Three-Dimensional Distance and Coverage Maps in the Assessment of Peritalar Subluxation in Progressive Collapsing Foot Deformity

Background: Progressive collapsing foot deformity (PCFD), formerly termed adult-acquired flatfoot deformity, is a complex 3-dimensional (3D) deformity of the foot characterized by peritalar subluxation (PTS). PTS is typically measured at the posterior facet, but recent studies have called this into question. The objective of this study was to use 3D distance mapping (DM) from weightbearing computed tomography (WBCT) to assess PTS in patients with PCFD and controls. We hypothesized that DMs would identify the middle facet as a superior marker for PTS. Methods: We analyzed WBCT data of 20 consecutive stage I patients with PCFD and 10 control patients with a novel DM technique to objectively characterize joint coverage across the entire peritalar surface, including both articular and nonarticular regions. Joint coverage was defined as the percentage of articular area with DMs <4 mm and impingement when distances were <0.5 mm. Comparisons were performed with independent t tests or Wilcoxon tests. P values <.05 were considered significant. Results: Overall, coverage was decreased in articular regions and impingement was increased in nonarticular regions of patients with PCFD with a significant increase in uncoverage in the middle (46.6%, P < .001) but not anterior or posterior facets. Significant increases in sinus tarsi coverage were identified (98.0%, P < .007) with impingement in 6 of 20 patients with PCFD. Impingement of the subfibular region was noted in only 1 of 20 cases but narrowing greater than 2 standard deviations was noted in 17 of 20 patients. Conclusions: Objective DMs identified significant markers of PTS in the middle but not posterior or anterior facets. We confirmed prior 2-dimensional data that suggested uncoverage of the middle facet provided a more robust and consistent measure of PTS than measures in the posterior facet. Level of Evidence: Level III, case-control study.

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Ataxia is a neurodegenerative syndrome, which can emerge as a major element of a disease or represent a symptom of more complex multisystemic disorders. It comprises several forms with a highly variegated etiology, mainly united by motor, balance, and speech impairments and, at the tissue level, by cerebellar atrophy and Purkinje cells degeneration. For this reason, the contribution of astrocytes to this disease has been largely overlooked in the past. Nevertheless, in the last few decades, growing evidences are pointing to cerebellar astrocytes as crucial players not only in the progression but also in the onset of distinct forms of ataxia. Although the current knowledge on this topic is very fragmentary and ataxia type-specific, the present review will attempt to provide a comprehensive view of astrocytes’ involvement across the distinct forms of this pathology. Here, it will be highlighted how, through consecutive stage-specific mechanisms, astrocytes can lead to non-cell autonomous neurodegeneration and, consequently, to the behavioral impairments typical of this disease. In light of that, treating astrocytes to heal neurons will be discussed as a potential complementary therapeutic approach for ataxic patients, a crucial point provided the absence of conclusive treatments for this disease.

Streamlining universal screening for lynch syndrome (LS): Towards improved yield of genetic counseling (GC).

503 Background: LS is largely underdiagnosed although Universal Screening (US) in colorectal cancer (CRC) patients through MisMatch Repair deficiency (MMR-d) testing is widely endorsed. Low adherence to guidelines among oncologists may be partly due to a lack of consensus on whether all MMR-d patients should be referred to GC/Genetic Testing (GT). As BRAF mutation rules out LS, we estimated the increased yield of LS diagnosis from GC /GT which could be obtained by selecting candidates for GC through BRAF testing. Methods: From 2011 to 2016, 1447 consecutive stage I-IV CRC surgical patients at a single institution, underwent immunohistochemistry (IHC) for LS using anti MLH1, MSH2, MSH6 and PMS2 antibodies. Oncologists were invited to refer all MMR-d patients to GC/GT. BRAFV600E testing was carried out only in case of MLH1 protein loss at IHC. Results: MMR-d was found in 194 patients (13%), with 171 showing loss of MLH1 expression (88%). Oncologists referred 27 (16%) to GC. Among the 21 who underwent GC, BRAF testing and GT, 9 were BRAF wild type (wt) (43%) and none had LS. Among the 23 MMR-d patients with loss of expression of MSH2, MSH6 or PMS2 (≠MLH1), oncologists referred 9 to GC (39%): 7 underwent GC / GT and 3 carried LS (43%) at GT. Median age was 76 years (range 30-97) in the MMR-d group, 78 (range 41-97) in the MLH1 group and 63 (range 30-86) in the ≠MLH1 group. Overall, LS was diagnosed in 3 of the 28 MMR-d patients (11%) who underwent GC /GT, possibly an underestimate due to the advanced median age of our MLH1 loss patients. Had we only offered GC to the 9 BRAF wt patients among the 21 with MLH1 loss, we could have avoided 12 (57%) of the GC sessions conducted, increasing the yield of LS diagnosis from 3/28 (11%) to 3/16 (19%) (75% increase). Conclusions: When US for LS is adopted, a GC referral rate reduction of 57% among MLH1 loss patients, and an overall increase in the yield of GC of about 75% can be obtained by testing for BRAF mutation before oncologist referral to GC rather than after. As multistep selection of patients by oncologists may be unfeasible, CRC pathology reports with combined MMR-d and BRAF testing (for MLH1 loss at IHC) and an ‘LS suspicion alert’ could improve oncologists’ awareness of LS and compliance with guidelines.

Problems of Cancer Treatment. Part I. Theory of Treatment Based on Known Mechanisms of Anticancer Immunological Responses

SummaryVarious processes, taking place both in cells and in their environment, are linked to carcinogenesis. This paper aims at recalling the complex mechanisms of oncogenesis, with particular attention paid to responses of the immune system. In development of solid tumours, leukaemias and lymphomas several common stages can be noted. A neoplastic disease cannot be understood considering only phenomena of genetic mutations. Neoplastic cells are characterised by an extensive antigenic variability and resistance to apoptosis. The cells create around them a microenvironment which protects them from defensive activity of the host. In the paper we present the recognised mechanisms of anti-neoplastic defense as well as several elements allowing the solid tumours and leukaemias to escape from the immune surveillance. The generally accepted treatment of tumours aims at reducing numbers of tumour cells. Following resection of a tumour, radiotherapy or chemotherapy, the parallel or consecutive stage of treatment was found to involve an increase in number of clones of immune system cells. One of the ways in which the immune system can be activated involves autovaccination of the host with own neoplastic cells in an apoptosis. However, attempts of such a therapy frequently brought no expected results due to blocked activity of cytotoxic cells. Therefore, the subsequent stage in activation of the immune system should involve elimination of the tumor-mobilized blockade of the system. Attempts toward this aim include neutralization of the tumour-blocked cytotoxic properties of defensive cells, first of all T lymphocytes. The recognized mechanisms of blocking T cells activity in the PD-1/PD-L1 system or due to inhibition of activation by CTLA-4 molecule provided rationale for development of effective tumour immunotherapy approaches.

Wineries and the liability of outsidership: cases from Brazil and Chile

This qualitative research was developed in light of behavioral theories regarding company internationalization. Its objective was to study the internationalization process of two wine exporters, one Chilean and one Brazilian, while focusing on the liability of outsidership. Data were collected from primary and secondary sources, mostly from semi-structured interviews with parties responsible for exportation. The data was treated with content analysis as grounded in current literature. The Undurraga winery (Chile) overcame the liability of outsidership by employing a market penetration strategy consisting of stages, with progression to each consecutive stage depending upon success in the current one. When the company enters into a new market, it identifies the liability and develops a strategy to deal with it. Even though the Brazilian winery, Salton, is over a century old, it has only attempted to internationalize recently. It showed characteristics of liabilities of foreignness and outsidership in practically every period analyzed, and has yet to resolve these problems.

CORRELATION OF RENOGRAM WITH CYSTATIN-C LEVELS AND CREATININE CLEARANCE IN MEASURING GLOMERULAR FILTRATION RATE

AbstrakRenogram 99mTc-DTPA (diethylenetriamine pentacetic acid) memiliki beberapa kelebihan dalam mengukur laju filtrasi glomerulus (LFG). Cystatin-c digunakan sebagai petanda biologik baru untuk memperkirakan LFG. Tujuan penelitian ini adalah untuk menentukan korelasi nilai LFG antara renogram dengan cystatin-c dan kliren kreatinin pada pasien dengan penyakit ginjal kronis (PGK). Subjek penelitian adalah pasien PGK stadium dua berdasarkan hasil estimasi LFG dengan rumus Cockroft-Gault. Pasien yang memenuhi kriteria diperiksa renogram, kadar kreatinin serum, cystatin-c dan klirens kreatinin.Rerata LFG dari 30 orang subjek yang diperiksa dengan renogram, cystatin-c, creatinine clearance, Cockroft-Gault’s formula berturut turut adalah 64.96 ml/min/1.73m2 (SD 28.047), 53.37 ml/min/1.73m2 (SD 21.29), 58.09 ml/min/1.73m2 (SD 35.45), 46.00 ml/min/1.73m2 (SD 12.06). Korelasi antara renogram dengan cystatin-c dengan nilai r = 0.585 dan p = 0.0007, antara renogram dengan klirens kreatinin dengan nilai r = 0.388 dan p = 0.03) dan antara renogram dengan rumus Cockroft-Gault’s dengan nilai r = -0.029 dan p=0.87. Pada penelitian ini didapatkan hasil korelasi yang lebih baik antara renogram dengan cystatin-c dari pada antara renogram dengan klirens kreatinin dan antara renogram dengan rumus Cockroft-Gault’s. Lebih lanjut, cystain-c merupakan alternatif yang lebih baik untuk memperkirakan LFG jika metode pemeriksaan LFG yang mendekati teknik pemeriksaan yang ideal tidak tersedia.AbstractRenogram using 99mTc-DTPA (diethylenetriamine pentacetic acid) has advantages in the measurement of glomerular filtration rate (GFR). Serum cystatin-c was recently projected to be the new marker of estimated GFR. The aim of this study is to establish correlation between GFRs, derived from renogram with cystatin-c levels and creatinine clearances in chronic kidney disease patients.We put to study thirty consecutive stage two of chronic kidney disease patients assigned based on GFR estimation by Cockroft-Gault’s formula, taking into account the serum creatinine. Cystatin-c and creatinine clearance were performed to determine of GFR and renogram was included in this study. A total of thirty subjects, the mean of GFRs were taken from renogram, cystatin-c, creatinine clearance, Cockroft-Gault’s formula were 64.96 ml/min/1.73m2 (SD 28.047), 53.37 ml/min/1.73m2 (SD 21.29), 58.09 ml/min/1.73m2 (SD 35.45), 46.00 ml/min/1.73m2 (SD 12.06) respectively. A correlation between renogram with cystatin-c (r = 0.585 and p = 0.0007) and renogram with creatinine clearance (r = 0.388 and p = 0.03) and renogram with Cockroft-Gault’s formula (r = -0.029 and p=0.87). This study has shown that a better correlation between renogram with cystatin-c than with creatinine clearance or Cockroft-Gault’s formula. Furthermore, cystain-c would be better alternative method incase having problems to obtain a closest ideal methods for GFR.

Safety and efficacy of adjuvant modified FLOX for patients (pts) with stage III colorectal cancer (CRC) treated in the community.

760 Background: Based on the NSABP-C07 trial, FLOX became one of the standard adjuvant regimens for pts with stage III CRC. However, its efficacy and safety have not been evaluated outside of clinical trials. Methods: Retrospective analysis of all consecutive stage III CRC pts who received adjuvant chemotherapy with modified FLOX (5-FU bolus 500 mg/m2 and bolus of LV 20 mg/m2 for 6 consecutive weeks and oxaliplatin 85 mg/m2 in 2 hours-infusion at weeks 1, 3 and 5, every 8 weeks). Logistic regression (LR) multivariable models were used to identify predictors of relapse at 2 years and factors associated with grade ≥3 toxicity. Two-sided p<0.05 were significant. Results: From Feb 2007 to Oct 2013, 267 pts were eligible: median age was 59 years, 53.2% were male and 83 (32.2%) were operated emergently. Most pts (68.2%) had stage IIIB CRC, with a median of 21 (range: 1-119) lymphnodes resected. Pathology characteristics: 32 (12%) were poorly differentiated, 132 (49.4%) had angiolymphatic invasion and 75 (28.1%) had perineural invasion. Median time to chemotherapy initiation was 63 days (range: 10-188). With a median follow-up of 24 months, 67 (25.1%) pts recurred. In LR, urgent surgery (odds ratio [OR]=1.9, 95% IC: 1.03-3.49; p=0.039), angiolymphatic invasion (OR=1.99, 1.09-3.64; p=0.024), and delay/dose reduction of chemotherapy (OR=2.62; 1.45-4.72; p=0.001) were predictors of recurrence at 2 years. Any grade ≥3 toxicity occurred in 98 (36.7%) pts, with diarrhea (16.1%), and neutropenia (15.3%) being the most frequent ones. A total of 9 (3.4%) pts died from any cause within 60 days of starting modified FLOX. Age ≥65 years (OR=2.6, 1.26-5.38; p=0.01) was associated with a higher risk of grade ≥3 toxicity in LR. Conclusions: The adjuvant modified FLOX was effective in stage III CRC pts treated in the community but offered significant risk of serious toxicity and death. This regimen should be probably restricted to fit pts who are ≤65 years. Also, similar to the stage II setting, we found that stage III CRC pts whose primary tumor were ressected emergently, those with angiolymphatic invasion or who received less dose-intense chemotherapy were at higher risk of recurrence.

Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m2 by intravenous bolus followed by paclitaxel 175 mg/m2 over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL · h v 1,717 ng/mL · h; P = .002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P = .012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

Extraperitoneal metastases after intraperitoneal chemotherapy of ovarian cancer patients with a negative second-look laparotomy

The site of the first detectable recurrence was recorded in 17 consecutive stage II–IV ovarian carcinoma patients who, after a negative second-look laparotomy, received intraperitoneal chemotherapy with cisplatin and thiosulfate kidney protection. Although the progression-free interval and survival were favorable, 11 patients eventually had a recurrence and in six (54.5%) of these it was extraperitoneal. Brain metastases were detected in three patients. The appearance of extraperitoneal metastases is not always ominous.