had a progression of the disease towards necrotizing fasciitis. The microbial spectrum of cultures obtained in patients with PNF consisted of mixed anaerobes and aerobes in 55%, and mixed aerobes in 36% of cases. Early aggressive therapy, including elective endotracheal intubation, immediate surgical debridement of the abdominal wall, antibiotics and supportive measurements resulted in a survival rate of 56%. Far from being satisfactory, this is nevertheless higher than the 12.5% to 45% survival rate quoted in previous publications.

Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications.

Resistance of myeloma to lenalidomide is an emerging clinical problem, and though it has been associated in part with activation of Wnt/ß-catenin signaling, the mediators of this phenotype remained undefined. Lenalidomide-resistant models were found to overexpress the hyaluronan (HA)-binding protein CD44, a downstream Wnt/ß-catenin transcriptional target. Consistent with a role of CD44 in cell adhesion-mediated drug resistance (CAM-DR), lenalidomide-resistant myeloma cells were more adhesive to bone marrow stroma and HA-coated plates. Blockade of CD44 with monoclonal antibodies, free HA or CD44 knockdown reduced adhesion and sensitized to lenalidomide. Wnt/ß-catenin suppression by FH535 enhanced the activity of lenalidomide, as did interleukin-6 neutralization with siltuximab. Notably, all-trans retinoic acid (ATRA) downregulated total ß-catenin, cell-surface and total CD44, reduced adhesion of lenalidomide-resistant myeloma cells and enhanced the activity of lenalidomide in a lenalidomide-resistant in vivo murine xenograft model. Finally, ATRA sensitized primary myeloma samples from patients that had relapsed and/or refractory disease after lenalidomide therapy to this immunomodulatory agent ex vivo. Taken together, our findings support the hypotheses that CD44 and CAM-DR contribute to lenalidomide resistance in multiple myeloma, that CD44 should be evaluated as a putative biomarker of sensitivity to lenalidomide, and that ATRA or other approaches that target CD44 may overcome clinical lenalidomide resistance.