An 8-year-old male patient reported to our institution with a chief complaint of facial asymmetry in the lower portion of his face for 5 months. The swelling was initially pea sized and gradually increased to its final dimensions. The patient gave a history of extraction of grossly carious lower right deciduous molar with no reduction in the size of the swelling. On extraoral examination, facial asymmetry with a solitary localised oval-shaped swelling measuring 20 mm × 20 mm was seen on the right side of the face near the body of mandible []. On palpation, the swelling was noted to be well defined, hard in consistency, non-tender, non-pulsatile and non-fluctuant. Localised ipsilateral submandibular lymphadenopathy was also evident. Intraorally, obliteration of the lower buccal vestibule on the right side was noted []. OPG revealed 'onion skin' appearance at the inferior border of the mandibular body suggestive of a periosteal reaction [].
Based on the clinical and radiographic findings, the lesion was diagnosed as Garre's osteomyelitis and surgical recontouring under general anaesthesia was planned []. Extraoral approach was used to expose the lesion, and the excess bony mass was excised using surgical bur and handpiece. The excised bone fragments [] were subjected to histopathological examination which revealed trabeculae of bone with osteoblastic rimming and reversal lines together with a chronic inflammatory infiltrate. The microscopic picture confirmed the diagnosis of Garre's osteomyelitis. The patient was followed up 3 months post-surgery with no recurrence of the lesion [].


A 19-year-old male patient, with no significant past medical history, wearing glasses for myopia, presented to St John Eye Hospital complaining of both eyes redness and a blurred vision of one-month duration following recovery from COVID-19 (). The patient tested positive for SARS-CoV-2 by RT-PCR obtained from a nasopharyngeal swab on Dec 1, 2020 (). He was suffering from fever with a temperature of (41°C), cough, headache, joint pain, and skin rash (). One month later he developed pneumonia, he was treated as an outpatient by systemic oral antibiotics (azithromycine 500 mg daily for one week and oral dexamethasone (6 mg daily for five days). The patient started to complain of blurred vision, redness, and pain in both eyes five weeks post-positive PCR testing. At the initial examination on Jan 28, 2021, his best-corrected visual acuity was 6/18 in the right eye and 6/60 in his left eye. Slit-lamp examination of the right eye showed conjunctival hyperemia, corneal edema and endothelial KPs (keratic precipitates), anterior chamber inflammatory cells with normal fundus examination. Left eye examination showed signs of more aggressive behavior with conjunctival hyperemia, corneal edema and kPs, anterior chamber hypopyon, iris deposits over the lens anterior capsule, clear vitreous, and normal fundus examination. Intraocular pressure measured with Goldmann tonometer was 13 mm Hg in both eyes. The patient was started on topical steroids (one drop/hour/daily in the first week then slowly tapered by decreasing one drop per day each week till stopping it,) systemic steroids (1 mg/kg) and cycloplegics, (cyclopentolate 1%). Laboratory tests to rule out other possible infectious or autoimmune diseases were performed and described in . The diagnosis of bilateral anterior uveitis secondary to COVID-19 infection was made. On his follow-up visit at the uveitis clinic on Feb 9, 2021, the patient showed a significant improvement, the best-corrected visual acuity was 6/12 in the right eye and 6/15 in the left eye, slit-lamp examination revealed clinical improvement with white conjunctiva, clear cornea, and a quiet and deep anterior chamber. His last follow-up was on May 11, 2021, he is off medications with quiet eye examination and best corrected visual acuity (BCVA) 6/6 in both eyes.


A 29-year-old male patient, wearing glasses for myopia and astigmatism, presented to St John Eye Hospital on Jan 24, 2021 complaining of blurred vision in both eyes and pain of six weeks duration (), there was no history of joint pain, oral or genital ulcers, or skin rashes. Two months prior to his presentation, the patient suffered from fever, cough, and headache but he ignored his symptoms and did not seek any medical advice, neither PCR nor serology test for COVID-19 were done at that time. At the initial examination, his best-corrected visual acuity was 6/18 in both eyes. Slit-lamp examination for both eyes showed vascular sheathing (), quiet anterior segment, minimal lens opacities, web-like vitreous veils with big white snowballs adherent to the vitreous webs (). Intraocular pressure measured with Goldmann tonometer was 13 mmHg in both eyes. The laboratory tests done for the patient are included in . Behçet's disease was ruled out (no positive criteria in the history for all the scoring systems). The patient was subjected to COVID-19 antibody test (IgG), six weeks post-development of his viral symptoms, the test came back positive. The diagnosis of intermediate and posterior uveitis secondary to COVID-19 was made after excluding all other possible infectious and noninfectious causes.
The patient was treated with prednisone 1 mg/kg for one week then tapered by 5 mg each week through his follow-up period, topical steroid pred forte (prednisolone acetate) was given every hour during the first week then tapered slowly. During his follow-up visits in February and March 2021, patient was doing well, his best-corrected visual acuity improved to 6/7.5 in both eyes. On April 8, 2021, the patient presented to the clinic with flare up in the right eye and increased vitreous opacity while he was on prednisone 5 mg daily. Leptospira immunoglobulin test was requested in April 2021—after the paper submission—but unfortunately is not available in Palestine and due to COVID-19 pandemic restrictions, we could not send him to do the test in nearby countries, However, he was discharged on prednisone 1 mg/kg, Imuran™ (azathioprine), steroid sparing agent was added. On May 6, 2021, the patient was on prednisone 20 mg daily, azathioprine 50 mg twice daily, with significant improvement upon examination.


A 62-year-old male patient, with no significant past medical history and known ocular history of right eye primary angle-closure glaucoma controlled by COSOPT® eye drops (timolol 0.5%, dorzolamide 2%), He underwent right eye phacoemulsification and intraocular lens implantation on Nov 29, 2020, due to a right eye cataract. On Dec 28, 2020, he tested positive for COVID-19 by RT-PCR. He did not complain of any respiratory symptoms and all blood tests were normal (). The only complaint was recurrent attacks of right eye pain, redness, and blurred vision with no photophobia. He was referred to our uveitis clinic on Feb 5, 2021, for further investigations. At the initial examination, his best-corrected visual acuity was 6/9 in the right eye and 6/6 in his left eye. Slit-lamp examination was remarkable for right eye mild conjunctival hyperemia, with multiple corneal keratic precipitates (KPs) (, white arrow), and a deep anterior chamber with +4 cells (, yellow arrows). Fundus examination revealed a clear vitreous and flat healthy retina. Intraocular pressure measured with Goldmann tonometer was 11 mmHg in both eyes. Under the diagnosis of right eye iridocyclitis mostly secondary to COVID-19 infection, the patient was treated with topical steroids (dexamethasone 1 mg/mL) one drop/hour/daily in the first week then slowly tapered by decreasing one drop per day each week till stopping it, cyclopentolate 1% was instilled three times daily for 1 week then stopped. Seven days later, the patient showed a significant improvement, the best-corrected visual acuity was 6/7.5 in the right eye, slit-lamp examination revealed clinical improvement with white conjunctiva, clear cornea with few KPs, and a few cells in the anterior chamber. The plan was to stop cycloplegics, tapering steroids, and to continue his follow-up in the glaucoma clinic.


A 77-year-old man presented with a 1-week history of asthenia, dyspnoea, and confusion after a dog bite on the left hand 10 days previously. He had a history of ischaemic stroke, dyslipidaemia, essential thrombocythaemia, and hypertension. He also reported histories of heavy alcohol consumption and 30 pack-year smoking. At admission, his temperature and heart and respiratory rates were 37.5°C, 100/min, and 20/min, respectively. Physical examination revealed oedema of the left leg. Blood tests showed haemoglobin 11g/dL, total leucocyte count 37,400/mm3, with 33,660/mm3 neutrophils, platelet count 734,000/mm3, C-reactive protein 320 mg/L, and serum creatinine 178 µmol/L. Thoracic-abdominal computed tomography angiography revealed aneurysms on the abdominal aorta (38 mm diameter), left common femoral artery (43 mm diameter), and left popliteal artery (33 mm diameter) (). Six days later, 18F-fluorodeoxyglucose positron emission tomography-CT confirmed three growing inflammatory aneurysms, on the left common femoral (diameter 64×72 mm, Standardised Uptake Value (SUV) 12) and left (diameter 43×29 mm, SUV 10) and right (diameter 35×28 mm, SUV 10) popliteal arteries (); the abdominal aorta was normal. Cerebral magnetic resonance imaging and transthoracic and transoesophageal echocardiography were normal. While hospitalized, his left leg was very painful and increased in volume. Ultrasonography Doppler revealed thrombosis of the deep common and superficial femoral veins. The left common femoral and popliteal aneurysms were resected and replaced using the right saphenous vein. After 11 days, cultures of the femoral aneurysm were positive for Capnocytophaga canimorsus. Identification was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) on three different isolates. The MALDI-TOF MS score identification was 2, 29. The strain was susceptible in vitro to beta-lactams, aminoglycosides, fluoroquinolones, tetracycline, and trimethoprim-sulfamethoxazole, and resistant to macrolides. A post-surgery blood culture was positive for Escherichia coli, probably due to a superinfection of aneurysms; identification was performed using MALDI-TOF MS; the bacteria has no acquired antibiotic resistance. The patient received piperacillin–tazobactam 12 g/day, and then amoxicillin/clavulanic acid 6 g/day for 1 month, which allowed to the treat the two bacteria. No aetiology other than bacterial infection was found to explain the rapid expansion of this aneurysm. The symptoms and the incubation period was not in favor for a rabies. Other aetiology of infected aneurysms was eliminated by blood culture and serological test. Temporal artery biopsy was not in favor for a Horton disease. Serological tests performed for auto immune disease were negative. As his brother also has a history of arterial aneurysms, genetic research for a familial form of aneurysm is planned. The outcome was favourable.


A 55-year-old male with a 2-year history of progressive numbness of the right lower extremity complained of weakness of the right leg for 4 months. He had no history of back pain or any injury. The patient went to the local hospital and was transferred to our institute for investigation. One month before referring, he developed urinary incontinence and constipation. The neurological examination revealed paresis of the right lower extremity (muscle strength 4/5). There was a decrease in pinprick sensation over the entire right lower extremity. Hyperreflexia and the presence of the Babinski sign were observed in the lower extremities. Magnetic resonance imaging (MRI) of the thoracolumbar spine revealed abnormal hyperintense T2 signal representing spinal cord congestion extending from the conus medullaris to the level of T5 and intradural flow voids along the anterior surface of the spinal cord [Figure and ]. Contrast-enhanced magnetic resonance angiography (MRA) of the thoracolumbar spine demonstrated hypertrophic PSA arising from the L3 segmental artery, fistulous point, and tortuous and enlarged intradural vessels in the midline location extending from the level of L3 to upper thoracic level []. Spinal angiography showed the FTAVF at the level of L3, which is supplied by the artery of the filum terminale continuing from the ASA originating from the left T10 intercostal artery with cranial drainage through the dilated vein of the filum terminale into the tortuous perimedullary veins []. In addition, the FTAVF received additional supply from the enlarged PSA arising from the right L3 segmental artery. The PSA connected with the ASA via the arterial branch along the right-sided conus medullaris [Figure , and ]. Spinal angiography of the bilateral iliac arteries showed no arterial supply to the fistula. Due to the enlarged of the PSA, we decided to proceed with endovascular as the first choice. We used Magic microcatheter 1.2 Fr (Balt, Montmorency, France). Fortunately, it was not difficult to navigate the microcatheter through the course of the PSA and the tip of microcatheter could be wedged stably the target point just proximal to the fistula. Without heparinization, transarterial embolization with N-butyl cyanoacrylate (NBCA) through the PSA was successfully performed with reaching the proximal draining vein [Figure and ]. Mixture of NBCA and an oil-based contrast agent (Lipiodol Ultra Fluid; Guerbet, Aulnay-sous-Bois, France) was prepared in proportions of 1:0.7 ratio of NBCA to Lipiodol. Spinal angiography after embolization demonstrated complete obliteration of the filum terminale arteriovenous fistula with preservation of the PSA and an anastomotic basket forming from the anterior and posterior spinal arteries [Figure and ]. After endovascular treatment, the patient had gradually improved. Follow-up MRI and MRA of the thoracolumbar spine, obtained 6 weeks after embolization, confirmed complete obliteration of the fistula the disappearance of intradural flow voids and significant resolution of spinal cord congestion []. At the 4-month follow-up, he had completely recovered without urinary incontinence and constipation.


A 58-year-old male with a 3-year history of low back pain radiating to both legs complained of progressive weakness and numbness of lower extremities for 3 months. He had no prior history of any injury. Urine retention and constipation were noticed 1 month before the hospitalization. He was unable to walk more than about 100 meters without stopping to rest. The neurological examination revealed the evidence of spastic paraparesis (muscle strength 4/5) and the lack of pinprick sensation below L1 level. Hyperreflexia and the presence of the Babinski sign were observed in the lower extremities. MRI of the lumbrosacral spine revealed abnormal hyperintense T2 signal with patchy enhancement representing spinal cord congestion extending from the conus medullaris to the level of T8. There were abnormal intradural flow voids on the posterior surface of the spinal cord from the level of T5 to the conus medullaris. Furthermore, there were herniated nucleus pulposus at the level of L2-S1, thickened ligamentum flavum with hypertrophic facet joints at the level of L3-5, and grade I degenerative spondylolisthesis at the level of L4-5 and hypertrophic facet joints, causing severe spinal canal stenosis at L4-5 compressing the cauda equina []. Contrast-enhanced MRA of the thoracolumbar spine demonstrates tortuous and enlarged intradural vessels in the midline location at the level of L4-5 [].
Spinal angiography demonstrated the FTAVF at the level of L4-5, which is supplied by the PSA, originating from the left L2 segmental artery, connecting with the ASA giving rise the artery of the filum terminale supplying the fistula with cranial drainage into the dilated vein of the filum terminale connecting to the medullary veins [Figure and ]. The fistula also fed by the left LSA, originating from internal iliac artery []. The patient underwent surgical treatment. After durotomy, the arachnoid membrane was found to be thickened and opaque. The filum terminale was adhered within the clumping of the cauda equina nerve roots []. Following lysis adhesions and displacement of nerve roots, the FTAVF was identified and obliterated with small silver vessel clips []. His postoperative course was uneventful. Spinal angiography obtained 2 weeks after the operation confirmed the disappearance of the fistula [Figure and ]. Three months after the surgery, follow-up MRI of the lumbrosacral spine also confirmed the regression of spinal cord congestion []. The patient had gradually improved until being ability to walk independently 6 months later.


A 44-year-old male presented with progressive weakness of left upper and lower limbs for 1 month. There was no history of headache, vomiting, or seizures. He did not have any other comorbid illnesses, addictions, allergies, or significant family history. On examination, his vital signs were stable. He was fully conscious and his cranial nerve examination was normal. He had Grade 4/5 power in the left upper limb. The power in the left hip and knee was 3/5 while ankle flexion and extension were 3/5 and 4/5, respectively. Both right upper and lower limbs had 5/5 power. The deep tendon reflexes were brisk on the left upper and lower limbs, and Babinski sign was positive on the left side. Examination of rest of the neurological system and that of other systems were normal.
His blood investigations were normal. Magnetic resonance imaging (MRI) of the brain with gadolinium contrast showed a 4.0 cm × 5.0 cm × 6.5 cm extra-axial mass lesion in the right mid-third of the parasagittal region [Figure and ]. The lesion was abutting the superior sagittal sinus and extending down along the falx and had multiple hypodense areas within the lesion. It showed weak heterogeneous enhancement with contrast [Figure and ]. There was mild mass effect on the adjacent brain parenchyma.
He underwent a right mid-third parasagittal craniotomy and tumor excision. The specimen was sent for histopathological examination. Following the surgery, his left sided weakness gradually resolved and wound healed. Postoperative contrast-enhanced MRI scan did not show any residual tumor [Figure and ].
The specimen was composed of multiple gray-white pieces together measuring 5 cm × 5 cm × 4 cm. Cut section of the larger pieces showed gray-white and yellowish areas. Light microscopy showed a tumor composed of meningothelial cells arranged in sheets and vague whorled pattern. There were multiple aggregates of foamy cells amid the meningothelial cells [Figure and ]. Occasional mitotic figures were noted. There was no pleomorphism, increased cellularity, necrosis, or brain invasion. Immunohistochemistry for epithelial membrane antigen (EMA) showed positivity in the meningothelial and xanthomatous areas [], but CD68 was positive only in the xanthomatous areas []. Considering these features, a diagnosis of xanthomatous meningioma of the World Health Organization (WHO) Grade I was made.


A 33-year-old female and her spouse were transferred to the emergency department of our teaching hospital after sustaining road traffic accident, when their motorbike was allegedly hit by a truck. The husband, who was in the driving seat, was pronounced dead immediately on arrival. The woman, who was a pillion rider, sustained severe head injuries with massive brain laceration and gross extrusion of brain tissues from the forehead []. Imaging revealed hemorrhagic contusions in bilateral frontal lobes, fracture of frontal bone involving frontal sinus, crista galli and anterior skull base with dural tears, blowout fracture of the left orbit, and all the walls of the right orbit. Emergency craniotomy with cranialization of frontal sinus was performed. Dural repair was carried out with synthetic polypropylene fabric patch (G-Patch; G. Surgiwear® Limited, India) to prevent CSF leak. Cranioplasty was not done due to the presence of open, contaminated wound. Our patient tolerated the procedure well and had an uneventful early postoperative period. Three months after the procedure, she presented to us with complaint of purulent discharge from an opening at the incision site. On inspection, a punched-out discharging wound of about 1 cm diameter was seen on the forehead []. Gram stain and culture from the discharge turned out negative. Contrast-enhanced MRI showed mixed intensity ring-enhancing lesions measuring 1.2 × 1.4 cm and 1.3 × 1.1 cm in frontobasal extradural space communicating with the skin of forehead suggestive of abscess formation []. Our patient was started on intravenous flucloxacillin for 6 weeks. Despite giving antibiotics, the discharge continued. Surgery was planned. Intraoperatively, abscess was identified between G-Patch (Surgiwear®) and duramater []. The synthetic dura was removed and abscess drained. Histopathology showed foreign body granuloma with giant cell and chronic inflammatory features. Follow-up after 6 months showed healed scar at the abscess site [].


A 63-year-old female presented with 30 years duration of acromegaly (i.e. a large forehead, jaw, nose, hands, and feet), newly presented with bilateral arm dysesthesias, and neck pain. On neurological examination, she exhibited no focal deficits. The cervical magnetic resonance (MR) showed a CM1 (i.e. 7 mm herniation of the cerebellar tonsils of below the foramen magnum), a C2-T5 syrinx, while the brain MR documented a pituitary adenoma [-].
The preoperative endocrine examination revealed that GH and insulin-like growth factor-1 (IGF-1) levels were elevated at 13.8–369 ng/ml, respectively. Further, the GH level was not suppressed after the oral glucose tolerance testing.
The patient underwent a suboccipital/foramen magnum decompression (FMD), with C1 posterior arch resection. Postoperatively, her forearm dysesthesias improved. Due to the need to treat newly diagnosed colon cancer, the patient’s GH-producing pituitary lesion was managed medically (i.e. with a long-acting somatostatin analog therapy). The subsequent endocrine examination after somatostatin analog therapy revealed that her GH and IGF-1 levels declined to 3.27–100 ng/ml, respectively.


A 47-year-old hepatitis B positive male underwent L4-L5 microdiscectomy 45 days ago. He newly presented with low back and bilateral gluteal pain (i.e., VAS score 8 and 5 respectively) and swelling under the surgical scar. The lumbar ultrasound showed a deep dorsal paraspinal collection extending from L3 to L5 in the subcutaneous and intramuscular region. The MRI additionally revealed diffused vertebral body edema with a large intraspinal/ paraspinal and anterior epidural fluid collection from L4 to S1 []. First, 5 cc of whitish pus was aspirated under ultrasound guidance and it was sent for RT-PCR MTB, culture/sensitivity(C/S), Gram staining, and ZN staining for acid-fast bacilli (AFB). The results of all samples came back negative. However, as the ESR (erythrocyte sedimentation count) and C-reactive protein (CRP) levels were elevated, the patient was presumptively treated for bacterial spondylitis with cefepime and amikacin. Surgically, the entire abscess was drained and the wound was debrided. Samples were sent for histopathological and RT-PCR evaluations. The patient’s clinical symptoms fully resolved postoperatively.
The histopathological report showed epithelioid cell granulomas with central caseation surrounded by Langhans type giant cells []. ZN stain for AFB was also positive []. The RT-PCR for MTB was again negative. Antitubercular drug therapy (ATT) of four drugs (HRZE) was started. One month later, both CRP and ESR decreased [].
The plan was to continue the four drugs for 2 months followed by a three drugs (HRE) regimen for another 10 months.


Case I. A 29-year-old woman with three pregnancy losses before 10 weeks’ gestation repeatedly tests positive for anticardiolipin antibodies with titers of 30 and 32 IgG (above 99th percentile) phospholipid units, respectively. Does treatment with aspirin and/or low molecular weight heparin (LMWH) improve her chance of a successful pregnancy?


Case II. A 40-year-old woman with two early pregnancy losses is found to have persistent presence of lupus anticoagulant. Should she be counseled for antithrombotic treatment to prevent a third pregnancy loss?
Obstetrical complications of the antiphospholipid syndrome can manifest in women with and without a history of thrombotic events. These include recurrent early pregnancy loss, fetal death or (pre)eclampsia, intrauterine growth restriction, and other consequences of placental insufficiency. Traditionally it is hypothesized that pregnancy complications in antiphospholipid syndrome are the result of a hypercoagulable state, partially mediated by thrombosis of the placental vasculature. Recent hypotheses describe a more intertwined pathophysiological mechanism in which the coagulation system as well as inflammation are involved., , , The inhibitory effect of antiphospholipid antibodies on proliferation of trophoblasts of the placenta has been proposed as the pathogenic mechanism in early pregnancy loss, whereas late obstetrical complications have been attributed to a dysfunctional vasculature of the placenta., , , These placenta-mediated complications include preeclampsia, late pregnancy loss, placental abruption, and intrauterine growth restriction.
Possible effects on complement activation may be of more importance and it has been hypothesized that the non-anticoagulant effects of heparins on inflammatory processes, vascular function, or placental pathology may play a role in prevention of pre-eclampsia, a disorder strongly associated with antiphospholipid syndrome., Moreover, antiphospholipid antibodies appear to affect the production of several chemokines and angiogenic factors by human endometrial endothelial cells, which may contribute to impaired placentation and vascular transformation. The risk of (recurrent) pregnancy complications may differ between women with and without previous complications, women with high and low antiphospholipid antibodies titers, and women with positive and negative LAC., , Antithrombotic therapy reduces the risk of recurrent (either venous or arterial) thrombosis in antiphospholipid syndrome., Both aspirin and heparin may have a beneficial effect on coagulation and inflammation,, , and are thought to reduce the risk of pregnancy loss in antiphospholipid syndrome.
To answer the questions posed by our patients, we performed a systematic review and meta-analyses of the evidence available from randomized trials to evaluate the effects of different antithrombotic therapies on pregnancy outcome in women with recurrent pregnancy loss and antiphospholipid antibodies., As antiphospholipid syndrome is a heterogeneous disease, we chose to focus specifically on women with a history of recurrent pregnancy loss. The primary outcome was defined as live birth. Eleven trials including 1672 women met the inclusion criteria. None of the trials had a no treatment comparator arm. Full details of the methods and extracted data are described in the supporting information. Here, we summarize our findings by addressing the questions most important for clinical practice, “who, what, and how” (Table ).
Based on the individual history of obstetrical complications, treatment during the subsequent pregnancy can be considered. Table provides an overview of current guidelines and recommendations for preventing pregnancy loss in women with antiphospholipid syndrome, stratified for history of obstetrical complications. It is important to note that all available evidence underlying these recommendations concerns women with persistent antiphospholipid antibodies and recurrent early pregnancy loss. High-level evidence for the other clinical criteria is virtually absent and management suggestions are extrapolated from mostly observational evidence and expert opinion. Non-criteria obstetric antiphospholipid syndrome is defined as two early pregnancy losses or delivery after 34 weeks of gestation due to severe (pre)eclampsia. In these women treatment might be considered based on the individual’s risk profile, for instance a high-risk antiphospholipid antibody profile but no history of thrombosis or pregnancy complications. A high-risk antiphospholipid antibody profile is defined as presence of lupus anticoagulant, double or triple antiphospholipid antibody positivity, or persistently high antiphospholipid antibody titers.
Our search identified 11 randomized trials evaluating antithrombotic treatment in women with recurrent pregnancy loss and antiphospholipid syndrome. Study characteristics are presented in Table . The identified trials differed in terms of inclusion criteria and compared a variety of interventions. One trial compared aspirin with placebo, five trials compared heparin (unfractionated heparin [UFH] or LMWH) plus aspirin with aspirin only,, , , , one trial compared LMWH with aspirin, two trials compared LMWH with UFH (both in combination with aspirin),, and two trials investigated the combination of different doses of heparin (either UFH or LMWH) with aspirin., We did not identify trials with a no treatment comparator arm during pregnancy. Three of 11 trials included women with two or more pregnancy losses. In 8 of 11 trials participants met the clinical criteria for antiphospholipid syndrome with three or more early miscarriages. The mean number of previous pregnancy losses ranged from 3.0 to 4.3. Previous pregnancy losses were mostly early pregnancy losses, but this was only specified in 5 of 11 included studies. All trials included participants with persistent presence of antiphospholipid antibodies, but the timeframe between tests varied.
The use of aspirin during pregnancy in antiphospholipid syndrome is widespread. Our search identified one placebo-controlled trial of 40 women with antiphospholipid antibodies and recurrent pregnancy loss evaluating aspirin treatment. This trial, at high risk of attrition bias due to incomplete reporting of outcome data, found no difference in live birth rate with aspirin compared to placebo (risk ratio [RR] 0.94; 95% confidence interval [CI] 0.71–1.25; GRADE very low-certainty evidence, Figure ).
The small sample size and methodological limitations hamper the conclusions that can be drawn from this study and these results do not provide evidence to support aspirin only for prevention of pregnancy loss in this population. In the general population as well as in women with a history of one to two previous pregnancy losses, preconception aspirin does not increase live births, as shown in the EAGER trial. However, aspirin is effective in reducing the risk of preeclampsia in high-risk women., Therefore, considering antiphospholipid antibodies a risk factor for preeclampsia, it is very reasonable to use aspirin for prevention of preeclampsia in women with recurrent pregnancy loss and antiphospholipid syndrome.
One trial of 141 women with antiphospholipid syndrome reported the results of a head-to-head comparison of LMWH only and aspirin only. Women treated with LMWH had a higher live birth rate of 86.3%, compared to a 72.1% live birth rate in the women treated with aspirin only (RR 1.20, 95% CI 1.00–1.43, 1 trial, 141 women, Figure in supporting information). All other trials evaluated heparin in combination with aspirin.
Five trials with a total of 1295 women that compared heparin (either UFH or LMWH) combined with aspirin to aspirin only, were included in a random-effects meta-analysis for the primary outcome live birth. The pooled RR for live birth was 1.27 (95% CI 1.09–1.49; Tau2 = 0.01; Chi2 = 7.71, I2 = 48%; GRADE low-certainty evidence) in favor of heparin plus aspirin compared to aspirin only., , , , There was significant heterogeneity between the subgroups of LMWH and UFH (RR for LWMH plus aspirin versus aspirin 1.20, 95% CI: 1.04–1.38; RR for UFH plus aspirin versus aspirin 1.74, 95% CI: 1.28–2.35; test for subgroup differences: I2 =78.9%, p = .03, Figure ). The observed live birth rate in the aspirin-only comparator arms of the UFH studies was considerably lower compared to these in the LMWH studies; 42.9% versus 70.4%. We performed a sensitivity analysis excluding two studies for serious methodological limitations; one (n = 50) at high risk of selection bias due to the quasi-randomized design, one (n = 1015) at high risk of attrition bias due to incomplete reporting of outcome data. This did not materially change the combined (UFH +LMWH) pooled result (RR for live birth 1.20, 95% CI 0.91–1.59; I2 = 58%), but the benefit of LMWH plus aspirin compared to aspirin only was attenuated (RR for live birth 1.07; 95% CI 0.88–1.29, Figure ). Furthermore, after excluding the largest and most recent trial, the statistical significance for all heparin trials was lost.
There was no statistically significant difference in live birth between LMWH and aspirin versus UFH and aspirin (RR 1.44, 95% CI 0.80–2.62, 2 trials, 86 women; p = .17; I2 = 48%; Figure in supporting information)., Heparin appears to improve live birth rates, but the low live birth rates in the comparator arms in the UFH studies may lead to an overestimation of the effect of UFH. The observed beneficial effect of LMWH plus aspirin on the other hand is mostly driven by a recently published large single-center trial (n = 1015) that found a 90.3% live birth rate in women treated with LMWH plus aspirin, compared to 70.1% in those treated with aspirin only. Table provides an overview of study outcomes and certainty of the evidence for the two main comparisons: (1) aspirin versus placebo and (2) heparin plus aspirin versus aspirin only.
Notably, adverse events associated with heparin therapy, easy bruising at injection site or allergies, did not seem to occur frequently or were not reported. LMWH is a reasonable alternative treatment and currently most often used in clinical practice, with its similar efficacy and superior safety profile compared to UFH.
We observed a wide variation in treatment initiation and duration between trials. Aspirin treatment was started preconceptionally in most trials and continued to 36 weeks of gestation, , , or full-term pregnancy., LMWH or UFH was started upon pregnancy confirmation in most studies evaluating heparin treatment. In the trial by Rai et al., aspirin treatment was started upon pregnancy confirmation and when fetal heart activity was confirmed on ultrasound women were randomized to additionally start UFH or continue aspirin only. Four trials initiated treatment at the first confirmation of pregnancy and treatment was continued until 34 weeks of gestation, 35 weeks of gestation,, or study duration. One trial started aspirin before conception, with heparin (LMWH or UFH) started in the luteal phase for a maximum of three cycles until delivery and continued postpartum in a prophylactic dose. The mean gestational age at randomization, and thus treatment initiation, varied largely between studies with one study allowing randomization before 12 weeks of gestation. Given the heterogeneity in treatment protocols, it is not possible to provide recommendations on optimal timing of treatment initiation and duration. A recent study that compared early initiation of LMWH (gestational age 5 weeks) to later initiation observed ongoing pregnancy rates of 81% at 12 weeks’ gestation and 61%, respectively. Live birth rates differed between the groups, 70.8% in the early initiation group and 56.5% in the later initiation group, respectively, but this difference was not statistically significant. Also, late pregnancy complications associated with antiphospholipid syndrome, including preeclampsia, intrauterine growth restriction, and intrauterine fetal death, were not statistically significantly different between the two study groups. Similarly, another placebo-controlled trial reported higher ongoing pregnancy rates at 24 weeks’ gestation in women treated with LMWH and aspirin preconceptionally, but live birth overall was not affected. Initiation of heparin preconceptionally would be undesirable from a patient’s perspective, but whether heparin can be safely discontinued after the first trimester of pregnancy requires further investigation. Three studies continued heparin treatment postpartum; either 3 weeks, or 6 weeks. The incidence of postpartum thrombosis in women with obstetric antiphospholipid syndrome is unknown. Therefore, the aim and duration of postpartum heparin treatment cannot be evidence based. In the absence of evidence, however, women with persistent antiphospholipid antibodies may be at higher risk of thrombosis and postpartum continuation of heparin treatment for prevention of venous thromboembolism can be considered.
Various doses of aspirin and heparin were used in the included studies (Table ). Due to small study sample sizes and limited data it was not possible to account for these differences in the analyses. Two small trials compared a higher and a lower dose of heparin (LMWH or UFH) both combined with aspirin.
A higher dose of LMWH did not improve the live birth rate compared to a lower dose of LMWH (RR 1.10, 95% CI 0.81 to 1.49, 1 trial, 60 women); similar to the effects of a higher dose of UFH compared to a lower dose of UFH (RR 1.05, 95% CI 0.78 to 1.41, 1 trial, 50 women; Figure in supporting information)., Importantly, the study evaluating different doses of UFH lacked the power to detect any significant differences and had methodological limitations due to the quasi-randomized design. This variation in initiation of treatment, in duration of treatment, as well as different doses and agents used, limits the possibilities of a cross-study comparison and thus clear treatment recommendations.
In general, although we focused on women with recurrent pregnancy loss, we observed significant clinical heterogeneity in the study populations. A substantial part of the studied population did not meet the full criteria of antiphospholipid syndrome, due to differences in the definition of prior pregnancy loss used as well as the timing (and interval) of repeat antibody testing. Criteria for antiphospholipid syndrome and pregnancy loss are consensus based and further research regarding which subgroups benefit from antithrombotic therapy should be carried out. It is known that the prognosis varies between subgroups of antiphospholipid syndrome patients., , , , , Reporting of antibody profiles or the number of previous pregnancy losses was incomplete and not in relation to the primary outcome live birth. For this reason, we were unable to perform subgroup comparisons based on number of previous miscarriages (two vs. three or more), previous placenta-mediated complications, high-titer antibodies versus low-titer antibodies, or positive LAC versus negative LAC.
In light of the limitations of the included studies in this review, the evidence is of low certainty, and a large multicenter randomized controlled trial with clearly defined patients with antiphospholipid antibodies and recurrent pregnancy loss is still warranted. Such a trial should include women with homogenous clinical characteristics and antibody profiles or be powered to analyze subgroups. We realize this is challenging but given the costs, nuisance, and side effects of heparin and aspirin observed in trials in non-antiphospholipid syndrome patients,, such trials should be performed to obtain a definite answer about the effectiveness in antiphospholipid syndrome. Unfortunately, despite the urgent need to get answers to our important clinical questions, this is challenging. For instance, the well-designed APPLE pilot study evaluating LMWH plus aspirin versus aspirin only during pregnancy in women with persistent antiphospholipid antibodies and a history of two or more early pregnancy losses or one or more late losses was terminated prematurely for feasibility reasons.
Our systematic review provides a contemporary and complete synthesis of all available evidence from randomized trials on antithrombotic therapy for improving pregnancy outcomes in women with a history of recurrent pregnancy loss and persistent presence of antiphospholipid antibodies. Based on the available but low-certainty evidence, heparin plus aspirin appear to improve live birth rates in women with recurrent pregnancy loss and persistent antiphospholipid antibodies.
So how do these findings translate to our own clinical practice? To summarize our “who, what, and how” for women with antiphospholipid antibodies and recurrent pregnancy loss:
Who do we treat? Women with recurrent early pregnancy loss (three or more) and persistent presence of antiphospholipid antibodies tested on two separate occasions at least 12 weeks apart. In women with a late pregnancy loss or late pregnancy complications in persistent presence of antiphospholipid antibodies treatment, treatment will be discussed as we also counsel these women on the absence of evidence on its effectiveness.
What do we prescribe? A combination of low-dose aspirin and LMWH in prophylactic dose.
How do we treat? Aspirin is started preconceptionally with LMWH added upon pregnancy confirmation. Treatment is continued for the full duration of pregnancy and stopped at either the first signs of labor or 24 hours prior to planned delivery. We consider continuation of LMWH postpartum based on the individual patient's risk profile for venous thromboembolism.


A 29-year-old Japanese woman was admitted with lowered consciousness and a high fever (>39°C), arthralgia, sore throat, and lymphadenopathy that had persisted for a week. She had a history of juvenile idiopathic arthritis and macrophage activation syndrome when she was 9 years old and was treated with oral prednisolone until she was 15 years old. Brain MRI showed bilateral swelling and high signal intensity in the basal ganglia and thalamus according to T2-weighted images and fluid-attenuated inversion recovery images (shown in Fig. , b). Blood examinations revealed the following: leukocyte count, 5,100/μL (88% neutrophils); hemoglobin, 14.3 g/dL; platelets, 110,000/μL; C-reactive protein, 5.36 mg/dL; erythrocyte sedimentation rate, 29 mm/h; slightly elevated liver enzymes (aspartate aminotransferase, 84 U/L, and alanine aminotransferase, 16 U/L), elevated soluble interleukin-2 receptor, 1,261 U/mL, and an elevated serum ferritin level of 4,088 ng/mL (reference range, 5–152 ng/mL). The kidney function test results were within normal limits, the antinuclear antigen was at the borderline level, and the rheumatoid factor and antineutrophil cytoplasmic antibody tests were negative. Her cerebrospinal fluid (CSF) on admission showed an opening pressure of 7 cm H2O, 7 cells/mm3 (71% lymphocytes), increased protein levels (265 mg/dL; normal, <40 mg/dL), and a slightly low glucose level (48 mg/dL; normal, >50 mg/dL). Blood, urine, and CSF cultures were negative. Viral meningitis (human herpesvirus 1–6) was excluded using CSF in a polymerase chain reaction assay. An extensive infectious disease evaluation was negative. Her consciousness disorder improved without treatment, and her brain MRI also showed an improvement 3 weeks after admission (shown in Fig. , d). Nevertheless, a high fever, arthritis, and salmon-colored rash on her trunk and limbs persisted (shown in Fig. ). Abdominal CT revealed splenomegaly.
After excluding infections, malignancies, and other rheumatic diseases, ASD was diagnosed based on the presence of fever, arthritis, rash, lymphadenopathy, splenomegaly, and hepatic dysfunction, according to the Yamaguchi criteria []. Her schistocytosis and worsening of anemia (hemoglobin, 8.7 g/dL) became clinically evident, and oral prednisolone of 45 mg (1 mg/day/kg) was administered. TMA was ruled out because of her normal platelet count (162,000/μL), normal kidney function (creatinine, 0.60), and normalized fever without any neurological signs. After administering oral prednisone for 2 days, the patient presented with blurred vision in the left eye and was referred to the ophthalmology department. Her best-corrected visual acuity was 20/17 in each eye, and her intraocular pressure was normal at the initial visit. A slit-lamp examination of the anterior segment of the eye was unremarkable. A funduscopic examination revealed bilateral cotton-wool spots, Purtscher flecken, and a small number of intraretinal hemorrhages around the optic nerve and in the posterior pole (shown in Fig. ), which were compatible with Purtscher-like retinopathy []. Optical coherence tomography showed inner retinal thickening consistent with cotton-wool spots in both eyes (shown in Fig. ). Fundus fluorescein angiography showed hypofluorescence in the early phase and increased permeability in the late phase, consistent with the lesions (shown in Fig. ). There was no apparent nonperfusion area in either eye.
Despite treatment with high-dose oral prednisolone for 2 weeks, her laboratory data gradually worsened, showing elevated serum ferritin levels (5,663 ng/mL) and developed macrophage activation syndrome []. Therefore, intravenous pulse methylprednisolone therapy was initiated at 1,000 mg/day for 5 days, followed by oral prednisolone of 90 mg (2 mg/kg/day). Nine days after the administration of intravenous pulse methylprednisolone therapy, the patient's serum ferritin levels dropped to 462 ng/mL, and aspartate aminotransferase levels and the platelet count fell within normal limits. TCZ (8 mg/kg every week during hospitalization and 8 mg/kg every 2 weeks after discharge) was administered considering the severity of ASD (shown in Fig. ). The patient visited the ophthalmology department again 15 days after the administration of intravenous pulse methylprednisolone therapy, and her funduscopic examination revealed reduced bilateral cotton-wool spots and Purtscher flecken (shown in Fig. ). Her ASD was successfully treated, and the oral prednisolone treatment was tapered. Although her Purtscher-like retinopathy improved as her ASD activity decreased, nerve fiber layer defect (NFLD) in both eyes appeared 7 months after initial visit (shown in Fig. ). Humphrey visual field testing showed visual field defect corresponding to NFLD (shown in Fig. ). At her last visit, that was 1 year after the administration of intravenous pulse methylprednisolone therapy, the patient was taking prednisolone (5 mg/day) and continuing TCZ, and she remained in good health without a major ASD flare.


A 67-year-old male patient was admitted to our hospital on March 20, 2020 with a complaint of sudden disturbance of consciousness. An emergency head CT scan showed 1. left basal ganglia haemorrhage with intraventricular extension, 2. bilateral lacunar infarctions at basal ganglia and senile brain degeneration, 3. mild bilateral inflammation of ethmoid sinuses. An emergency lung CT scan showed chronic bronchitis-emphysema, pulmonary bullae, and mild chronic inflammation of both lungs. Physical examination at admission showed a body temperature of 36.7°C, a pulse of 100 bpm, a respiratory rate of 21 breaths per minute, and a blood pressure of 156/92 mm Hg. The patient was in a light coma and showed no response to instructions or questions. Rough respiratory sounds were detected in both lungs, and no moist rale was detected in either of the lower lungs. Neurological examination showed eye opening and vocalization with strong pricking, binocular gaze to the left side, and pupils equal in size with a diameter of 3 mm, round, and reactive to light. No rigidity was detected in the neck and the patient could not cooperate in muscle strength examination. Voluntary movements of the left limbs were observed while no movement was observed in the right limbs. The patient could not cooperate during the examination of muscle tone or tendon reflexes. A positive Babinski sign was observed on the right side but negative on the left side, while a positive Kernig sign was present bilaterally.
Considering the clinical manifestations and examinations, a diagnosis of left basal ganglia cerebral hemorrhage and bilateral basal ganglia lacunar infarction were made. The symptomatic treatments were provided, including haemostasis, dehydration to decrease intracranial pressure, and blood pressure control. Bedside bilateral drill, craniotomy and ventricular drainage were performed. Bronchoscopy-guided nasotracheal intubation was performed. A repeat CT scan on March 21 showed that the right ventricular hematoma mostly resolved, and therefore the right ventricular drainage catheter was removed.
On March 23 (d3), the patient was still in a light coma, and moist rales in both lower lungs increased, along with an elevated white blood cell (WBC) count (15.36×109/L) and an elevated C-reactive protein (CRP) level (59.21 mg/L). Pulmonary infection was diagnosed, and intravenous infusion of piperacillin-tazobactam (4.5 g every 8 h) was used as an anti-infection treatment. A repeat head CT scan on March 25 showed a significant decrease in the volume of intraventricular hematoma. In order to avoid infection after long-term retention, the drainage catheter of the left ventricle was removed.
On March 30 (d10), the patient developed fever and was in the twilight state of consciousness with aggravation of neck rigidity. The WBC count increased to 17.17×109/L, and the first routine and biochemical tests of cerebrospinal fluid (CSF) showed significant increases in cell count, proportion of multinucleated cells, protein level ( and ), and slight decrease in sugar level (), leading to a diagnosis of possible intracranial bacterial infection. Piperacillin-tazobactam was discontinued, and the anti-infective therapy of intravenous infusion of vancomycin (1 g every 12 h) combined with ceftriaxone (2 g every 12 h) was administered with lumbar cistern drainage performed concurrently.
The vancomycin trough serum concentration on April 3 was 18.3 µg/mL. On April 8(d19), the patient still had fever with aggravated neck rigidity, accompanied by cough and sputum expectoration. Therefore, the combined anti-infective treatment was considered ineffective, and ceftriaxone was discontinued. A combination of vancomycin with continuous 2-hour intravenous infusion of meropenem (2 g every 8 h) was administrated.
On April 12 (d23), the patient was in the twilight state of consciousness with no fever. The volume of lumbar cisternal drainage was 150 mL with unobstructed CSF drainage, and the drainage fluid was light yellow and turbid. On April 13 (d24), the number of CSF WBC was 2.325×109/L, the concentration of protein in CSF was 760 mg/L, and the concentration of sugar in CSF was 3.00 mmol/L. Blood routine and CRP tests showed decreased WBC count and CRP. CSF routine and biochemical tests showed that cell count and protein level decreased significantly compared with previous results ( and ). The CSF biochemical tests showed that sugar level elevated to normal (). On April 18, the results of the first two CSF cultures revealed the presence of Staphylococcus epidermidis, which was resistant to oxacillin and sensitive to vancomycin (MIC = 2 µg/mL) and linezolid (MIC = 4 µg/mL). Both the MIC values of vancomycin and linezolid were determined by broth microdilution (BMD). The current anti-infective therapy was deemed effective, and the treatment of vancomycin combined with meropenem continued.
On April 27 (d38), patient’s neck rigidity improved, the number of CSF WBC was 0.079×109/L, the concentration of protein in CSF was 737 mg/L, and the concentration of sugar in CSF was 3.43 mmol/L. CSF routine and biochemical tests showed that cell count, proportion of multinucleated cells and protein level further decreased ( and ). The lumbar cisternal drainage catheter was removed. On April 29, the CSF metagenomic sequencing revealed Staphylococcus epidermidis (read count 1541), and the treatment of vancomycin combined with meropenem continued.
On May 6 (d47), the patient developed fever again, with a maximum body temperature of 38.4°C. The number of platelet count was 203×109/L. The number of CSF WBC was 0.569×109/L, the concentration of protein in CSF was 1089 mg/L, and the concentration of sugar in CSF was 5.06 mmol/L. CSF examination showed turbid CSF with elevated WBC count (), increased proportion of multinucleated cells, and elevated protein level compared with previous tests ( and ), leading to the conclusion that the infection aggravated again. The CSF concentration of vancomycin was 5.0 µg/mL. The anti-infective regimen was adjusted to 0.6 g linezolid every 12 h combined with 2 g ceftazidime every 8 h.
On May 10, the patient’s liver function test showed 528 U/L alanine transaminase (ALT) and 323 U/L aspartate transaminase (AST). Considering possible linezolid-induced liver injury, linezolid was discontinued. On May 11 (d52), the patient had no fever and showed improved neck rigidity. The results of CSF routine and biochemical tests showed significant improvement ( and ), and Staphylococcus epidermidis was isolated from the CSF culture. On May 12, given the isolation of Staphylococcus epidermidis from several CSF cultures and the poor outcome of vancomycin treatment, anti-infective treatment with linezolid was resumed, combined with entecavir (0.5 mg once a day P.O.) for anti-HBV (hepatitis B virus) treatment. A repeat blood biochemical test on May 16 showed 58 U/L AST and 125 U/L ALT. On May 21, the number of platelet count was 182×109/L. On May 24 (d64), routine CSF tests showed normal results (). On May 25, repeat head and lung CT scans showed left thalamic post-haemorrhagic encephalomalacia, while the rest were similar to previous results.
On May 26, the patient was in the twilight state of consciousness. After tracheotomy, the patient exhibited smooth spontaneous breathing and was supported by liquid diet. The patient had no fever, and there was a slight improvement of neck rigidity. The antibacterial drugs, including linezolid and ceftazidime, were discontinued. On June 1, the patient regained consciousness and was transferred to the Department of Rehabilitation Medicine for comprehensive rehabilitation. On June 16, the number of platelet count was 269×109/L. On June 28, the recovery was satisfactory and the patient was discharged from hospital. The treatment regimens and CSF cell counts, proportion of multinucleated cells during hospitalization in Department of Neurosurgery are shown in . The trends of concentration of protein and sugar in CSF are shown in .


A 60-year-old man presented with an asymptomatic scalp mass and was referred to the plastic and reconstructive surgery department. The lesion had been slowly growing for approximately 2 years, reaching a size of 1 cm in diameter at the time of the visit. On physical examination, the mass was found to be a single well-defined, fixed, skin-colored indurated nodule on the temporal scalp just above the hairline (). The suspected diagnoses included epidermal cyst, lipoma, or other benign neoplasms, and a further differential diagnosis was deemed necessary. Excision and biopsy were performed for an accurate diagnosis and treatment. The incision line was designed with a 5-mm free margin from the mass. After dissecting the skin and soft tissue, an irregularly shaped mass with heterogeneous high vascularity attached to the frontalis muscle was observed ( and ). The mass was completely removed without any remnant tissue, and the skin was sutured. Microscopic findings of the scalp mass revealed tubular structures lined by mucin-secreting columnar epithelium in the dermis, consistent with metastatic adenocarcinoma ().
A thorough history was taken to identify the primary cancer of cutaneous metastasis. The patient had a history of advanced gastric cancer (T3N1M0, stage IIB) and undergone total gastrectomy and Roux esophagojejunostomy 3 years previously. Considering the biopsy findings and the patient’s history, the metastatic adenocarcinoma was thought to have originated from advanced gastric cancer. As a cutaneous metastasis was found, an exploratory laparotomy was performed for re-staging. In the operative field, peritoneal seeding, pancreatic invasion, and celiac trunk invasion were observed. Since the tumor invaded adjacent structures and distant metastasis was found, the stage of advanced gastric cancer was finally determined as T4bN1M1 (stage IV). The patient then received combined chemotherapy treatment with leucovorin, fluorouracil, oxaliplatin, ramucirumab, and paclitaxel. During chemotherapy, a stricture of previous surgical site was found, and the patient underwent palliative surgery. Whole-body computed tomography revealed a gastric tumor with blood vessel infiltration, peritoneal carcinomatosis, liver metastasis, and multiple disseminated subcutaneous metastases. One year later, the patient died.


A woman in her early 70s underwent radical nephrectomy for clear cell RCC followed by systemic therapy, including anti-PD-1. The patient’s clinical course, including development of an irAE in the form of a lichenoid dermatitis (LD), and biospecimen collection are shown in . The immune-related LD (irAE) persisted despite two treatment breaks and systemic prednisone (). Anti-PD-1 therapy was discontinued because of the severity of the irAE. Progressing metastases in the small bowel and a new brain metastasis were confirmed by biopsy. The patient died approximately 2 months after cessation of anti-PD-1 therapy and a rapid autopsy was performed. Findings included metastatic RCC involving the brain (specimen TM1), jejunum (specimen TM2), and mesentery (specimen TM3). Of the three mediastinal lymph nodes (LNs) sampled, one was histologically unremarkable (LN1); one showed multiple large fibrotic nodules (LN2); and one showed multiple small subcapsular fibrotic nodules (LN3). An inflamed seborrheic keratosis (benign skin lesion) was sampled from the skin (SK) as well as uninvolved normal tissues from the left kidney and normal small bowel (NSB).
To test for possible T-cell cross-reactivity among the tumor and irAE (), TCR Vβ CDR3 sequencing was performed on all specimens (). The irAE shared 147 unique clonotypes (4.7%) with the pretreatment primary tumor (Tp) and 118 unique clonotypes (3.7%) with jejunal metastasis (TM2) (). In total, 127 unique T-cell clones present in the irAE (4.0%) were also found in at least one tumor specimen and absent in all healthy, non-lymphoid specimens (). We next tested if library size (the total number of productive sequencing reads) influences T-cell repertoire overlap among specimens. The number of clones shared with a given specimen was highly correlated with library size, illustrated for the irAE (Spearman’s rho, R=0.7, p=0.031; , left) and LN2 (R=0.78, p=0.012; , right). Random subsampling weighted by clonal abundance within each specimen was used to equalize library sizes to eliminate this confounding (). Not surprisingly, a strong correlation was observed between library size and the number of unique clonotypes (R=0.93, p<2.2e−16; ). The degree of clonal sharing was also correlated with the number of unique clonotypes in each specimen (R=0.85 and p=0.0035 for the irAE, and R=0.92 and p=0.00047 for LN2; ). Using weighted downsampling, we normalized specimens to the same library size, which eliminated the correlation between the number of unique clonotypes in a specimen and clonal sharing (). Therefore, we used weighted downsampling for the remainder of our analyses.
Tumor-specific T cells can be detected in paired uninvolved tissue, even when the normal tissue is collected 10–15 cm from the tumor itself. Likewise, clonotype sharing analyses could be confounded by bypassing viral-specific T cells. We performed a reanalysis of a previously published functional assay and found that viral-specific T-cell clones showed notable clonotype sharing across multiple tissue compartments, including the tumor, in a patient with non-small cell lung cancer. A similar pattern was previously observed with neoantigen-specific T-cell clones, suggesting that T cells can traffic across tumor involved/uninvolved compartments regardless of the presence of antigen (). Indeed, after mapping the TCRs from our present study to a public TCR database with annotated antigen specificity (vdjdb, ), we found an Epstein-Barr Virus (EBV)-specific clone that was detected in tumor-involved tissues from our study participant (). This emphasizes that clonotype sharing alone is not necessarily associated with biological relevance. Additional abundance measurement and antigen specificity analyses are warranted to assist further interpretation. The SK and LN outliers in (red arrows) also indicate increased T-cell repertoire sharing between specimens from the same tissue compartment, even when collected at different locations and timepoints (ie, the irAE and SK). Tissue compartment confounding—a greater degree of T-cell repertoire overlap between specimens collected from the same tissue site—is illustrated with pairwise comparisons in . While T-cell repertoire sharing is reduced in samples from different tissue compartments, shared clones are still detected between seemingly unrelated specimens. These could reflect circulating clones at the time of tissue collection and are not necessarily reflective of biologically meaningful clonal sharing, (ie, batch effect confounding). We used the Morisita Overlap Index (MI), which incorporates relative clonal abundance and is not influenced by library size in our dataset (), to calculate the overlap between the irAE and all other specimens. The relative clonal sharing among all specimens is illustrated in a chord diagram (), in which the width of the bands is proportional to the MI values. The highest MI was observed between specimens collected from the same batch and from the same tissue compartment (). These population-level comparisons likely capture a combination of biological and batch effects, which cannot be distinguished in this dataset.
We next tested for evidence of cross-reactive T cells in the tumor and irAE while accounting for the sources of confounding identified previously (). Within the limitations of specimen availability, tissue compartment and batch effect were considered in selecting comparator specimens for meaningful analyses. First, the T-cell repertoire overlap between the primary tumor and the metastases was quantified using MI, which demonstrated a significantly higher overlap among the progressing metastases relative to the mediastinal LNs and normal tissues (p=0.044; ). A chord diagram highlights population-level sharing among all tumor specimens (), with the greatest TCR repertoire overlap observed between the metastases from the brain (TM1) and mesentery (TM3, MI 0.47). Although batch effect is a potential confounder, this degree of overlap is not observed with the small bowel metastasis (TM2, MI 0.03 and 0.04 with TM1 and TM3, respectively), also collected at autopsy. Since the primary tumor and metastases were collected at different time points and from different tissue sites, batch and tissue compartment effects could not be confounders in this analysis. We recognize that a small sample size limits interpretation of the aforementioned findings, given that TM1 and TM3 have the smallest library sizes (), even though they satisfied our criteria for inclusion. Consequently, we focused on the metastasis with the largest library size (TM2, 6945 reads) for additional analyses.
Following library size normalization, 9.1% of unique primary tumor clonotypes are shared with TM2 relative to 5.8% (95% CI 5.2% to 6.8%) and 3.7% (95% CI 3.3% to 4.3%) of Tp clonotypes shared with LN2 and NSB, respectively (). Clonal expansion of shared clones in the primary tumor was greatest for those shared with TM2, with shared clones representing 27.1% of total primary tumor reads. The TCR repertoire overlap between the primary tumor and LN2 may suggest an antitumor signature in the mediastinal LNs, a site of radiographical tumor regression. The same approach was used to evaluate TCR repertoire overlap between the irAE and tumor specimens. The irAE repertoire was most similar to TM3, TM1, and the regression site LNs (), with intermediate overlap with Tp and the least overlap with the normal control specimens. Although the relative degrees of overlap with the irAE potentially suggest a biologically relevant pattern, the magnitude of population-level TCR repertoire sharing is quite small relative to values observed among other specimens ().
Specimen libraries were then normalized to allow direct pairwise comparison of clonal sharing with the irAE. Sharing between the irAE and Tp (largest library size of 12,588 reads) was compared with LN2 and NSB. A similar degree of irAE clonotype sharing was observed in Tp and LN2, which was greater than that observed for NSB (). There was no evidence of clonal proliferation in the irAE or Tp (). Finally, we evaluated the most abundant clonotypes in each specimen for overlap with the irAE, given that prior studies have implicated the highest-frequency intratumor clonotypes in mediating antitumor immunity. There was no enrichment of irAE-shared clones in the tumor relative to the non-tumor specimens ().
Based on observations that antigen specificity may be determined by limited contact sites in the TCR CDR3, we applied the grouping lymphocyte interactions by paratope hotspots 2 (GLIPH2) algorithm to identify and cluster TCR sequences into possible antigen specificity groups. In order to be included in downstream analyses, clusters had to contain ≥3 unique CDR3s, ≥10 reads for each CDR3, a variable gene beta (vb) score of <0.05, and a length score <0.05. One cluster with significant enrichment in the irAE was identified. Notably, the primary tumor (3.66%) had the highest abundance of T-cell clones in the ‘SSQD’ CDR3 motif cluster (), followed by the irAE (2.42%), which were both higher than representation of this motif in non-diseased TCR repertoires from four healthy donors (range: 0.03%–1.67%, ). Though the human leukocyte antigen (HLA) information is unknown, three of the four healthy donors had common clonotypes shared with the patient in our study, indicating that at least one HLA allele was shared among them. By querying additional published skin/tumor-reactive TCR data, the specific motif SSQD was reported in a T-cell clone recognizing an epitope derived from Maspin, which functions as a tumor suppressor gene in epithelial cells. Collectively, this indicates that, though analyses of the total TCR repertoire and a subset of high abundance clones do not show a signature of enriched sharing between the irAE and tumor specimens relative to non-tumor specimens at the clonotype level, more ‘antigen-driven’ approaches may be useful to identify potential specificity clusters, especially when coupled with functional assays to confirm antigen specificity and cross-reactivity between irAEs and tumors.


A 45-year-old female presented to the general surgery OPD with nodular swelling in the right parotid region. The examination of the nodule revealed firm-to-hard consistency with restricted mobility. The swelling was single in the preauricular area. FNAC was carried out. Smears revealed a typical ductal cell carcinoma cytomorphology that showed the cytoarchitecture of sheets and ductal placements of malignant ductal cells. The background showed tumor necrosis and malignant diathesis. The diagnosis of metastases of well-differentiated ductal carcinoma was offered [] with advice to search for primary in the breast. On examination, ipsilateral breast revealed 2 cm lump in the upper inner quadrant. The lump underwent FNAC followed by tru-cut biopsy. The offered diagnosis on these investigations was of well-differentiated ductal carcinoma. The patient later underwent the surgical management for the lump in the right breast.


A 56-year-old female came with the chief complaints of deep nodular swelling in the left parotid region. The examination of the nodule revealed firm to hard in consistency with restricted mobility. The swelling was solitary. FNAC was carried out. Smears revealed discohesive cell sheets with internal attempted ducts. The cells carried hyperchromatic pleomorphic nuclei with irregular chromatin and infrequent nucleoli. The nuclei of the cell sheets showed rare mitosis. The background was hemorrhagic with dissociated malignant cells. The diagnosis of metastases of well-differentiated ductal carcinoma was presented [] with advice to search for primary in the breast. On examination, left breast revealed 1.5 cm lump in the upper outer quadrant. The lump underwent FNAC followed by tru-cut biopsy. The offered diagnosis on these investigations was of well-differentiated ductal carcinoma. The patient later underwent surgical management for the lump in the left breast.


A 68-year-old male complained of superficial but nodular swelling in the right parotid region. The patient complained of pain in ear and the swelling. The swelling measured 3 cm in diameter with restricted mobility and showed erythematous skin over it. The examination of ear, nose and throat was reported to be normal. The patient was advised to be assessed by USG-guided FNAC. The aspirate revealed dissociated to polygonal cells carrying centrally placed hyperchromatic nuclei with rounds prominent nucleoli. Few of the cells showed bi-nucleation. The cytoplasm of these cells carried granules of altered hue. The background showed infrequent melanin containing macrophages []. Cytodiagnosis of melanoma was made with advice to search for primary of melanoma. The re-examination showed 1 cm size of brown-colored tumorous lesion uncomplained by the patient. This primary lesion of the scalp underwent FNAC followed by excision revealing similar diagnosis of melanoma on both occasions.


A 65-year-old male patient sort medical advice for complains of hematuria, lump in abdomen and shortness of breath along with a nodular swelling in the right parotid. The patient was provisionally diagnosed of lump in the abdomen probably malignant arising from right kidney. Meanwhile, his workup for other complains was being carried out, nodule in the right parotid underwent FNAC. It revealed the tubular structures of cuboidal epithelial cells in isolation or within the sheets of cells. The cells carry low-grade malignant nuclei but revealed vacuolated clear appearing cytoplasm with little granularity in a few. Background of smear shows fine vesicles of lipids with few loops of endothelial cells due to consideration to his clinical presentation, a diagnosis highly suspicious of metastases of clear cell RCC was offered []. The patient underwent multiple investigations. FNAC from the sites of renal mass and suspected metastatic nodule of the left lung revealed the cytomorphology consistent with RCC and metastases of RCC in the lung, respectively.
Superficial parotidectomy was performed in one case of melanoma. The other cases (n = 2) of metastatic ductal carcinoma breast underwent excision of the nodule within the parotid. The cases diagnosed with metastases of small cell carcinoma and RCC underwent medicinal management (chemotherapy). All five cases showed complete concordance between cyto-histological diagnoses.


A 51-year-old male patient with type 2 diabetes mellitus complicated by end stage kidney disease (ESKD) presented with painful swelling of his left thigh for 1 week. Three months earlier, he had undergone emergency hemodialysis via a temporary central venous catheter inserted into the left internal jugular vein. After 10 days, he developed fever and purulent discharge from the catheter exit site. Pus and blood cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). The infected catheter was removed, and the patient was treated with appropriate intravenous (IV) antibiotics for 2 weeks. The repeat blood culture after 7 days of antibiotic therapy yielded no bacterial growth. The current presentation was one and a half months after this episode. He denied a history of trauma to the thigh. No attempts had been made to cannulate the femoral vein for central venous access.
On admission, the patient was afebrile. The left thigh and leg were swollen. A tender, pulsatile bulge was noted on the medial aspect of the mid-thigh. Popliteal and pedal pulses were not felt on the affected side, but the foot was completely viable. His white blood cell count was 15,000/µL, with 82% neutrophils and the C-reactive protein level was 20.6 mg/dL. A duplex ultrasound scan of the left thigh revealed a 4 cm pseudoaneurysm arising from middle segment of the left SFA. The adjacent segment of the femoral vein was thrombosed. Computed tomography angiography revealed bilateral SFA pseudoaneurysms (). The left-sided lesion was located 16 cm below the inguinal ligament, and measured 4.8 cm×6.2 cm. On the right side, it was 10 cm below the inguinal ligament and measured 1.5 cm×1.5 cm. The two-dimensional echocardiogram was negative for infective endocarditis.
Infected pseudoaneurysms as a consequence of previous MSSA sepsis were suspected, and the patient was restarted on 6 hourly IV flucloxacillin at a dose of 500 mg. Repeated blood cultures were negative. We decided to operate on the symptomatic left pseudoaneurysm with pain and deep vein thrombosis (DVT). The SFA was explored proximal and distal to the lesion. The artery was extremely calcified. After administering 5,000 IU of IV heparin, the artery was clamped, and the pseudoaneurysm was opened. Surprisingly, the SFA was completely transected within the capsule of the pseudoaneurysm (). The vessel was ligated on either side of the rupture, and thorough debridement of the surrounding tissue was performed. The contralateral great saphenous vein (GSV) was harvested, reversed, and tunneled lateral to the surgical field just beneath the deep fascia. Vein-to-SFA end-to-side anastomoses were performed proximally and distally to restore limb perfusion.
Histology of the pseudoaneurysm capsule revealed inflamed fibrous tissue. Bacteriological culture and special staining of debrided tissue failed to identify an organism. Postoperative recovery was complicated by the breakdown of the thigh wound. A decision was made to warfarinize the patient for 3 months for DVT and to conservatively follow up the pseudoaneurysm on the contralateral side for the time being. The patient was discharged on oral flucloxacillin for 3 months.
Two months later, the patient presented with massive bleeding from the left thigh. The prothrombin time international normalized ratio (INR) were within therapeutic limits. Anticoagulation was reversed, and re-exploration revealed dehiscence of the distal anastomosis of the bypass. The graft was ligated for hemostasis. Considering the physiological parameters at that time, we felt that he was not a candidate for a repeat bypass. The limb rapidly became ischemic. Despite extensive counseling, the patient refused amputation and died 2 days later.


A 62-year-old Chinese male presented to the Emergency Department of our hospital with complaints of myoclonus, consciousness disturbance and vomiting for 1 h.
In the absence of a caregiver, the patient was found lying unconscious with myoclonic movements, surrounded by vomit. The number of remaining tablets suggested 125 mg clozapine had been taken.
According to medical history, the patient has had TRS for 40 years, presenting with hallucinations, delusions, splitting of thought and a weak response to olanzapine, risperidone and perphenazine. The patient has been regularly taking clozapine 62.5 mg/d and quetiapine 300 mg/d for the last 10 years, and the mental symptoms were well controlled.
The patient has been regularly taking clozapine 62.5 mg/d and quetiapine 300 mg/d for the last 10 years, and the mental symptoms were well controlled. No family history of mental illness was reported.
Upon admission, the patient had a generalized tonic-clonic seizure (GTCS) lasting for about half a minute with persistent consciousness disturbance, fever, cough and bloody sputum.
Emergency laboratory tests revealed a white cell count of 10.11 × 109/L, 89.3% of which were neutrophils, and a high-sensitivity C-reactive protein content of 4.8 mg/L; the sputum culture indicated the presence of gram-negative bacilli. The blood concentration of clozapine was higher than 1500 ng/mL (reference: 350-600 ng/mL) at the 24th h and the 48th h after last administration. No other obvious abnormalities were found upon cerebrospinal fluid examination.
On the 10th day of hospitalization, the blood concentration of clozapine was 153 ng/mL (reference = 350-600 ng/mL).
Emergency chest computed tomography indicated bilateral pneumonia with bilateral pleural effusion (Figure ), and no other obvious abnormalities were found upon cranial computed tomography.
On the 3rd day of hospitalization, electroencephalogram (EEG) showed slow-wave and no epileptiform discharges (Figure ).


A 29-year-old man was unresponsive for 5 d.
A 29-year-old man was admitted to our hospital after experiencing out-of-hospital cardiac arrest during sleep at home. He was found unresponsive by his wife, who is a nurse, and she initiated cardiac pulmonary resuscitation (CPR) immediately before the patient was emergently admitted to the local emergency department. The patient presented with VF and subsequently received two defibrillator-delivered electrical shocks (200 J and 300 J). He was intubated to maximize ventilation/oxygenation until the return of spontaneous circulation to sinus tachycardia (120 bpm). He did not experience an episode of chest pain, palpitations, syncope, or SCD prior to admission. His blood pressure was 122/70 mmHg, temperature was 38.5 °C, pulse was 102 bpm, and respiratory was 22 bpm. A small amount of moist rales could be heard in the lungs. The other general physical examinations were normal.
The patient had no history of any previous disease.
There was no family history of SCD.
Post-arrest ECG demonstrated a typical type 1 Brugada ECG pattern, with coved-type ST-segment elevations of > 2 mm in V1 to V2 followed by a negative T-wave in two of the right precordial leads[] (Figure and ). A typical type 2 Brugada ECG pattern of his brother (25 years old, who had amaurosis) showed a convex ST-segment elevation (> 0.5 mm) in one right precordial lead followed by a positive T-wave (Figure ).
Routine blood tests showed a white blood cell count of 21.9 × 109/L (Normal reference range: 3.5-9.5 × 109/L), neutrophil count of 92.7 % (40 %-75 %), and hemoglobin level of 71 g/L (130-175 g/L). He had elevated creatine kinase (CK), 4600 IU/L (50-310 IU/L); CK-MB, 75 IU/L (0-25 IU/L); urea, 36 mmol/mL (3.1-8.0 mmol/mL); and creatinine, 1079 µmol/mL (53-115 µmol/mL). Serum alanine transaminase was 296 IU/L (15-40 IU/L), aspartate aminotransferase was 426 IU/L (9-50 IU/L), total bilirubin was 40.9 µmol/L (5,5-27.5 µmol/L), direct bilirubin was 12.8 µmol/L (0-8.6 µmol/L), procalcitonin was 22 ng/mL (0-0.5 ng/mL), D-dimer was 7141 ng/mL (< 280 ng/ml), fibrinogen degradation products were 93 µg/mL (0-5 µg/mL), activated partial thromboplastin time was 91.4 s (23-38 s), and brain natriuretic peptides was 5623 ng/L (0-125 ng/L). All the electrolytes were within the normal range. Echocardiography revealed no structural disease.
Chest radiography revealed pulmonary infection, and head computed tomography did not reveal any infarction or hemorrhage.


John* is a 70-year-old man with schizophrenia who lives in a residential aged care facility (RACF) [nursing home/long-term care facility]. He was referred for an involuntary admission to the OPMHU by the consultation-liaison psychiatry (CLP) team for management of psychosis, after being admitted to a general hospital for hemoptysis. Medical imaging had demonstrated a spiculated lung lesion, highly suspicious for malignancy. Additional medical issues included bilateral lower limb oedema of uncertain cause, and an unexplained mobility decline. John had refused further investigations and management of these issues. The medical team had recommended discharge with a plan for outpatient investigations.
The CLP team concluded that John’s psychotic symptoms impaired his decision-making capacity in relation to treatment and follow-up of his numerous medical issues and therefore recommended inpatient treatment of his psychosis. On the OPMHU he demonstrated grandiose and persecutory delusions, including beliefs that he could control weather events and that he was being targeted by free radicals and radio waves. These delusions had been present for many years despite treatment with depot antipsychotics. Cognitive testing with the Rowland Universal Dementia Assessment Scale (RUDAS) revealed mild impairment (23/30). He was commenced on fortnightly risperidone depot.
Despite treatment of his psychotic symptoms, John continued to lack capacity for treatment consent. He believed his hemoptysis was due to poisoning at his RACF, and that he could not have cancer as he was no longer symptomatic. He refused the recommended investigation (a positron emission tomography [PET] scan) due to fears of radiation poisoning. John also demonstrated instability of choice with respect to investigations and management.
In Australia, a range of laws exist to guide appointment of substitute decision-makers for adults unable to give consent., As John was socially isolated with no informal substitute decision-maker, he was appointed a Public Guardian. A Public Guardian in New South Wales (NSW), the jurisdiction of this case, is a public official appointed by the Guardianship Division of the NSW Civil and Administrative Tribunal with powers for substitute consent for health care and treatment for people with decision-making disabilities including, as in John’s case, authority to override the person’s objections.
Venous ultrasound of John’s lower limbs revealed a unilateral deep vein thrombosis (DVT). Treatment was complicated by John’s intermittent refusal of therapeutic enoxaparin injections, which resulted in temporarily switching treatment to oral rivaroxaban as this was more acceptable to John, where possible trying to respect his will and preferences and minimize the over-riding of such. No cause was found for John’s mobility decline. He engaged intermittently with physiotherapy, although did not progress to his premorbid level of walking independently likely due to sarcopenia from prolonged inactivity.
In liaison with respiratory medicine and with consent from the Guardian, after considering the risks and benefits of investigation and the potential severity of John’s underlying lung condition, a decision was made to proceed with an endobronchial ultrasound (EBUS) of the mediastinal lymph nodes and a biopsy of the lung lesion. Consent for pre-anesthetic sedation was also provided, given John’s refusal. Notably, John later communicated that he had been metaphorically “raped” by the involuntary invasive medical procedure.
Biopsy results of John’s lung lesion revealed aspergillosis rather than malignancy. He assented to a course of an oral antifungal. There were residual, but improved, symptoms of psychosis on risperidone. After 13 weeks John was discharged to his RACF with follow-up appointments for management of his aspergillosis and DVT.


Chris* is an 84-year-old man with schizophrenia who lives alone and has no family or friends. He was admitted involuntarily to the OPMHU for an exacerbation of his chronic psychotic symptoms. Chris had persecutory delusions which incorporated his neighbors, the department of public housing, police and health services. Consequently, he had a life-long mistrust of health services and avoidance of care. Treatment with risperidone was commenced.
Multiple previously unknown comorbidities were found on routine screening at admission, including anemia with severe vitamin B12 and iron deficiencies. Cognitive testing revealed moderate impairment (RUDAS = 17/30), possibly secondary to nutritional deficiencies. It also transpired that a pituitary lesion, suspected to be a macroadenoma, was identified the year before, although Chris had not followed-up with investigations.
Chris refused recommended management of these issues. He was assessed as lacking decision-making capacity with regards to health care and treatment consent. He had persecutory delusions, accusing the treating team of dishonesty and feigning his pathology results in order to appear superior to other hospitals. He also demonstrated illogicality, concrete thinking, perseveration and poor recall for medical information.
Chris was appointed a Public Guardian for health care and treatment consent. The Guardian consented to Chris having an intravenous iron infusion and a course of vitamin B12 injections. Parenteral administration was recommended by the gastroenterology team due to the severity of his nutritional deficiencies. Midazolam sedation was administered prior to the iron infusion to facilitate safe administration given Chris’ ongoing refusal of treatment. He was subsequently administered a course of seven vitamin B12 injections over two weeks. A colonoscopy to investigate his nutritional deficiencies was cancelled because of his refusal to take the bowel preparation. An endoscopy revealed atrophic gastritis.
Chris was not amenable to magnetic resonance imaging (MRI) of his brain or visual field testing to investigate the pituitary lesion. However, there was biochemical evidence of hypogonadism, with associated long-term risk of osteoporosis/fracture, in addition to pituitary hemorrhage. These risks were contrasted with the risks of testosterone replacement and invasive surgical intervention. Upon further discussion with endocrinology and the Guardian, and taking these risks into account, it was concluded not to proceed with further intervention.
Chris’s distress and preoccupation with his persecutory delusions attenuated during the admission. He was frustrated by the length of his admission and declared the numerous imposed injections (iron, vitamin B12 and risperidone) unnecessary and unjust. Following a 9-week admission, Chris was discharged home with follow-up appointments for his atrophic gastritis and pituitary lesion.


Rose* is a 70-year-old woman with schizophrenia living in a boarding house. She had no informal substitute decision maker. She was admitted involuntarily to the OPMHU for treatment of an acute exacerbation of her chronic psychotic symptoms. These symptoms included delusions of pregnancy, delusions about her identity (having multiple people living inside her) and grandiose delusions that she, along with her “squires”, could cure diseases and fight wars. She was cognitively impaired, scoring 21/30 in the Montreal Cognitive Assessment (MOCA). Rose was trialed on two different antipsychotic depots (paliperidone and zuclopenthixol) over the course of the admission.
During her admission, Rose had a mechanical fall which resulted in a left neck of femur and left distal radius fractures. Her treatment refusal for surgery was based on a delusional interpretation of her injuries, namely that they were incurred after being pushed over when out working with squires and did not result in fractures. She also believed her medical records had been falsified. On this basis she was found to lack capacity for treatment consent.
She was transferred to the orthopedic ward for operative management of her fractured hip. Consent was given for the operation by the Medical Superintendent according to Australian Mental Health Laws. Her distal radius fracture was managed conservatively.
Rose was required to remain non weight-bearing (NWB) for a period of six weeks postoperatively. She required a 1–1 nurse to effectuate this as she continued to deny having fractured her hip. She was transferred back to the OPMHU for ongoing treatment of her psychosis and completion of her NWB period. Rose was reviewed by the orthogeriatric team but not transferred to the rehabilitation unit due to a lack of beds, her preference to stay in the OPMHU, and concerns about disruptive behaviors. Although she continued to deny she had had a fracture or an operation, she was cooperative with physiotherapy and occupational therapy provided on the OPMHU. A Public Guardian was appointed to evaluate further healthcare decisions.
Rose had a second fall, this time sustaining an open fracture of her left distal radius. This was repaired surgically, with consent from her Guardian. Due to her multiple low trauma fractures, the geriatrics and endocrine teams recommended treatment for osteoporosis. Rose’s Public Guardian provided consent for a zoledronic acid infusion and for investigation and management of emergent rectal bleeding/iron-deficiency anemia. A colonoscopy revealed hemorrhoids and she was treated with an iron infusion.
The intensity of Rose’s psychotic symptoms improved over the course of the admission on zuclopenthixol. Following a seven-month admission she was discharged home with follow-up appointments for her osteoporosis and hemorrhoids.


A 37-year-old man was admitted to local hospital with weight loss, night sweat,
repeating fever for a week in April 2018. The patient’s initial laboratory
examination showed that leukocyte count was 12.48×109/L with 37%
eosinophilia in the peripheral blood, hemoglobin concentration was 127 g/L and
platelet count was 146×109/L. The initial bone marrow (BM)
aspirates and biopsy showed hyper leukocytes and significantly increased eosinophils
(8%), and neutrophil alkaline phosphatase score was 18 ( and ). Above all, these inspections were consistent with a diagnosis of
MPN. Then the patient was administrated with 20 mg prednisone per day, but it showed
no any effect with white blood cell (WBC) 15.1×109/L, hemoglobin
108 g/L, platelet 114×109/L, eosinophils
5.13×109/L (33.91%) in peripheral blood.
The suite of fluorescence in situ hybridization (FISH) assay on the
BM aspirate was used to detect BCR-ABL,
PDGFRA, PDGFRB, and FGFR1
rearrangement. MPN FISH assay showed PDGFRB arrangement positive.
The karyotype analysis of BM cells showed 46,XY[20].
Patient’s RNA was extracted from BM cell by Trizol methods according to the
manufacturer’s protocol (Invitrogen, Waltham, MA) for RNA-sequencing
(RNA-seq) in July 2018. RNA quality and concentration were estimated by Nano Drop
ND-2000 (Thermo Fisher Scientific, Waltham, MA). Paired-end reads were generated
from the complementary DNA (cDNA) libraries using an Illumina Next Seq 550
instrument (Illumina, San Diego, CA). Then we used star-fusion software to analyze
the RNA-seq raw data [] (). Standard
settings were applied for all three tools and reads were aligned to the Genome
Reference Consortium Human Build 37 (GRCh37). RNA-seq revealed that
PDGFRB fused with CSNK2A1 gene. To confirm the
fusion, reverse transcription–polymerase chain reaction (RT-PCR) was
performed with CSNK2A1-PDGFRB forward primer:
5′-GTGCCAAGCAGGGCCAGAGT-3′, reverse primer
5′-AGGGTGCGTCCCAGCACAAG-3′. The reciprocal
PDGFRB-CSNK2A1 fusion forward primer:
5′-TCAGAGCTGACACTGGTTCG-3′, reverse primer:
5′-GATGTTGGGACCTCCTCTCAA-3′. The PCR products was purified with PCR
purification kit (Tiangen, Beijing, China) and sequenced by GENEWIZ Biotechnology
Co., Ltd. (Suzhou, Jiangsu, China). The sequence was analyzed using the BLAST
program ().
Given the existence of PDGFRB fusion, he received imatinib therapy with 200 mg every
day orally in September 2018. Two months later, the laboratory examination showed
that WBC was 6.14×109/L with 2.8% eosinophilia in the peripheral
blood (). Finally, real-time quantitative reverse transcription PCR was
performed to quantify the fusion gene and showed negative in 8 months after imatinib
treatment. To date, the patient acquired sustained molecular complete remission for
2 years until the last follow-up.


A 41-year-old man with an unremarkable medical history was referred to our institution for an incidental left thyroid nodule. Physical examination revealed a hard mass measuring approximately 15 × 10 mm2 that was palpable in the left thyroid gland and moved up and down when the patient swallowed. The results of routine blood examination and thyroid function tests were within the normal ranges. Ultrasonography demonstrated a 12-mm nodule with unclear borders and an irregular shape located in the upper left thyroid. Moreover, multiple dot-like calcifications and blood flow signals were observed. Blood flow signals appeared as more intense and star- or dot-shaped centrally and peripherally; therefore, a malignant nodule was suspected (). Another 5.4- × 3.4-mm2, oval-shaped, anechoic, cystic lesion with well-defined margins was noted at the inferior aspect of the thyroid that was superior to the suspicious malignant nodule (). The patient elected not to follow the recommendation to undergo fine needle aspiration (FNA). As a result, he underwent left hemithyroidectomy, and intraoperative biopsy was performed. The reporting of this study conforms to the CARE guidelines.


An 81-year-old woman with a history of Graves’ disease, treated with both levothyroxine 50 µg and thiamazole 5 mg, was diagnosed with stage IIIB malignant mesothelioma in 2017. She underwent chemotherapy with carboplatin and pemetrexed for 10 courses. As disease progression was observed during chemotherapy, nivolumab (240 mg every 2 weeks) was initiated in October 2018. In January 2019, after the eighth course of nivolumab treatment, the patient underwent laparoscopic sigmoid colectomy for sigmoid colon cancer. During the perioperative period, nivolumab administration was continued. Just after the surgery, she noted mild intermittent abdominal pain, which continued for 2 months. An abdominal CT scan was performed but showed no causative abnormalities, even at the surgical sites. Two weeks later, just after the 12th course of nivolumab, the patient visited an emergency department and complained of worse abdominal pain and general fatigue.
On physical examination, her level of consciousness was normal, and her vital signs were as follows: blood pressure 88/77 mm Hg, pulse rate 115 beats per minute, SpO2 95% on ambient air, respiratory rate 16 per minute, and body temperature 37.2°C. Even after infusion of 1.5 litres of intravenous physiologic saline, her blood pressure remained around 100/80 mm Hg. Vasopressor drugs were not used. Abdominal examination showed tenderness in the right lower quadrant without signs of peritoneal irritation. The physical examination was otherwise normal.


A 99-year-old African-American female with a medical history of dementia, diabetes mellitus, hypertension, and a cerebral vascular accident with right-sided weakness who presented to an emergency department (ED) in Long Island, New York, on April 24, 2020, with the chief complaint of the right ankle pain. The patient was accompanied by her granddaughter who reported that the patient had a series of the falls over the past several weeks. She first fell 3 weeks before presentation at which time she complained of the right ankle pain. Due to concerns regarding COVID-19 exposure, especially in light of the patient’s son passing away from complications of the disease, the patient did not seek further medical evaluation. The granddaughter who was also a nurse placed the ankle in a home fashioned posterior slab splint and she proceeded to weight-bear as tolerated.
Two days before presentation, the patient had another fall but again did not seek medical evaluation. On the day of presentation, the granddaughter was concerned regarding the patient’s skin overlying the ankle due to a malodorous wound prompting the evaluation. On examination, the patient had a temperature of 36.7, blood pressure of 111/65, heart rate of 82 beats/min (bpm), respiration rate of 18 bpm, and oxygen saturation of 94% on room air. There was a malodorous 20 cm area of necrosis on the anterior aspect of the distal tibia with a 10 cm × 5 cm open wound overlying the lateral malleolus (). The wound was explored and distal fibula, tibia, talus, and peroneal tendons were noted. The ankle was tender to palpation about both the medial and lateral ankle with significant bony instability. Sensation and motor strength of the right lower extremity including ankle and foot were unable to be assessed due to the patient’s current mental status. The foot was edematous with overlying blistering. Dorsalis pedis and posterior tibial pulses were not appreciated by palpation, with a +1 dorsalis pedis pulse on Doppler.
Laboratory testing demonstrated an initial white blood cell count of 12.67 K/µL (3.8–10.5 K/µL), erythrocyte sedimentation rate of 97 mm/h (0–22 mm/h), and C-reactive protein of 36.82 mg/dL (0.00–0.40). Blood cultures had growth in both aerobic and anaerobic bottles with Gram-negative rods (Morganella morganii). COVID-19 polymerase chain reaction testing was negative.
Anteroposterior, lateral, and oblique radiographs taken in the ED showed a bimalleolar ankle fracture with a transverse fracture line about the medial malleolus and an oblique fracture line about the lateral malleolus (, ). Air and gas were noted in the anterior margin of the tibiotalar joint. The patient’s clinical examination was consistent with an open right ankle bimalleolar fracture with presumed osteomyelitis of the right lower extremity and a gangrenous foot. On secondary examination, the patient had no other injuries.
A lengthy discussion was had with the health-care proxy about the patient’s diagnosis, prognosis, and treatment options, especially limb salvage versus amputation. The health-care proxy initially wanted to attempt lower extremity salvage, but after discussion regarding overall success of salvage and associated morbidity versus amputation, the health-care proxy agreed to amputation. The following day, the patient underwent a successful right guillotine amputation by vascular surgery, with plan for a return to the operating room for a formal below-knee amputation (BKA) once her condition stabilized. OR cultures demonstrated a polymicrobial infection with Proteus mirabilis, Klebsiella oxytoca, Enterococcus faecalis, and Stenotrophomonas maltophilia. The patient received IV antibiotics for the treatment of sepsis related to her previously infected Grade III A open right ankle bimalleolar fracture and gangrenous foot. The patient’s overall condition improved with no growth on repeat blood cultures and a clean non-bleeding guillotine amputation site. The patient eventually returned to the operating room and underwent a successful formal BKA ().