Improved response rate in patients with prognostically poor locally advanced rectal cancer after treatment with induction chemotherapy and chemoradiotherapy when compared with chemoradiotherapy alone: A matched case-control study.

INTRODUCTION: The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics. METHODS: All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was performed based on the aforementioned characteristics. RESULTS: Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013). CONCLUSION: Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prognostically poor characteristics.

Impact of a history of metastases or synchronous metastases on survival in patients with locally recurrent rectal cancer.

AIM: Patients with locally recurrent rectal cancer (LRRC) frequently present with either synchronous metastases or a history of metastases. This study was conducted to evaluate whether LRRC patients without metastases have a different oncological outcome compared to patients with a history of metastases treated with curative intent or patients with potentially curable synchronous metastases. METHOD: All consecutive LRRC patients who underwent intentionally curative surgery between 2005 and 2017 in a large tertiary hospital were retrospectively reviewed and categorized as having no metastases, a history of (curatively treated) metastases or synchronous metastases. Patients with unresectable distant metastases were excluded from the analysis. RESULTS: Of the 349 patients who were analysed, 261 (75%) had no metastases, 42 (12%) had a history of metastases and 46 (13%) had synchronous metastases. The 3-year metastasis-free survival was 52%, 33% and 13% in patients without metastases, with a history of metastases, and with synchronous metastases, respectively (P < 0.001) A history of metastases did not influence overall survival (OS), but there was a trend towards a worse OS in patients with synchronous metastases compared with patients without synchronous metastases (hazard ratio 1.43; 95% CI 0.98-2.11). CONCLUSION: LRRC patients with a history of curatively treated metastases have an OS comparable to that in patients without metastases and should therefore be treated with curative intent. However, LRRC patients with synchronous metastases have a poor metastasis-free survival and worse OS; in these patients, an individualized treatment approach to observe the behaviour of the disease is recommended.

Dysplasia in Random Biopsies from Barrett's Surveillance Is an Important Marker for More Severe Pathology.

BACKGROUND AND AIM: Although endoscopic recognition of dysplasia in Barrett's esophagus is difficult, experience in recognition of early neoplastic lesions is supposed to increase the detection of early neoplastic lesions. The aim of this study was to assess the significance of dysplasia in random biopsies in Barrett's esophagus, in the absence of reported visible lesions as well as the difference in final outcome of pathology. METHODS: We retrospectively identified all patients with Barrett's esophagus with suspicion of dysplasia or early adenocarcinoma who were referred to our center between February 2008 and April 2016. We analyzed all endoscopy reports, pathology reports, and referral letters from 19 different hospitals. Patients were divided into two groups, based on the presence or absence of visible lesions reported upon referral. RESULTS: In total, 170 patients diagnosed with dysplasia or adenocarcinoma were referred to our tertiary center. Ninety-one of these referred patients were referred with dysplasia or adenocarcinoma in random biopsies, without a reported lesion during endoscopy in the referral center. During endoscopic work-up at our center, a visible lesion was detected in 44 of these 91 patients (48.4%). After endoscopic work-up and treatment, adenocarcinoma was found in an additional 21 patients. Two of these patients were initially referred with low-grade dysplasia, and 19 patients were initially referred with high-grade dysplasia. The final pathology was upstaged in 35.8% of the patients. CONCLUSIONS: The presence of any grade of dysplasia in random biopsies during surveillance in referral centers is a marker for more severe final pathology. Training in recognition of early neoplastic lesions in Barrett's esophagus imaging is recommended for endoscopists performing Barrett's surveillance.

COVID-19 during pregnancy: non-reassuring fetal heart rate, placental pathology and coagulopathy.

We report a case of a pregnant woman with COVID-19 who developed coagulopathy in the absence of severe clinical symptoms. A polymerase chain reaction test of a vaginal swab was positive for SARS-CoV-2 RNA, suggesting a possibility of perinatal transmission. Cesarean delivery was performed because of a non-reassuring fetal heart rate; the placenta showed increased perivillous fibrin deposition and intervillositis. Moreover, placental infection with SARS-CoV-2 was demonstrated by placental immunostaining. The findings suggest a possible relationship between placental fibrin deposition and chronic and acute intervillositis, non-reassuring fetal heart rate and coagulopathy in pregnant women with COVID-19. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Improved Outcomes for Responders After Treatment with Induction Chemotherapy and Chemo(re)irradiation for Locally Recurrent Rectal Cancer.

BACKGROUND: Despite improvements in the multimodality treatment for patients with locally recurrent rectal cancer (LRRC), oncological outcomes remain poor. This study evaluated the effect of induction chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes. METHODS: All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and metastasis free survival (MFS). RESULTS: A pathologic complete response was observed in 22 patients (17%), a "good" response (Mandard 2-3) in 74 patients (56%), and a "poor" response (Mandard 4-5) in 36 patients (27%). An R0 resection was obtained in 83 patients (63%). The degree of pathologic response was linearly correlated with the R0 resection rate (p = 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (p = 0.004, p = 0.003, and p = 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (p = 0.020 and p = 0.028, respectively). CONCLUSIONS: Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation is a promising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.

Adherence to pre-set benchmark quality criteria to qualify as expert assessor of dysplasia in Barrett's esophagus biopsies - towards digital review of Barrett's esophagus.

Background: Dysplasia assessment of Barrett's esophagus biopsies is associated with low observer agreement; guidelines advise expert review. We have developed a web-based review panel for dysplastic Barrett's esophagus biopsies. Objective: The purpose of this study was to test if 10 gastrointestinal pathologists working at Dutch Barrett's esophagus expert centres met pre-set benchmark scores for quality criteria. Methods: Ten gastrointestinal pathologists twice assessed 60 digitalized Barrett's esophagus cases, enriched for dysplasia; then randomised (7520 assessments). We tested predefined benchmark quality criteria: (a) percentage of 'indefinite for dysplasia' diagnoses, benchmark score ≤14% for all cases, ≤16% for dysplastic subset, (b) intra-observer agreement; benchmark score ≥0.66/≥0.39, (c) percentage agreement with 'gold standard diagnosis'; benchmark score ≥82%/≥73%, (d) proportion of cases with high-grade dysplasia underdiagnosed as non-dysplastic Barrett's esophagus; benchmark score ≤1/78 (≤1.28%) assessments for dysplastic subset. Results: Gastrointestinal pathologists had seven years' Barrett's esophagus-experience, handling seven Barrett's esophagus-cases weekly. Three met stringent benchmark scores; all cases and dysplastic subset, three met extended benchmark scores. Four pathologists lacked one quality criterion to meet benchmark scores. Conclusion: Predefined benchmark scores for expert assessment of Barrett's esophagus dysplasia biopsies are stringent and met by some gastrointestinal pathologists. The majority of assessors however, only showed limited deviation from benchmark scores. We expect further training with group discussions will lead to adherence of all participating gastrointestinal pathologists to quality criteria, and therefore eligible to join the review panel.

Improved diagnostic stratification of digitised Barrett's oesophagus biopsies by p53 immunohistochemical staining.

AIMS: Interobserver agreement for dysplasia in Barrett's oesophagus (BO) is low, and guidelines advise expert review of dysplastic cases. The aim of this study was to assess the added value of p53 immunohistochemistry (IHC) for the homogeneity within a group of dedicated gastrointestinal (GI) pathologists. METHODS AND RESULTS: Sixty-single haematoxylin and eosin (HE) slide referral BO cases [20 low-grade dysplasia (LGD); 20 high-grade dysplasia (HGD); and 20 non-dysplastic BO reference cases] were digitalised and independently assessed twice in random order by 10 dedicated GI pathologists. After a 'wash-out' period, cases were reassessed with the addition of a corresponding p53 IHC slide. Outcomes were: (i) proportion of 'indefinite for dysplasia' (IND) diagnoses; (ii) interobserver agreement; and (iii) diagnostic accuracy as compared with a consensus 'gold standard' diagnosis defined at an earlier stage by five core expert BO pathologists after their assessment of this case set. Addition of p53 IHC decreased the mean proportion of IND diagnoses from 10 of 60 to eight of 60 (P = 0.071). Mean interobserver agreement increased significantly from 0.45 to 0.57 (P = 0.0021). The mean diagnostic accuracy increased significantly from 72% to 82% (P = 0.0072) after p53 IHC addition. CONCLUSION: Addition of p53 IHC significantly improves the histological assessment of BO biopsies, even within a group of dedicated GI pathologists. It decreases the proportion of IND diagnoses, and increases interobserver agreement and diagnostic accuracy. This justifies the use of accessory p53 IHC within our upcoming national digital review panel for BO biopsy cases.

Preliminary results of a cohort study of induction chemotherapy-based treatment for locally recurrent rectal cancer.

BACKGROUND: A significant number of patients treated for locally recurrent rectal cancer have local or systemic failure, especially after incomplete surgical resection. Neoadjuvant treatment regimens in patients who have already undergone preoperative (chemo)radiotherapy for the primary tumour are limited. The objective of the present study was to evaluate the influence of a neoadjuvant regimen incorporating induction chemotherapy (ICT) in patients with locally recurrent rectal cancer who had preoperative (chemo)radiotherapy for the primary cancer or an earlier local recurrence. METHODS: Patients were treated with a sequential neoadjuvant regimen including three or four cycles of 5-fluorouracil and oxaliplatin-containing chemotherapy. When no progressive disease was found at evaluation, neoadjuvant treatment was continued with chemoradiation therapy (CRRT) using 30 Gy with concomitant capecitabine. If there was a response to ICT, the patient was advised to continue with systemic chemotherapy after CRRT as consolidation chemotherapy while waiting for resection. These patients were compared with patients who received CRRT alone in the same time interval. RESULTS: Of 58 patients who had ICT, 32 (55 per cent) had surgery with clear resection margins, of whom ten (17 per cent) exhibited a pathological complete response (pCR). The remaining 26 patients had 23 R1 and three R2 resections. In 71 patients who received CRRT, a similar rate of R0 (35 patients) and R1 (36) resection was found (P = 0·506), but only three patients (4 per cent) had a pCR (P = 0·015). CONCLUSION: The incorporation of ICT in neoadjuvant regimens for locally recurrent rectal cancer is a promising strategy.

Variation in circumferential resection margin: Reporting and involvement in the South-Netherlands.

BACKGROUND: Since the introduction of total mesorectal surgery the outcome of rectal cancer patients has improved significantly. Involvement of the circumferential resection margin (CRM) is an important predictor of increased local recurrence, distant metastases and decreased overall survival. Abdomino perineal excision (APE) is associated with increased risk of CRM involvement. Aim of this study was to analyze reporting of CRM and to identify predictive factors for CRM involvement. METHODS: A population-based dataset was used selecting 2153 patients diagnosed between 2008 and 2013 with primary rectal cancer undergoing surgery. Variation in CRM reporting was assessed and predictive factors for CRM involvement were calculated and used in multivariate analyses. RESULTS: Large variation in CRM reporting was found between pathology departments, with missing cases varying from 6% to 30%. CRM reporting increased from 77% in 2008 to 90% in 2012 (p < 0.001). CRM involvement significantly decreased from 12% to 6% over the years (p < 0.001). In multivariate analysis type of operation, low anterior resection or APE, did not influence the risk of CRM involvement. Clinical T4-stage [odds ratio (OR) = 3.51; 95% confidence interval (CI) = 1.85-6.65) was associated with increased risk of CRM involvement, whereas neoadjuvant treatment (5 × 5 gray radiotherapy [OR 0.39; CI 0.25-0.62] or chemoradiation therapy [OR 0.30; CI 0.17-0.53]) were associated with significant decreased risk of CRM involvement. CONCLUSION: Although significant improvements are made during the last years there still is variation in reporting of CRM involvement in the Southern Netherlands. In multivariate analysis APE was no longer associated with increased risk of CRM involvement.

The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients.

BACKGROUND: Molecular markers in colon cancer are needed for a more accurate classification and personalized treatment. We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma. PATIENTS AND METHODS: Stage II colon carcinoma patients (n = 106) treated with surgery only and 258 stage III patients all adjuvantly treated with 5-fluorouracil chemotherapy were included. KRAS mutations in codons 12 and 13, V600E BRAF mutation and MSI status were determined. RESULTS: Older patients (P < 0.001), right-sided (P = 0.018), better differentiated (P = 0.003) and MSI tumors (P < 0.001) were significantly more frequent in stage II than stage III. In both groups, there was a positive association between mutated BRAF and MSI (P = 0.001) and BRAF mutation and right-sided tumors (P = 0.001). Mutations in BRAF and KRAS were mutually exclusive. In a multivariate survival analysis with pooled stage II and stage III data, BRAF mutation was an independent prognostic factor for overall survival (OS) and cancer-specific survival [hazards ratio (HR) = 0.45, 95% confidence interval (CI) 0.25-0.8 for OS and HR = 0.47, 95% CI 0.22-0.99]. KRAS mutation conferred a poorer disease-free survival (HR = 0.6, 95% CI 0.38-0.97). CONCLUSIONS: The V600E BRAF mutation confers a worse prognosis to stage II and stage III colon cancer patients independently of disease stage and therapy.

Improving lymph node detection in colon cancer in community hospitals and their pathology department in southern Netherlands.

AIM: The aim was to investigate whether a set of measures directed at increasing lymph node (LN) detection among colon cancer patients led to clinically relevant changes in LN detection rate. METHODS: Data of all patients with curative colon cancer (pT(any) N(any) M0) diagnosed in 1999-2007 whose resection specimens were evaluated by the Institute for Pathology and Medical Microbiology in Eindhoven (n=1501) were included. Feedback to specialists, increased fixation time, and ex-vivo injection of the specimen with Patent blue V dye were used to increase LN detection rate. Trends in the proportion of patients with insufficient LNs examined were investigated; moreover, the Patent blue-stained patients (n=86) were compared with a group of unstained patients (n=84). Based on the decrease in the proportion of high-risk node-negative patients, a calculation of chemotherapy-related costs saved was made. RESULTS: The proportion of patients with <12 LNs examined decreased from 87% in 1999 to 48% in 2007 (p(trend)<0.0001). In the stained group this was 37%, versus 56% for the unstained group (p=0.010). In 1999, 79% of stage II patients were high-risk compared to 55% in 2007, which translates to a saving of almost 1,000,000 euro based on 92 stage II patients diagnosed in 2007. CONCLUSION: A diverse set of measures increased the number of examined lymph nodes among patients with colon cancer. Large savings can be made due to the reduced proportion of high-risk node-negative patients who would otherwise have received adjuvant chemotherapy.

Systemic air embolism after cardiopulmonary resuscitation in a preterm infant.

UNLABELLED: We report a preterm infant with extensive systemic air embolism after cardiopulmonary resuscitation for cardiac arrest due to an occluding thrombus in the inferior vena cava. After excluding other potential causes (air infusion, necrotizing enterocolitis or pulmonary leakage syndrome), we postulate that the pressure gradient needed for air embolism to occur is related to the resuscitation procedure. An important clue of air embolism was noted on the chest X-ray taken before death showing intracardial air. CONCLUSION: Systemic air embolism may occur as a very rare complication after cardiopulmonary resuscitation.

[Eosinophilic fasciitis; the importance of early detection for optimal outcomes]. / Eosinofiele fasciitis, het belang van een tijdige herkenning voor de genezing.

Eosinophilic fasciitis (EF) is a disease with unknown aetiology, although an immunologic pathogenesis is suspected. The characteristic features of this inflammatory disease include scleroderma-like skin indurations, predominantly on the extremities, and peripheral blood eosinophilia. Internal organs are generally not affected. Initiation of systemic glucocorticoid therapy at an early stage results in a good response and remission of symptoms. This is illustrated in 3 cases of EF to demonstrate the importance of early detection in this disease.

A highly active and tolerable neoadjuvant regimen combining paclitaxel, carboplatin, 5-FU, and radiation therapy in patients with stage II and III esophageal cancer.

BACKGROUND: The present phase II study aimed to assess the feasibility and efficacy of a new paclitaxel-based neoadjuvant chemoradiation regimen followed by surgery in patients with stage II-III esophageal cancer. METHODS: From January 2002 to November 2004, 50 patients with a potentially resectable stage II-III esophageal cancer received chemotherapy with paclitaxel, carboplatin, and 5-FU in combination with radiotherapy 45 Gy in 25 fractions. Surgery followed 6-8 weeks after completion of neoadjuvant treatment. PATIENT CHARACTERISTICS: male/female: 44/6, median age 60 years (34-75), median WHO 1 (0-2), adenocarcinoma (n = 42), squamous cell carcinoma (n = 8). Toxicity was mild, and 84 % of the patients completed the whole regimen. Forty-seven patients underwent surgery with a curative intention (transhiatal n = 44, transthoracic n = 3). Pathologic complete tumor regression was achieved in 18 of 47 operated patients (38%). R0 resection was achieved in 45 of 47 operated patients (96%). There were four postoperative deaths (8.5). Postoperative complications were comparable with other studies. After a median follow-up of 41.5 months (21-59) estimated 3- and 5-year survival on an intention-to-treat basis was 56 and 48%. Estimated 3-year survival in responders was 61%, in nonresponders 33%. CONCLUSION: This novel neoadjuvant chemoradiation regimen for treatment of patients with stage II-III esophageal cancer is feasible. Results are encouraging with a high pathologic complete tumor regression and R0 resection rate and an acceptable morbidity and mortality. Preliminary survival data are very promising.

[A patient with vague inguinal complaints due to a leiomyosarcoma of the inferior caval vein]. / Een patiënt met vage liesklachten door een leiomyosarcoom van de v. cava inferior.

A 64-year-old male presented with progressive right-sided inguinal pain radiating to the right flank and lower back. He had noticed an infrequent altered sensibility on frontal parts of his right upper leg. Physical examination demonstrated the presence of a process in the lower abdomen. Computer tomography showed a retroperitoneal tumor with a 10 cm diameter that probably originated from the inferior caval vein (ICV). During an explorative laparotomy a tumor that was compressing the right N. genitofemoralis was radically removed together with the right kidney and the ventral wall of the ICV. The histological diagnosis was a radically removed leiomyosarcoma. Based on the clinical picture, diagnostic imaging and pathologic examination the diagnosis leiomyosarcoma ofthe ICV was confirmed. A leiomyosarcoma of the ICV is a rare tumor with atypical symptomatology and a slow growth rate often leading to a late diagnosis. Surgery is the only effective treatment. The prognosis is moderate.

Intrauterine fetal death due to Farber disease: case report.

We report a case of Farber disease in a fetus who died in utero at a gestational age of 29 weeks. Macroscopic examination showed moderate postmortem changes in a microcephalic female fetus (46,XX) with mild internal hydrops, two vessels in the umbilical cord, and a moderately enlarged, relatively well-preserved spleen. Microscopic examination showed foamy cells in the spleen. Electron microscopic examination revealed the presence of Farber bodies within these foamy cells. Enzyme studies of the fetus were not possible because all tissues were formalin fixed. Lipids were extracted from formalin-fixed tissues and increased levels of ceramide and the presence of hydroxyceramide in tissue of the spleen, liver, and lung were found. Glucosylceramide was not increased excluding saposin-precursor-deficiency. Because of these findings, both parents were tested for acid ceramidase activity in their leukocytes. They both had markedly reduced enzyme activity consistent with heterozygosity for Farber disease. To the best of our knowledge, this is the first published case of Farber disease in Dutch nonconsanguineous parents.

Occult abortion: not a major cause of infertility.

OBJECTIVES: To determine whether occult abortion is a frequent cause of infertility. DESIGN: Prospective observational clinical study. SETTING: Hospital based infertility clinic, serving as the only primary infertility care facility to a population of 250,000 people. PATIENTS: 102 subsequent infertility patients. INTERVENTIONS: Ultrasound ovulation detection, timed hCG determinations. MAIN OUTCOME MEASURE: Proportion of patients with serum hCG levels > 2.0 mIU/mL (> 2.0 IU/L) on days 12 or 13 after ultrasound-proven ovulation with subsequent appearance of the menstrual period before or at postovulation day 14. RESULTS: In 18 of 102 patients increased hCG was found. All these patients became clinically pregnant (9 spontaneous abortions, 9 ongoing pregnancies). No occult abortion occurred (95% confidence interval 0-4%). CONCLUSIONS: Occult abortion is not a frequent cause of infertility in an unselected population.

Fluorescence in situ hybridization on paraffin-embedded abortion material as a means of retrospective chromosome analysis.

A fluorescence in situ hybridization (FISH) procedure was used to detect chromosome abnormalities in archival abortion material. Nuclei were isolated from 50-microns-thick tissue blocks from 18 selected and karyotyped abortions. Five probes for repetitive centromeric sequences of chromosomes 1, 16, 18, X and Y were used. For each chromosome, at least 200 nuclei were scored blindly, i.e. without knowledge of the karyotype. The FISH results obtained were compatible with the cytogenetic data in 14 cases. There were four discrepancies. Two of these were observed for cases karyotyped as trisomy 16. Furthermore, FISH results showed trisomy 18 in two cases having normal chromosomes 18 and 18q+, respectively. The latter case was not discrepant if the structural rearrangement involved chromosome 18 material. The remaining discrepancies could be explained by chromosomal mosaicism. Admixture of normal maternal cells was also noted. It is concluded that FISH can be used to study retrospectively the presence of chromosome abnormalities in abortion material. However, the quality obtained after the use of fresh material is superior.

Comparison of histological features in early spontaneous and induced trisomic abortions.

Qualitative and quantitative histological features of a series of induced (n = 6) and spontaneous (n = 24) trisomic abortions were compared. The chorionic villi of induced abortions were large and of irregular contour. The stroma contained many blood vessels and did not show fibrohyalinic change. The intact trophoblast demonstrated 'hyperplasia'. Contrastingly, spontaneous abortions were composed of smaller villi with somewhat more fibrohyalinic stroma containing a few blood vessels. The trophoblast did not show 'hyperplasia'. However, many syncytial knots were present. Although some of histological features were shown to relate to gestational age, which could not be completely matched for, it was unlikely that this could account for the observed differences. Analysis restricted to induced and spontaneous abortions of comparable gestational age demonstrated the same differences. The time-lag between first blood loss and final gestational loss in spontaneous abortions did not appear to be of influence on any of the variables. The striking histopathological differences between induced and spontaneous abortions are mainly considered to be due to cessation of circulation at some time and to disintegration of trophoblast as a result of ischaemia in spontaneous abortions.