The pedigree of the family is shown in Fig. . The proband (Ib in Fig. ) was a 47-year-old female of Han Chinese ethnicity (with family from Shandong province, China), who was admitted to our hospital with a chief complaint of “fatigue and chest tightness for 7 days”. She never had a similar episode before. She had neither intellectual disability nor a history of seizures. Her blood pressure was 135/85 mmHg. Physical examination revealed typical facial angiofibromas (adenoma sebaceum) and multiple periungual fibromas (Fig. ), and obvious abdominal distention. Her biochemical laboratory test demonstrated renal insufficiency (serum creatinine levels: 3.1 mg/dL, normal values 0.5–1.1 mg/dL; estimated glomerular filtration rate: 17.1 ml/min/1.73 m2, estimated by CKD-EPI formula) and moderate anemia (hemoglobin of 8.6 g/dL, normal values 11–15 g/dL). Ultrasonography of her both kidneys manifested a heterogeneous mass with a large echogenic fatty component and a less echogenic soft-tissue component with prominent vessels within it, which was suggestive of giant bilateral renal angiomyolipomas (AML) (Fig. ). Highly vascular fatty masses were seen on Color Doppler scans (Fig. ). Ultrasonography of the left eyes demonstrated a hyperechogenic lesion with posterior shadowing due to calcifications (Fig. ). Fundus photograph showed a hamartoma with central calcifications and a surrounding translucent zone in the left eye, suggesting the retinal hamartoma (Fig. ). Thereafter, non-contrast-enhanced computed tomography (CT) of the abdomen confirmed the ultrasonography diagnosis of giant bilateral renal AMLs with prominent fatty components and internal prominent vessels. Multiple variable-sized air-filled cysts throughout the parenchyma were noted in both lungs consistent with lymphangioleiomyomatosis (LAM) on lung CT. And brain CT revealed multiple calcified subependymal nodules. Images of spine displayed multiple patchy sclerotic lesions (Fig. ).
Therefore, we considered that the patient fulfilled the diagnostic criteria of TSC []. The patient accepted the treatment with the mTOR inhibitor everolimus (10 mg/d) because her AMLs nearly invaded all tissues of bilateral kidneys which could not be removed completely. Two months later, the patient felt a significant alleviation in the feeling of abdominal swelling. Regrettably, she had to discontinue her treatment because of financial difficulties. After half a year follow-up, the patient remained in a stable condition. Besides, she had a son (IIc) who died of epilepsy at the age of six. Her daughter (IIa) also had the presentation of typical facial angiofibromas and multiple periungual fibromas, but she denied further imaging examination. Her husband (Ia) and granddaughter (IIIa) did not show any significant symptoms or abnormalities on testing. To further confirm the diagnosis of TSC, mutation analysis of the TSC1 and TSC2 gene and bioinformatics analysis were performed by the methods in Additional file . The CARE guidelines were followed in reporting this case.
By the next generation sequencing, the proband was found to carry a heterozygous guanine to adenine substitution of the last nucleotide in exon 29 of TSC2 (c.3610G > A), resulting in a single amino acid substitution from Glycine to Arginine at amino acid position 1204 (p.Gly1204Arg) (Fig. ). Sanger sequencing validation of all family members revealed that the proband’s daughter (IIa) carried the same heterozygous p.Gly1204Arg mutation in TSC2 gene, whereas other family members and 100 unrelated controls did not harbor this mutation. No mutation was identified in TSC1 gene.
The c.3610G > A variant was considered as novel since it was neither present in ExAC, 1000G, nor in HGMD databases (HGMD Professional 2017.4). However, another substitution at the same codon (c.3611G > A, p.Gly1204Glu) has been reported to be related with TSC [].
The p.Gly1204Arg alteration was predicted as deleterious by three different softwares (i.e. MutationTaster, SIFT and PolyPhen-2). Moreover, the p.Gly1204Arg variant is highly conserved among 8 different species (human, Callorhinchus milii, Macaca mulatta, chimpanzee, house mouse, rat, xenopus tropicalis and zebrafish) by using Vector NTI Advance 10-Align.
It was noteworthy that the c.3610G > A was a nucleotide substitution at the last position of exon 29, which was located at the upstream close neighbor nucleotide of classical donor splicing site (GT) of intron 29. Therefore, this position may play an important role as splicing modulator. The BDGP and the NetGene2 splice prediction programs were then employed to test whether this mutation could alter the splicing of the TSC2 transcript. Both predictions resulted in the abolishment of the donor splice site. Finally, the in silico analysis by ASSP software showed that the splice donor site strength remarkably decreased from a score of 8.434 to 4.895 (cut off: 4.5).
The mini-gene assay performed to study the effects at the transcript level of the novel c.3610G > A variant showed that the wild-type gave rise to a 476 bp PCR product containing exon 29, the empty pSPL3 control gave rise to a 263 bp PCR fragment missing exon 29 of TSC2 gene. However, the c.3610G > A mutant construct produced two transcripts corresponding to 263 and 476 bp PCR fragments, respectively (Additional file : Figure S1). We then investigated whether the mutation c.3610G > A really led to exon 29 skipping in an actual patient. The cDNA was reverse transcribed from total RNA extracted from peripheral blood leucocytes of the proband. By cDNA sequencing, the exon 29-excluded transcript was identified only in the proband and not in a not-mutated individual. Approximately 44% of the cDNA products inserted into the pGEMT Easy vector were missing exon 29, whereas 56% were in-frame cDNA with the single nucleotide change c.3610G > A (Fig. ).


A 60-year-old male patient presented to the dermatology outpatient department (OPD) with a two-month history of diffuse facial erythema, itching, and burning sensation. Raised skin lesions were noted on the forehead, nose, and left cheek. He also complained about the exacerbation of lesions upon exposure to the sun. On dermatological examination, well-defined annular erythematous lesions over the forehead, with a sharp margin and a raised edge, and scaly plaques with papular to papulopustular lesions involving both the eyebrows, the nose, and the left cheek were revealed, as shown in Figure .
The patient gave a history of myocardial infarction and cardiac surgery and was on antidiabetic and antihypertensive drugs. He gave a history of sharing linen and admitted to the habit of sleeping outside the house in the open air during the summer season. The patient also informed about a rodent infestation in his immediate surroundings and frequent animal contact. A history of previous nail infection on the right great toe, which was otherwise normal upon examination, was noted. No other concomitant infections were observed. The patient denied any application of topical corticosteroids or any self-medication. An intramuscular injection of dexamethasone was given 10 days before by a local practitioner, which gave temporary relief from erythema and tingling.
Processing of the specimen for a mycological/microbiological examination
Skin scrapings were taken under aseptic precautions from the extending and raised margins of the lesion on the forehead. Potassium hydroxide preparations revealed more than five Demodex folliculorum mites measuring ~ 0.3-04 mm in a scraping of 1 cm2 area along with a moderate number of hyaline septate hyphae, with a few hyphae breaking into chains of arthroconidia under 40X magnification of the microscope.
The mite was semitransparent, with an elongated body formed by two fused segments. The first segment had four pairs of legs and a hairless and colorless body surface. The second or posterior segment had secondary striations. The longer posterior segment at the opisthosomal end was round, differentiating it from D. brevis, which has a short and pointed opisthosomal end, as shown in Figure [].
Repeated slit skin smear examinations were negative for acid-fast bacilli. A diagnosis of Pityriasis folliculorum with concomitant dermatophytosis (Tinea faciei) was made.
The specimen was later inoculated on a dermatophyte test medium (DTM) agar base with a dermato supplement and Sabouraud’s dextrose agar (SDA) with 50 mg chloramphenicol and 0.05% cycloheximide (HiMedia, India) and incubated in ambient air at 28°C (Biological Oxygen Demand/Biochemical Oxygen Demand (BOD) incubator).
Growth started to appear after five days of incubation, which was later subcultured on to potato dextrose agar (PDA).
Routine slide culture, microplate culture, and adhesive tape preparations for the phenotypic identification of the dermatophyte fungus along with a urease test and a hair perforation test were performed.
Phenotypic identiﬁcation and morphological description of T. mentagrophytes
The surface texture of the colonies on DTM agar base initially showed downy, later turning into pleomorphic and powdery, growth with a flat surface after two weeks of further incubation. When subcultured on to PDA, a pale brown to buff or yellow surface producing a characteristic stellate powdery surface growth was observed after two weeks of incubation. The reverse showed a dark red pigment rather than the usual light yellow or brown-tan color. When grown on cornmeal agar (CMA), there was no reverse pigment.
Macroconidia were demonstrated only in the early colonies grown on the DTM agar base and PDA, which were noted to be thin, smooth-walled and cigar-shaped, with a few of them bearing narrow attachments to the vegetative hyphae. Microconidia were spherical to pyriform and arranged in grape-like clusters.
Older cultures exhibited pleomorphism with antler-like hyphae and peridial hyphae with the terminal branches bearing two or three cells with an abundance of spiral hyphae, as shown in Figure .
The isolate was positive for the urease and hair perforation tests and was phenotypically confirmed as T. mentagrophytes. Due to its variable morphological and cultural attributes, the isolate was submitted for confirmation and antifungal susceptibility data to the national reference centre, National Culture Collection of Pathogenic Fungi (NCCPF), an Indian Council of Medical Research (ICMR), New Delhi, sponsored center at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Confirmation of Trichophyton interdigitale by molecular identification
Molecular identiﬁcation of the culture with submission identification (ID) nccpf IL-2878 was performed at the national reference center by amplifying the DNA and sequencing the internal transcribed spacer (ITS) region of rDNA using the ITS1 and ITS2 primers. T.interdigitale was conﬁrmed by comparing the sequence in Centraalbureau voor Schimmelcultures (CBS), Utrecht, The Netherlands, the Dermatophytes database [], and the National Center for Biotechnology Information (NCBI) GenBank database, respectively, which showed a 99.61% similarity with the type strain CBS 130940 T.interdigitale.
GenBank direct submission and accession ID: The T.interdigitale ITS sequence was deposited in GenBank ITS databases and published in the NCBI database on 16/5/2018 with accession number MH327513 and name T.interdigitale - IL2878/333.
Antifungal susceptibility testing
Antifungal susceptibility testing (AFST) was performed following the Clinical Laboratory Standards Institute (CLSI) guidelines (M38-A2). The broth microdilution (BMD) method was used to determine the minimum inhibitory concentrations (MICs) of the test isolate against various antifungal drugs, which included itraconazole, sertaconazole, terbinafine, griseofulvin, and amorolfine. All the antifungal drug powders were reagent grade and were procured directly from Sigma Aldrich (Missouri, United States) by PGIMER/NCCPF, Chandigarh, India. RPMI-1640 (HiMedia, India) with L-glutamine, without bicarbonate, buffered at pH 7.0 with 0.165 M morpholine propane sulfonic acid (MOPS buffer) was used for inoculum preparation and to perform broth microdilutions. All the antifungal powders tested were dissolved in dimethyl sulphoxide (DMSO). Three quality control strains, including Candida parapsilosis American Type Culture Collection (ATCC) 22019, Candida krusei ATCC 6258, and Aspergillus flavus ATCC 204304 were included. Inoculum suspension and dilutions were performed as described by Adimi et al. []. Endpoint determination and interpretation of MICs was done according to CLSI M38-A2 and from the recent AFST studies [-].
The results of the antifungal susceptibility testing of five antifungal agents are shown in Table .
Antifungal and acaricide therapy
The patient was treated with oral terbinafine 500 mg once daily for four weeks. Combination topical therapy involving a cleanser containing selenium sulfide 2.5% lotion followed by the application of 2% sertaconazole twice daily and 1% metronidazole gel for three weeks was initiated. The patient had an uneventful recovery.


A 68-year-old male with a past medical history of schizophrenia and polysubstance abuse presented to the emergency department with a chief complaint of neck pain following minor trauma after sustaining a mechanical fall complicated by a television set then falling on him, striking him on the back of his neck. He denied loss of consciousness, paresthesias, or focal weakness but reported an increasing number of falls for the past two years. He endorsed daily intravenous heroin and methamphetamine use with social alcohol use and having previously quit smoking twenty years ago.
Vital signs were temperature 37.3°C, blood pressure 141/108 mmHg, heart rate 105 beats per minute, respiratory rate 24 breaths per minute, and oxygen saturation 97% on room air. Physical examination revealed a thin, cachectic African American male. He was noted to be without obvious signs of trauma to the head or neck. Cardiac examination revealed sinus tachycardia with no obvious murmurs, rubs, or gallops. Pulmonary examination was clear to auscultation in all lung fields. Abdominal examination was soft without evidence of distention or tenderness to palpation in all four quadrants. Skin examination showed no evidence of rashes, erythema, or trauma. Neurological examination was significant for cervical spinal tenderness to palpation but without evidence of step-off or gross deformity. Strength was noted to be diffusely diminished (4/5 throughout bilateral upper and lower extremities) without hyperreflexia or pathologic reflexes (negative Babinski and Hoffman tests). Anal wink was present. Sensation was preserved throughout. Laboratory results demonstrated white blood cell count 5540/mm3 with normal differential, serum creatinine 1.6 mg/dL (baseline 0.6 mg/dL), C-reactive protein (CRP) 25.2 mg/L, and erythrocyte sedimentation rate (ESR) 48 mm/hr, and urine drug screen was positive for amphetamines and opiates. HIV testing was negative. Hepatitis C testing revealed a positive antibody test but a negative viral load, suggestive of cleared prior infection. He denied prior treatment of Hepatitis C.
Computed tomography (CT) and magnetic resonance imaging (MRI) of the cervical spine revealed lytic destructive changes involving the C5 and C6 vertebral bodies, concerning for osteomyelitis. Due to clinical stability, antibiotics were held and he was admitted to the hospital for planned CT-guided aspiration. Five sets of blood cultures drawn over two consecutive days while off antibiotics were negative. Transthoracic echocardiography revealed a 3 × 4 mm echodensity attached to the noncoronary cusp of the aortic valve that was not independently mobile and without associated aortic regurgitation. In addition, there was a 3 × 5 mm echodensity attached to the anterior leaflet of the mitral valve that was not independently mobile and without associated mitral regurgitation.
During his hospitalization, the patient remained afebrile and hemodynamically stable but began to report tingling in his right thumb and index finger and decreased dexterity in terms of handwriting and grip strength, resulting in dropping objects. Due to new neurologic symptoms, the patient went to the operating room on hospital day #3 and underwent C5-C6 corpectomy, C4-C7 anterior fusion with allograft, and C3-T1 posterior fusion with allograft. Intraoperative findings demonstrated soft bone from the inferior portion of C4 to the superior portion of C7 with granulation tissue noted at the posterior longitudinal ligaments. There was no obvious evidence of tissue necrosis or purulent material. Postoperative vancomycin and piperacillin/tazobactam were started. Deep operative cultures subsequently grew Burkholderia cepacia complex, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Susceptibilities determined by the Kirby–Bauer method revealed susceptibility to ceftazidime, trimethoprim/sulfamethoxazole, and minocycline, with intermediate resistance to levofloxacin.
His antibiotics were narrowed to intravenous ceftazidime 2 g every 8 hours. He was evaluated by the Improving Addiction Care Team (IMPACT) and started on medication-assisted treatment for his opioid use disorder with Suboxone while being an inpatient. He was discharged to a skilled nursing facility where he completed 6 weeks of ceftazidime. At the end of his intravenous antibiotic therapy, his CRP was noted to be 0.7 mg/L, and his ESR was 39 mm/hr. He was prescribed indefinite minocycline 100 mg by mouth twice daily due to vertebral hardware placement. He subsequently missed his follow-up clinical and opiate counseling appointments and was ultimately lost to follow-up.


A 75-year-old man was admitted to our hospital on June 15, 2016 with a chief complaint of coughing and blood-stained sputum for over 1 month. He presented chest stuffiness and shortness of breath and required continuous oxygen inhalation. The patient also presented coronary arteriosclerosis. There were no symptoms of dizziness, chest pain, fever, and vomiting. He had a smoking history of over 60 years and smoked up to 30 cigarettes a day. Tumor markers carcinoembryonic antigen and neuron-specific enolase were within the normal range. Chest computed tomography (CT) revealed a soft mass (63 × 48 mm) and signs of pneumonia in the left lung (Figure ). Swollen lymph nodes above the left clavicle were evident on color Doppler ultrasound images. CT-guided lung biopsy was conducted. The mass was histologically diagnosed as sarcomatoid carcinoma, which was staged as IV according to the 8th edition of the AJCC/UICC TNM staging system for lung cancer. Supraclavicular lymph node metastasis was detected. Immunohistochemistry showed that tumor cells were positive for cytokeratin (CK) 7, CK8, and thyroid transcription factor 1 (TTF-1) and negative for CK5/6, p63, p40, CD56, and synaptophysin. Of note, the tumor was abundantly vascular, with strong immunostaining for smooth muscle actin (SMA), CD31, and CD34 (Figure ). As determined by next-generation sequencing, this patient displayed 4 mutations in NF1 (p.Q347Sfs*29), CDKN2A (p.G23V), ERBB3 (p.V104L), and TP53 (p.V157F) genes (Table ).
The patient had an ECOG performance status of 3 and thus was precluded from chemotherapy. After receiving informed consent, he was given apatinib (250 mg) orally once per day from June 27, 2016. Haemoptysis symptoms disappeared and chest stuffiness was relieved 5 days after apatinib treatment. At 10 days after treatment, he restored normal breathing. Follow-up CT at 1 (Figure ), 3 (Figure ), and 9 (Figure ) months showed that the tumor regressed to 54 × 43 mm, 41 × 40 mm, and 36 × 28 mm, respectively. Until drafting the manuscript (14 months after therapy), tumor regression was observed. There was no evident complication associated with apatinib therapy.


A 12-year-old female presented with intermittent lumbosacral pain for 2 years and worsening walking instability for half a year. This study was approved by the Institutional Review Broad of Honghui hospital, and the patient provided signed informed consent. She was admitted to the local hospital 2 years ago and underwent lumbar and pelvic frontal and lateral radiographs, which suggested sacral deformity. Over the past 6 months, she presented aggravating sedentary lumbar pain, gait instability, and lumbar tilt. She came to our institution for further medical advice. The patient was in good health before without any trauma or operation history. She was of full-term normal delivery without birth trauma or asphyxia, and her physical and mental developments were appropriate for her age.
Physical examination revealed that the patient had an abnormal gait and asymmetric pelvis, with the left iliac crest higher than the right. Left spinal rotation, scoliosis, and left buttock atrophy could be observed. Motion and sensation of limbs appeared intact, and bilateral physiologic reflexes were normal. X-ray of her spine suggested lumbar scoliosis from L1 to L5 and left sacrum agenesis with 10° Cobb angle (Fig. A). Computed tomography (CT) reconstruction revealed sacral wing agenesis from S1 to S5 with rotational displacement of left sacrum and sacroiliac dissociation (Fig. B). In the standing position, the patient's left sacrum was higher than the right, with obvious pelvis tilt (Fig. C). The diagnosis of congenital sacral agenesis combined with spinopelvic dissociation and spinal scoliosis was made. The preoperative scoliosis research society-22 (SRS-22) scores in terms of function/mobility, pain, appearance, and mental health were 10, 6, 13, and 6, respectively, with an average score of 6.2. The postoperative SRS-22 scores were 18, 14, 16, and 13, with an average score of 13.8.


An 8-year-old girl was admitted to the Emergency Department of our hospital on April 10, 2015 because of accidental aspiration of a plastic bead 7 hours ago. A transient bout of coughing and labored breathing appeared, which spontaneously resolved without subsequent breathing difficulty. She had cough, transient throat wheezing, and intermittent cough. Examination at admission showed that the child was in a general good condition. No throat wheezing was present. There was no cyanosis and the inspiratory 3-concave sign was negative. The child had no breathing difficulty and hoarseness. Bilateral lung sounds were coarse on auscultation and chest expansion was largely symmetrical. No slap sound by a foreign body was heard. Chest computed tomography scan revealed a round shadow 1.2 cm in diameter in the right main bronchus, but was otherwise unremarkable. A diagnosis of foreign body in the right main bronchus was entertained.
Emergency bronchoscopy was carried out upon admission, and the child underwent rigid bronchoscopy (STORZ) under general anesthesia for retrieval of the foreign body. A blue plastic bead was visualized directly under the rigid bronchoscope and was found to be closely impacted on the opening of the right main bronchus (Fig. ). The bead was 1.0 cm in diameter with a central hole 1 mm in diameter and was not readily mobile and cannot be retrieved by forceps. A fiberoptic bronchoscope (Olympus BF-P260, Olympus medical corporation, Tokyo, Japan the external diameter 4.0 mm) was advanced through the laryngeal mask airway for re-exploration and a balloon-tipped catheter (lacrosse balloon catheter 4.0 mm × 20 mm) was entered at the same time via the maneuvering channel. The balloon was advanced through the central hole in the plastic bead and released and inflated after passing beyond the hole. The inflated balloon was 4 mm and after it was secured, it was pulled out along with the plastic bead (Fig. ). The child had an uneventful recovery.
We searched PubMed for published cases of bronchial aspiration of plastic beads using the keywords “bead,” “endobronchial foreign bodies,” “foreign body bronchus,” “Fogarty catheter,” and “balloon.” A total of 4 cases (including our current case) of bronchial aspiration of plastic beads published between January 1975 and November 2017 were identified in PubMed (Table ). One report described the retrieval of the foreign body by surgery in a child in a critical condition.[ Their age ranged from 6 to 12 years. These children had varied manifestations. Chest X-ray findings were positive in most patients, including atelectasis, hyperventilation, and shadow of a foreign body. Except in the surgical case, all the plastic beads were removed using the “balloon bead technique.” Three cases underwent successful retrieval of the foreign body on the first attempt. In the remaining child, the balloon was improperly positioned and improper force was used to pull out the balloon, leading to rupture of the balloon. The plastic bead was retrieved on the second attempt under C-arm guidance. All the children recovered uneventfully after foreign body removal.[


A 68-year-old woman was admitted by her general practitioner (GP) with chronic pain situated in the epigastrium lasting for several years. No complaints of nausea, vomiting, body weight loss, or other symptoms were noted. The patient had no history of oedema of the lower limbs, varices, and trauma. Her only prior surgery was a Fothergill-Manchester operation in 2004 due to genital prolapse and urinary incontinence. The GP performed an abdominal ultrasound revealing a fluid-filled tumour (5.5 × 5.5 cm) situated between the common iliac arteries (Fig. ).
No pathology was noted during the complete gynaecological examination. Subsequently, computed tomography (CT) of the abdomen and pelvis was performed revealing an enormous mass in the presacral space. The CT image clearly suggested the presence of a neoplasm in the abdominal cavity (Figs. and ).
After the CT, the patient was admitted to the Department of General and Vascular Surgery and Angiology. An arterial and venous Doppler ultrasound was performed that indicated proper arterial flow and no deep vein thrombosis in the lower limbs. The Doppler ultrasound was followed by a direct phlebography that revealed a large venous aneurysm of the right common iliac vein with an adhering thrombus and a large collateral circulation (Fig. ). All of the imaging studies excluded the presence of arteriovenous fistula. The D-dimer value was in the normal range. No other pathology was noted. The patient was offered surgical treatment but refused. Anticoagulation therapy with rivaroxaban was administered.
She received anticoagulant treatment for 2 years, and no thromboembolic complications or aneurysm growth has been noted thus far.


A 5.5-year-old boy visited the Endocrinological section of the Pediatric Unit of the General Hospital of Terni, Italy, due to short stature. His mother's height was 170 cm, and his father's height was 172 cm (target height: 177.5 cm = >50° centile). In his family history, there was paternal familiarity for psychotic crises in his adolescence and mother with thrombophilia and history of five pregnancies with three spontaneous abortions and two parts. The mother took cardioaspirine during the pregnancy. No genetic disease was reported in his family. The child was born at term via spontaneous vaginal delivery. The birth weight was 3.050 gr (10°-25° centile), and the birth length was 45 cm (below the third centile). A villocentesis performed at week 12 of gestation due to an alteration in nuchal translucency on obstetric ultrasound did not reveal any abnormality (46, XY). After birth, a small ventricular septal defect and mild bilateral pyelectasis were detected, but within 6 months, both of these abnormalities spontaneously disappeared. Bilateral orchiopexy was performed at 19 months of age for undescended testicles. Regarding linear growth, auxological data recorded by the primary care pediatrician revealed short stature that was 2 standard deviation (SD) below the 3° centile on the Italian cross-sectional growth charts for height () since the first months of life. In the last 2 years, the child has exhibited an even more exacerbated decline in his growth curve. Before entering the hospital, first-level laboratory tests for the evaluation of short stature (i.e., full blood count, inflammatory markers, renal function, hepatic function, coeliac screening, and thyroid function tests) had been already performed. No abnormal results were evidenced. The bone age was delayed by 2 years.
In the hospital, his height was 99.2 cm (<3 SD), his weight was 15.5 kg (<3° centile), and his growth velocity was 4 cm/year (<3° centile). His arm span was of 94 cm, and his sitting height was of 55 cm: height ratio was <95%, his sitting height: height ratio was therefore >56% (slightly over the upper normal limit of 55.5%), and his body mass index was below the 50th centile (pathological Rappold index >8). Furthermore, he presented with unusual facial features that included hypertelorism, low-set ears, a low posterior hairline, down-slanting palpebral fissures, pectus excavatum, and ogival palate (Figure ).
However, Madelung deformity was not suggested by clinical examination and not detected by wrist X-ray findings. Radiological and laboratory tests to rule out related renal, cardiac, ophthalmologic, and audiological abnormalities did not find any significant alterations. At an evaluation conducted by an infant neuropsychiatrist, the patient exhibited a mild cognitive impairment compared with the standard for his age that included a prevalent verbal difficulty compatible with the diagnosis of NS. EEG and cerebral magnetic resonance imaging results were normal. The peak growth hormone (GH) value in a clonidine stimulation test was in the normal range (12.7 mg/L). The IGF-1 level was 47 ng/mL (normal values for age: 32–259 ng/mL).
Although short stature was disproportionate, diagnosis of NS was suspected, and genetic tests of the PTPN11 gene were requested. The entire coding regions and intron-exon boundaries of the PTPN11 gene were amplificated by polymerase chain reaction using genomic DNA and sequence specific primers. Both forward and reverse strands were directly sequenced using an automatic DNA sequencer. The results confirmed NS because a c.922A>G (rs28933386) heterozygous mutation in exon 8 of the PTPN11 gene leading to a p.Asn308Asp substitution was identified (reference transcript NCBI NM_002834.3 and NP002825.3). This mutation has already been described as pathogenic by Siegfried et al. ().
Due to the presence of a mesomelic short stature, the concurrent presence of two genetic mutations was considered and a genetic evaluation of the SHOX gene was requested. A test of chromosomal microarray analysis performed with the CGH array led to the identification of a micro-duplication at the level of the region PAR 1 (Xp22.33/Yp11.32) extended about 680 kb involving the SHOX gene. The microduplication in the pseudoautosomal region PAR1 has already been described in NS and its clinical significance therefore appears to be certain ().
GH treatment (0.2 mg/kg/wk) was prescribed. At a follow-up assessment 18 months after the initiation of GH treatment (weight-appropriate dosage), the following data were collected: height, 109.8 cm (<2 SD); weight, 18 kg (<3° centile); growth velocity, 7 cm/year (>90° centile); arm span:height ratio, 96%; sitting height:height ratio: 56%. Further evaluations have been scheduled for every 6 months.
Management of the case was approved by the Ethics Committee of General Hospital of Terni, Italy (2017-PED-03). The patients' parents provided their written informed consent for the publication of this case report, including the photo of their child.


An 80-year-old male was being investigated at a tertiary hospital for iron deficiency anaemia. His medical history, symptomology and physical examination did not indicate a cause. After gastroscopy and colonoscopy were also unremarkable he was referred for capsule endoscopy. The delivery of the capsule in the morning was routine; however, review of the images 8 hlater showed a static picture and no evidence the capsule had entered the stomach. The patient was clinically stable and contacted to present to the emergency department with a suspicion of capsule impaction.


An independent, healthy 48-year-old female presented to her general practitioner with a 3-week history of slurred speech, unsteadiness and fatigue. She took occasional iron supplements, but no regular medications.
Her past medical history included iron deficiency anaemia and a melanoma, which had been excised 13 years previously.
One year prior to this presentation she had an admission spanning 4 weeks, with lingering depressive and anxiety symptoms after a presumed viral infection 6 months earlier. She had experienced lethargy, intermittent headaches, nausea, diarrhoea and 16 Kg of unintentional weight loss over a 6-month period. Following investigation with biochemical assessment, endoscopy, colonoscopy and a CT abdomen she was diagnosed with an episode of major depression and started on an antidepressant.
Clinical examination at this presentation demonstrated ataxia, with the patient being unable to walk heel-to–toe. Romberg’s test was negative. She had a subtle dysarthria. No other focal neurology was elicited on neurologic examination. Cardiorespiratory examinations were unremarkable. The general practitioner arranged a CT brain, which identified multifocal haemorrhagic sites in the right cerebellar and both cerebral hemispheres (). These ranged from subcentimetre in size to the largest—a 3-cm right cerebellar lobar bleed. The differential diagnoses postulated in the report were haemorrhagic metastases—possibly recurrent melanoma, or an atypical presentation of amyloid angiopathy.
The patient was commenced on dexamethasone and referred to the neurosurgical department. She was booked for a staging CT chest/abdomen and pre-operative stealth brain MRI, with a view to excise the right cerebellar lesion for histological diagnosis. The MRI confirmed multiple supra- and infratentorial lesions. Haemosiderin staining was seen in multiple sulci at the vertex in keeping with a low volume of subarachnoid blood, and a 4 mm posterior inferior cerebellar artery aneurysm was detected (–). The CT chest identified a mass in the left atrium concerning for an atrial myxoma (). In view of the suspected cardiac mass the neurosurgical biopsy procedure was postponed pending further work up.
Echocardiography showed a large, mobile left atrial mass compatible with an atrial myxoma. There was no associated obstruction despite the mass occupying half of the left atrial volume. Left ventricular function was normal (Ejection Fraction 62%). Without histological support a melanoma deposit remained a possible diagnosis and, after discussion between neurosurgery, cardiology and cardiothoracic teams, a decision was made to proceed with the cerebellar excision. A cardiac MRI was also arranged.
The cerebellar excision was uncomplicated, but histological assessment was non-contributory towards a diagnosis. No melanoma or other malignant cells were identified. The excised material consisted of haemorrhage and some distortion of the underlying vascular architecture, without evidence of vasculitis or amyloid angiopathy. In the interval, the cardiac MRI demonstrated an interatrial septal stalk pathognomonic for atrial myxoma. The new favoured diagnosis was haemorrhagic transformation of embolic ischaemic infarcts secondary to the atrial myxoma.
The patient showed some symptomatic improvement with steroids and was referred to Interventional radiology for formal cerebral angiography assessment to evaluate for cerebral vasculitis. Both internal carotids and vertebral arteries were imaged. The procedure revealed extensive abnormalities, with diffuse irregularity of the medium to small vessels, most pronounced in the peripheral ICA and PCA branches. Distal, fusiform aneurysm formation was identified in at least two distinct sites in the peripheral intracranial branches (,). No central aneurysm was detected around the arterial circle of Willis.
The patient underwent excision of the left atrial mass under therapeutic heparin cover on a cardiopulmonary bypass machine. Histological assessment confirmed a left atrial myxoma, with the friable specimen demonstrating classical stellate mesenchymal tumour cells set in a loose myxoid stroma. The patient had an uncomplicated post-operative course and a normal post-operative echocardiogram. She was discharged home with a follow-up MRI and neurosurgical review booked at 6 weeks.


A 70-year-old female with no significant past medical history, Eastern Cooperative Oncology Group performance status 0 and no prior incidence of hypersensitivity reactions, was incidentally found to have a small nodule in the proximal right posterolateral vaginal wall after presenting with post-menopausal bleeding. Subsequent biopsy demonstrated a 9 mm invasive melanoma and the patient underwent wide local excision with confirmed negative margins. 4 months later, she developed a right periclitoral mass. Positron emission tomography/CT scan at that time demonstrated focal uptake in this area but no regional/distant metastases (). Excision demonstrated a large submucosal mass of atypical epithelioid cells with evidence of melanin synthesis, consistent with malignant melanoma. Breslow depth was 9 mm (3 mitoses/mm2) with a positive deep margin, and there was no evidence of lymphatic invasion. Her case was presented at a multidisciplinary tumour board and either additional surgery or radiation therapy was recommended to the patient. Owing to the significant morbidity anticipated with additional surgery, the patient opted for radiation therapy. Given the high risk of both local and regional/distant failure, concurrent chemotherapy was proposed. Owing to the historically poor response rates with standard chemotherapy, an immune pathway targeted agent was considered. This non-standard approach was actually initially proposed by the patient. After being thoroughly explained the current standard of care, in addition to the pros and cons of pursuing concurrent radiation and immunotherapy, the patient chose to proceed with combination immunotherapy and radiation treatment. Several studies have demonstrated that local radiotherapy primes and/or enhances an immune response through cytotoxic T lymphocytes. Concurrent immunotherapy may then further enhance the activity and/or duration of the downstream immune response. Given the historically low efficacy of our current treatment paradigms in this disease, as well as the preclinical/clinical rationale to combine radiation and immunotherapy, a strategy of pursuing a combination of ipilimumab with radiation was felt to be reasonable.
Radiation was planned with intensity-modulated radiation therapy (IMRT) to the vulva and vagina (no elective nodal radiation to the groin) to an initial dose of 45 Gy (1.8 Gy/fraction over 25 fractions), and was to be followed by an electron boost to a total dose of 63 Gy (1.8 Gy/fraction over 10 fractions) at the site of the positive margin (). A thermoluminescent dosimeter was placed on the vulva at the start of treatment to measure the skin dose and read as 1.78 Gy [95% confidence interval (1.66–1.90)], confirming that the planned dose was accurate on the skin. The patient received her first cycle of ipilimumab (3 mg kg−1) 7 days after the start of radiation, and the second cycle was delivered 3 weeks later when the patient was at a dose of 36 Gy. Around this time (3 weeks post ipilimumab cycle 1), she began to develop non-painful erythema in the vulvar and perianal area, as well as a pruritic, grade 2 cutaneous eruption that morphologically showed distinct erythematous papules that coalesced into thin plaques over the upper arms, chest, back and face/ears (all toxicities were graded using Common Terminology Criteria for Adverse Events version 4.03). She did not experience any fevers or other systemic symptoms. By 48.6 Gy dose (10 days post ipilimumab cycle 2), the patient developed a grade 3 skin reaction () that was characterized as a moist desquamation with significant oedema, erythema and pain in the vaginal/vulvar/perianal region and was restricted to the radiation field (). A timeline of these events is illustrated in . After proper consent, a 4 mm punch biopsy of the affected skin was performed and histopathological examination demonstrated spongiotic and interface dermatitis with a perivascular inflammatory infiltrate consisting of numerous eosinophils, consistent with a fixed drug eruption.
Radiation and ipilimumab were held given the severity of the moist desquamation, and the patient was referred to a dermatologist for evaluation of the ipilimumab-associated cutaneous eruption. It is noted that the patient had no existing risk factors or hypersensitivities predisposing her to an enhanced skin toxicity. The patient was started on 0.1% topical triamcinolone cream along with a methylprednisone dosepak. Given only mild improvement after 1 week, she was started on prednisone 60 mg daily (tapered over 7 days) with oral diphenhydramine for pruritus as needed. This resulted in significant improvement in her cutaneous eruption and pruritus. She then received a third cycle of ipilimumab (4 weeks after cycle 2) and resumed her periclitoral radiation boost without further issues after a 1-month break from radiation treatment. She went on to receive a fourth cycle of ipilimumab after completion of radiation without any complications.
At follow-up 8 months post completion of radiotherapy, she had complete resolution of the in-field toxicity and improvement of her ipilimumab-associated cutaneous eruption (). Clinical examination and positron emission tomography/CT imaging 10 months after completion demonstrated no evidence of disease recurrence. Most recently, at her 15-month follow-up, she remains disease- and symptom-free ().
At each follow-up visit, the patient has repeatedly expressed satisfaction with her decision to pursue immunotherapy rather than standard chemotherapy to complement her radiation treatment. She admits the initial side effects and intensity of the treatment course were difficult, although she is very pleased with the outcomes and would make the same decision if asked to do so again.


A 67-year-old man was brought to the emergency department by ambulance after being found lying on the floor of his home. He reported a fall onto his right hip with a long lie for an estimated 24 hours. His medical history was significant for opioid use disorder, gout, hypertension, and osteoarthritis. He had undergone prosthetic joint replacement of the left shoulder nine years before this presentation. He had chronic bilateral knee pain but reported acute worsening of pain in his right knee starting one day before the fall. He endorsed a history of intramuscular injection of opioids to his buttocks and upper arms but denied injection to his hip or knee.
On examination, he was found to have a swollen right knee with no erythema or signs of trauma. The X-ray of the right knee is shown in . His initial blood pressure was 240/120 mmHg. His serum creatinine of 159 µmol/L was significantly increased from baseline, but creatine kinase was not markedly elevated (447 U/L). Laboratory testing also revealed leukocytosis (20.2 × 109 cells/L) with neutrophil predominance (18.2 × 109 cells/L) as well as elevated C-reactive protein (292 mg/L). Serological tests for HIV, hepatitis B, and hepatitis C were negative.
After admission to hospital, the patient's kidney injury resolved promptly with volume repletion, and his hypertension responded to antihypertensive medication. On his third day in hospital, the patient reported urinary urgency without dysuria or gross hematuria, which prompted investigation though he later denied having had urinary symptoms. Urine dipstick showed positive blood (250 ery/µL), positive leukocyte esterase, and positive nitrite; according to local laboratory protocol, microscopy of urine sediment and Gram stain were not performed. Urine culture showed >100 × 106 CFU/L yellow-grey colonies and nonlactose fermenting colonies on blood agar and MacConkey agar, respectively, after 24 hours of incubation. Oxidase test was positive. It was identified as B. vietnamiensis, a B. cepacia complex organism, by BD™ Bruker MALDI Biotyper™.
During his admission, the patient's right knee became more swollen and painful until he could no longer mobilize. Treatment for gout was ineffective in relieving his symptoms, so a joint aspiration of the right knee was performed. The knee joint aspirate was frankly purulent fluid with a nucleated cell count of 26 766 × 106 cells/L, of which 95% were neutrophils, and microscopy revealed intracellular calcium pyrophosphate crystals. Culture grew >100 × 106 CFU/L grey colonies on blood and chocolate agar plates after 24 hours of incubation. The Gram stain from the growth showed Gram-negative rods, which were also identified as B. vietnamiensis by MALDI. For the synovial fluid isolate, susceptibility testing by E-Test® indicated minimum inhibitory concentration values in the susceptible range for meropenem, levofloxacin, trimethoprim/sulfamethoxazole, ceftazidime, and minocycline (0.5 µg/mL, 1 µg/mL, 0.75–1 µg/mL, 0.75–1 µg/mL, and 0.38–0.5 µg/mL, respectively) according to Clinical and Laboratory Standards Institute breakpoints []. Antibiotic susceptibility profile for the urine culture isolate using Vitek 2® was similar to the results from the knee joint aspirate. Blood cultures had no growth of bacteria. Transthoracic echocardiogram showed no evidence of endocarditis.
The patient was treated with three days of empiric meropenem, which was subsequently switched to ceftazidime with a plan to complete six weeks of therapy. Irrigation and debridement of the knee joint was performed four days after the diagnostic aspiration. His knee pain improved significantly, and after twenty-eight days of antibiotic therapy, the patient left the hospital against medical advice. By the time of discharge, the patient's leukocyte and C-reactive protein levels had normalized.


A 61-year-old homeless man with a past medical history significant for benign
spindle-cell thymoma presented with acute hypoxic respiratory failure. Two months
prior, he was treated for Bordetella bronchiseptica pneumonia and
empyema with intravenous (IV) antibiotics and right pleural decortication.
Evaluation during the first hospitalization was negative for HIV, hepatitis B
infection, syphilis, blastomycosis, and coccidioidomycosis. He was discharged but
was subsequently rehospitalized within 1 week with recurrent pneumonia. During this
second hospitalization, he was treated with another 2-week course of antibiotics
with some improvement in symptoms and was discharged home. Two days after being
discharged, he presented to our institute with hypoxic respiratory failure requiring
endotracheal intubation. Pertinent findings on physical examination were fever,
hypoxia, and tachycardia. Oral candidiasis was noted. Lung auscultation revealed
coarse and mechanical breath sounds bilaterally. Chest radiographic findings showed
bilateral patchy airspace opacities (). Computed tomography scan of the
chest showed a stable, large anterior mediastinal mass, multiple cavitary lesions,
and diffuse ground-glass opacities (). The patient was started on broad-spectrum IV antibiotics
with cefepime and vancomycin. Examination of the bronchoalveolar lavage revealed
B bronchiseptica and Pneumocystis jirovecii.
The patient’s antibiotics regimen was changed to piperacillin/tazobactam,
sulfamethoxazole-trimethoprim with prednisone, and fluconazole. Repeat HIV serology
was negative. Laboratory results showed panhypogammaglobulinemia and low total B-
and CD4 T-cells (). IV immunoglobulin (IG) treatment (400 mg/kg every 3-4 weeks) was
initiated. He was evaluated for possible thymectomy but was not a surgical candidate
due to his clinical condition. His clinical status continued to deteriorate, and he
subsequently suffered cardiac arrest and death.


A 63-year-old Caucasian male veteran was referred to the chiropractic clinic with a 2-year history of insidious, worsening low back and bilateral leg pain. The patient complained of pain and cramping in his lower legs that was provoked with walking and immediately relieved with sitting. He further described the left leg as mildly worse than the right. His walking was limited to approximately 50-ft due to pain, but leaning forward on a grocery cart greatly increased his capacity. His medication list included 81 mg aspirin once daily and short-term dose of hydrocodone/acetaminophen 30/300 mg for an unrelated condition (excision of a cervical sebaceous cyst). He was previously prescribed a trial of 300–900 mg Gabapentin, but discontinued without relief. His relevant medical history included right femur internal fixation for a traumatic intertrochanteric fracture, diabetes mellitus, open mandible surgery with hardware placement in the 1970’s, and left ankle surgery with temporary hardware in 1995. He did not have any history of anabolic or corticosteroid use, Cushing’s disease, or history of epidural steroid injections.
Relevant physical examination included a body mass index of 38. He reported weight gain in response to his pain, and chart notes corroborated a BMI of 32.5 approximately 2-years prior to presentation. The patient had moderate flexion and extension limitation with lumbosacral pain on extension. Sensory, motor and tendon reflexes were within normal limits. Lumbosacral pain was present with facet loading. Hip internal rotation and flexion limited bilaterally due to hamstring and hip musculature tightness. All other lumbar and pelvic orthopedic tests were unremarkable. On initial presentation, pain disability questionnaire [] was scored as 63 out of 150, with a functional status component of 37 and a psychosocial component of 26. The patient presented with computed tomography; revealing suspected left foraminal disc protrusion at L4–5 and bilateral L4–5 and L5-S1 facet hypertrophy, but no bony spinal stenosis (Fig. ).
He was diagnosed with neurogenic claudication and treated six times with flexion-distraction to the lumbar spine and high-velocity low amplitude manipulation to the lumbar and thoracic spine. Soft tissue manual therapy was performed on the hip external rotators bilaterally. He was instructed in repetitive lumbar end-range flexion (centralization phenomenon observed), hip mobility exercises, and sciatic nerve glides. At his seventh session a re-examination was performed. His hip flexion range of motion was improved, however he continued to experience pain with walking and cramping in his lower legs. Orthopedic testing was without significant change. His updated pain disability questionnaire scored 96/150, indicating a potential progression of his disability.
At this time the patient was able to be cleared for a lumbar MRI which revealed no signs of bony or discogenic spinal stenosis; however circumferential epidural fat was present at L5-S1. Inspection of the patient’s T1 weighted MRI revealed the grade III pathognomonic “Y” sign (Fig. ). A measurement of the patient’s epidural fat using the modified method (a method used when a straight anterior to posterior measurement is not possible) developed by Borre et al. [] revealed the following: dural sac / epidural fat value of 0.19 and epidural fat / spinal canal value of 83.9% as measured by the authors (Fig. ). This measurement also categorized the patient as a grade III. The patient was seen for two additional visits without any further durable gains and was referred by his medical provider for a neurosurgery consult. After meeting with the neurosurgeon, the patient opted not to pursue surgical intervention.


A 51-year-old African American male veteran was referred to a pain management physician for a lumbar epidural steroid injection (LESI) for low back pain with radiculopathy. The patient had a history of low back pain and lower extremity pain for three and half years. Previous treatments included naproxen, arch supports, proper lifting education, and physical therapy. Radiographs demonstrated minimal spondylosis at the L4 and L5 vertebral bodies and a MRI demonstrated a mild posterior central disc herniation at L5-S1, but no evidence of SEL (Figs. & ).
The patient’s medical history included low back pain, hip pain, plantar fasciitis, obesity, and benign prostatic hyperplasia. The patient’s active medications included: meloxicam, terazosin HCL, ibuprofen, bisacodyl, cyclobenzaprine, methocarbamol, tramadol HCL, acetaminophen/hydrocodone, omeprazole, and ketorolac tromethamine. The patient had no history of anabolic or corticosteroid use or Cushing’s disease; BMI at the time of treatment was 34.
Over a five-week period the patient received a series of three interlaminar L4–5 LESI. The patient reported short-term relief with each injection in the series. Three months after the final injection the patient was referred for a neurosurgery consult. The patient’s neurological exam was fully intact and a repeat MRI was ordered with the following impression: L2 level degenerative changes of the lumbar spine with epidural lipomatosis at lower lumbar levels which result in severe central canal stenosis at L4–5 and L5-S1 and varying degrees of neural foraminal narrowing. When measured by the authors using the method developed by Borre et al. [], the dural sac diameter/epidural fat diameter was 1.07, and the epidural fat/spinal canal diameter was 48.3%, categorizing the patient as a grade I (borderline grade II) (Figs. & ). The initial MRI measured 2.09 (DS/EF) and 32.4% ((EF/SC) as measured by the authors, which results in a grade 0 categorization. It is important to note that in one review [] only 14.5% of grade II cases, and 0% of grade I, were symptomatic. The time between the initial and repeat MRI was 5 months and the only two interventions during this time were a series of three LESI and the introduction of acetaminophen/hydrocodone. As a result of the repeat MRI findings surgical decompression was recommended.


A 78-year-old woman was admitted to the Department of Neurology on the third occurrence of generalized tonic clonic seizures (GTCS). A glioma had been diagnosed, and resection was performed 5 years previously. Following surgery, levetiracetam (LEV), 500 mg once daily was prescribed but discontinued by the patient 1 month later. The past medical history was otherwise unremarkable, except for 14 years of warfarin use at 1.875 mg per day prescribed for the secondary prevention of embolic events from paroxysmal atrial fibrillation (AF). The patient’s INR had not been monitored for 6 months, but there was no overt bleeding.
On the day of admission, 10 mg of diazepam was given intravenously to terminate a five-minute of GTCS while en route to a brain computerized tomography (CT) scan. The working diagnosis was status epilepticus (SE), and a loading dose of intravenous valproate sodium (1200 mg) was administrated to relieve the recurrent GTCS and frequent focal aware seizures. The patient remained physically well during interictal phase. Oral LEV of 500 mg twice daily was prescribed when the patient had regained consciousness. Oral warfarin was not discontinued based on the initial INR of 2.02. The patient was also on 40 mg oral isosorbide mononitrate sustained release tablets once daily and 12.5 mg succinate metoprolol tablets twice daily as needed. The brain CT scan showed left frontal and parietal craniectomy and encephalomalacia at the left frontal lobe.
On the second day of admission, routine laboratory studies revealed otherwise unremarkable results, including PT 22.70 s, PT% 36, albumin 38.5 g/L, total protein 59.50 g/L, TBIL 41.6 μmol/L, DBIL 7.10 μmol/L, IBIL 34.50 μmol/L, LDH 243 U/L, and NT-pro BNP 1906 pg/ml. ECG showed paroxysmal AF with a ventricular rate of 73 bpm. Carotid Doppler ultrasonography showed hypoechoic plaques on the anterior wall of the bifurcation of the right common carotid artery (Table ).
The intravenous valproate sodium was discontinued at 44 h after admission, and a total dosage of which was approximately 2200 mg. Although seizure ceased from the start of VPA infusion, 18 h of video-monitoring electroencephalogram (EEG) commenced 5 h later. This demonstrated global interictal θ waves (4-7 Hz), but without epileptiform discharges.
On the 3rd hospital day, the patient developed a renal dysfunction based on the results of BUN 13.74 mmol/l and serum creatinine 126 μmol/l, which was attributed to insufficient fluid intake. Coincidentally, the INR was found to be 8.26, and INR 9 h later was 5.52. Oral warfarin was paused but was mistakenly given again 6 h later by a caregiver. A third INR revealed an almost identical value of 5.32. Following consultation with a hematologist, 5 mg of vitamin K1 was given intravenously and the INR 8 h later was 2.16. The patient remained asymptomatic and without evident bleeding. A repeat brain CT scan revealed no intracranial hemorrhage. The renal dysfunction was corrected on the 4th day. The repeat BUN and serum creatinine were 9.33 mmol/l and 79 μmol/l, respectively. Based on the observation of an INR of 2.16, warfarin was carefully restarted with a dose of 1.25 mg and titrated back to 1.875 mg with steady monitoring of the INR to ensure a value between 2 and 3 (Table ).


A 50-year-old woman presented, in 2010, with galactorrhoea and oligomenorrhea of 4 years. Her past medical history included a right nephrectomy following a road traffic accident as a child. She had five children. The galactorrhea persisted since the birth of her last son when she was 31 years old. Endocrinology assessment revealed raised serum prolactin at 1444 mu/L with suppressed gonadotrophins and oestradiol. The patient was not taking any medication at the time. Renal function and thyroid function were both normal. A pituitary MR scan showed a 6 mm diameter microadenoma with inferior extension towards the sphenoid sinus on the left hand side (). The patient also suffered from headaches and visual disturbance, although the tumour was confined within the sella turcica and was not thought to be causal. Taken together, these findings were interpreted as diagnostic of a microprolactinoma.
After the patient’s eldest daughter died in her early 20s in 2013 from ovarian cancer, genetic testing was carried out within the family. The patient, as well as the patient’s mother and half-sister were found to carry a DICER1 gene mutation. There is no other significant family history of pituitary disorders. As part of DICER1 follow-up, she had regular scans of her thyroid, which revealed the expected multinodular goitre, and in 2018, she was diagnosed with a differentiated papillary carcinoma thyroid.


A 48-year-old woman with breast cancer underwent mastectomy (histology: invasive ductal carcinoma, histology grade 2; estrogen receptor: positive; progesterone receptor: positive; HER2: positive; Ki67: 10%, n+[27/28]) at the department of surgery in a previous hospital. Subsequently, she underwent chemotherapy with paclitaxel and doxifluridine and hormonal therapy with tamoxifen. Six years after surgery, bone metastasis was noted in the vertebra, and she was treated with a combination of radiotherapy and chemotherapy with trastuzumab. However, the metastatic disease progressed. Liver metastasis was also noted at 57 years of age, and the treatment was switched to capecitabine plus lapatinib, which was shortly discontinued because of adverse effects. Disease progression continued, although fulvestrant was also added. Eventually, she underwent chemotherapy with trastuzumab emtansine (T-DM1).
For the inhibition of bone metastasis, zoledronate was initiated at 54 years of age and was continued for 5 years until renal failure. After discontinuation of zoledronate, denosumab was used for 3 years until the detection of AFFs in both proximal femurs on the bone scintigraphy at 62 years of age (). Eventually, BMAs had been administered for 8 years. Right hip pain occurred temporarily, whereas left hip pain persisted for a long time. She experienced a left displaced femoral subtrochanteric fracture after falling at the age of 63 years (). At that point, the doctors in the previous hospital made a diagnosis of a pathological fracture caused by bone metastasis and consulted with our department for specialized treatment. After the patient was transferred to our hospital, we examined whether that fracture was due to bone metastasis, but no metastatic lesion was noted at the fracture site. In addition, radiography of the fracture area exhibited a beak on the lateral side of the fracture site associated with cortical bone sclerosis, which was characteristic of an AFF () []. Considering the long-term administration of BMAs, the fractures were diagnosed as AFFs.
For treating the displaced AFF, we could select either IMN or prosthetic reconstruction. For appropriate selection, evaluation of the patient's prognosis is required because recovery of ADL/QOL is the priority in cancer patients with limited life expectancy. The Katagiri score as a predictor of prognosis in patients with skeletal metastasis was high () [], and similarly, the score of another scoring system for metastatic breast cancer was also high () []. Thus, both predicted a poor prognosis. IMN is a less invasive approach, and it might successfully induce bone healing. However, delayed union/nonunion and implant failure are possible issues. To achieve early weight bearing and avoid these issues, we performed endoprosthetic reconstruction (Zimmer Biomet, OSS Proximal Femur) on the seventh day after the injury (). Two weeks after surgery, she achieved walker-assisted gait. After subsequent rehabilitation, prophylactic IMN was performed for the right incomplete AFF (). Six months after surgery, the Musculoskeletal Tumor Society (MSTS) score recovered (47%) to almost the preoperative level (50%) before the injury (). However, she died of breast cancer 1 year and 2 months after the endoprosthetic reconstruction.


A 14-years-old girl came to our attention because of severe and persistent lymphopenia during an episode of autoimmune hemolytic anemia. Her familiar history was negative for invasive infections and autoimmune diseases. Patient medical history was unremarkable for infections. In addition, previous blood counts were normal. The study conformed to all the protocols of Asst Spedali Civili of Brescia. Informed consent for blood tests and genetic studies was obtained from her parents.
She presented with acute onset anemia (hemoglobin 5.5 g/dl) with positive direct antiglobulin test (Coombs test, IgG 2+), normal platelets (299.000/μL), and white cell count (total leucocytes 5.760/μL, neutrophils 4.160/μL, lymphocytes 1.330/μL). At the beginning she was treated with oral prednisone (2 mg/kg/day), but poor response to the treatment was observed. Therefore, she was switched to four intravenous pulses of methylprednisolone each one at 2 mg/kg within 72 h, followed by intravenous immunoglobulins (1 g/kg).
The laboratory tests showed normal white cell counts, except for marked lymphopenia (Figure ), reduction of CD4+ cells (ranging from 50 to 300 cells/μL), increase of fetal hemoglobin, (6.4–13.9% during follow-up), supposedly related to reticulocytosis. While autoantibodies, including Anti-Nuclear Antibodies, Extractable Nuclear Antigen, Anti-DNA antibodies, Anti-Smooth Muscle Antibodies, Anti-phospholipid Antibodies, complement factors, and serum immunoglobulins were within the normal ranges. Immunological screening for celiac and thyroid disease were also negative. Serologic tests for Parvovirus B19, EBV, CMV, and Waaler-Rose test, were consistent with prior infection or non-immunized state. The fecal occult blood test was negative; chest radiograph, echocardiography and abdomen ultrasound were all unremarkable.
She underwent also bone marrow aspirate, that showed normal proportion of myeloid cells, presence of megakaryocytes, and mild dyserythropoiesis, without evidence of cytogenetic abnormalities.
During corticosteroid therapy, hemoglobin levels slowly increased and Coombs test became negative within 3 months. Prednisone (1 mg/kg/bid) was continued for 10 months with progressive tapering. However, this therapy was associated with multiple side effects, such as alopecia, weight gain, moon face, stretch marks, including lymphopenia. This was also associated with reduction of IgG concentrations (IgG 520, n.v. 640–1909 mg/dl; IgM 115, n.v. 59–297 mg/dl, IgA 121, n.v. 61–301 mg/dl) which prompted us to start IVIG every 4 weeks for 3 months. In addition, because of the risks related to lymphopenia and to prolonged immunosuppressive therapy with corticosteroids, prophylaxis with cotrimoxazole and acyclovir was prescribed.
In order to exclude an underling immunodeficiency, we examined lymphocyte subsets. Flow cytometric immunophenotyping showed marked alterations in the distributions of the T-lymphocytes (Table ): reduction of the CD3+CD4+ T cells (19.7%), especially the Recent Thymus Emigrants (RTE) CD4+ T Cells (2.9%), and increase of the TCR γ/δ T cells (24.7%). Transitional B cells (0.4%), and terminal differentiated B cell subsets (0.06%) were reduced, while Switched Memory B cells (34.2%) were increased. T-cell Receptor Excision Circles (TRECs) and Kappa-deleting Recombination Excision Circles (KRECs) were below normal range, while analysis of the T-cell receptor repertoire showed a marked monoclonal expansion of TCRBV6 expressing cells. Increase of TCR γ/δ T cells could be related to many conditions, including infections. CD3+/CD4−/CD8− (double negative T cells) subset were in the normal range, thus ruling out the hypothesis of Autoimmune lymphoproliferative syndrome.
Next, we analyzed by next generation sequencing (Ion Torrent pgm, Thermo Fischer) a panel of genes that are associated with SCID or CID/lymphopenia. Genetic analysis revealed an heterozygous mutation in exon 10 of the gene encoding for adenosine deaminase (ADA, p.S291L c.561C>T), while other genes that are associated with autoimmune diseases, including LRBA and CTLA4 were negative for mutations. Sanger sequencing of ADA gene coding and non-coding flanking regions revealed the same mutation. The assessment of adenosine and deoxyadenosine nucleotides levels in the patient at the time of lymphopenia revealed a moderate increase of both metabolites: adenosine was 3.6 μMol/ml RBC (n.v. 0.8–1.6) while deoxyadenosine was 0.006 uMol/ml RBC (n.v. < 0.005), respectively. Total AXP and dAXP in RBC were quantified by high performance liquid chromatography measuring the levels of Ado and dAdo formed by treating neutralized acid extracts with alkaline phosphatase and venom phosphodiesterase ().
Analysis of ADA activity in red blood cells lysates, as measured by spectrophotometric analysis of the absorbance change at 265 nm (), was reduced but within the normal range (0.8 U/g Hb; n.v. 0.8–2.5) while PNP activity in red blood cells lysates was normal (200 μ/g Hb; n.v >330). Analysis of ADA activity, of total AXP and dAXP in RBC in her parents were normal; unfortunately, their genetic status has not been investigated for parental decision.
After corticosteroid tapering the patient's total numbers of lymphocytes gradually increased and reached normal levels (Figure ). One year after stopping corticosteroid therapy lymphocyte count was 1.410 cells/μL, with 550 CD4+cells/uL. Thus, she interrupted the prophylactic therapy with acyclovir and cotrimoxazole.


A 19-year-old male presented to the emergency department with a two-week history of pleuritic chest pain, dyspnoea, and non-productive cough. He denied fevers, night sweats, or weight loss. He had no articular, cutaneous, or ocular symptoms. He had mild childhood asthma in the past. He was not on any regular medications. There was no significant family history. He had moved to New Zealand from Fiji eight years earlier. He had regularly smoked tobacco through a “shisha” pipe for the preceding 3 months.
On examination, he was afebrile, with a heart rate of 90 beats per minute, blood pressure of 110/80 mmHg, and oxygen saturations of 98% on air. His cardiac and respiratory examination was normal. His abdomen was non-tender without evidence of masses. He had no peripheral lymphadenopathy. His testicular examination was normal.
A full blood count showed normal haemoglobin of 147 g/L (normal range 130–175), white blood cell count of 8.8 × 109 (normal range 4–11), and eosinophil count of 0.2 × 109 (normal range 0–0.5). C-reactive protein was 25 mg/L (normal range 0–5).
His chest radiograph showed multiple ill-defined opacities in both lower lung fields. A subsequent computed tomography (CT) scan of the chest and abdomen (Fig. ) showed multiple poorly marginated and irregularly contoured enhancing nodules through both upper and lower lobes bilaterally, more numerous at the bases. There were no pleural effusions or lymphadenopathy, and appearances of the abdomen were normal.
Further blood tests showed a negative antinuclear antibody (ANA), extractable nuclear antigen (ENA) panel, anti-neutrophil cytoplasmic antibodies (ANCA), serum angiotensin-converting enzyme (ACE), alpha-feto protein, Beta human chorionic gonadotropin (hCG), and Quantiferon-Gold.
He proceeded to a CT-guided fine needle aspirate and core biopsy of the most peripheral lesion in the left lower lobe. Histology (Fig. ) demonstrated preserved lung alveoli but prominent expansion of the lung interstitium with frequent necrotizing granulomas. There was a mixed inflammatory infiltrate of lymphocytes and occasional plasma cells and eosinophils. Fungal and mycobacterial stains were negative, as was culture for bacteria, mycobacteria, and fungi. Mycobacterium tuberculosis polymerase chain reaction (TB PCR) on biopsy specimen was negative. There was no evidence of malignancy, vasculitis, or foreign bodies, nor any features of Langerhans cell histiocytosis (LCH). Cell marker studies showed no evidence of monoclonality. Overall, the pathology impression was of necrotizing granulomatous inflammation.
The patient was given no specific treatment other than simple analgesia. While awaiting the histology results, he was discharged home with advice to avoid further shisha tobacco. Serial chest radiographs were performed at intervals of two weeks, six weeks, 12 weeks, and nine months. These demonstrated progressive resolution of the pulmonary opacities, with a clear chest radiograph at 12 weeks (Fig. ). A spirometry performed at nine months was normal.
The impression was of bilateral pulmonary granulomatous nodules most likely related to shisha smoking, with complete resolution following cessation.


A 15-year-old Indian Hindu boy from a low socioeconomic stratum presented to Surgical emergency with complaints of difficulty in passing stools for 1 month, passage of blood and mucus per rectum for 15 days, abdominal distension for 1 week, and obstipation for 3 days. These symptoms were associated with significant appetite and weight loss but there was no history of fever, jaundice, melena, hematemesis, hemoptysis, cough, chest pain, or shortness of breath. There was no history of similar illness or other malignancy in his family. He was not on any medication.
On examination he was conscious and oriented. He had a thin build and pallor. He was afebrile. His pulse rate was 84/minute and blood pressure (BP) was 110/74 mmHg. His abdomen was distended with no local bulge. On digital rectal examination, a circumferential proliferative growth was felt 1 cm above the anal verge, which was almost completely occluding the lumen. On scrotal examination, a small nodule was felt in his right testis. The rest of the systemic examination was normal.
An abdominal and chest X-ray was done as preliminary investigation which revealed signs of intestinal obstruction (Fig. ).
In view of intestinal obstruction, he was taken into our emergency operation theater and a diverting loop sigmoid colostomy was performed. His symptoms were relieved, and stoma was well functioning and healthy.
A punch biopsy was taken from anorectal growth. The histopathological examination (HPE) report suggested signet ring cell adenocarcinoma of rectum (Fig. ). Tumor markers report showed: carcinoembryonic antigen (CEA) 499.93, alpha-fetoprotein (AFP) 2.42, beta human chorionic gonadotropin (HCG) < 1.2, and lactate dehydrogenase (LDH) 593.
Routine investigations including complete blood count (CBC), and liver and renal function tests were within normal limits. His urine analysis was also normal.
Contrast-enhanced computed tomography (CECT) of his chest, abdomen, pelvis, and brain was done as a part of metastatic workup which showed diffuse circumferential homogenous thickening involving rectum approximately 1 cm from the anal verge and extending into sigmoid colon proximally up to colostomy site. Multiple enlarged lymph nodes, some showing necrosis, were noted in perirectal, iliac, bilateral para-aortic, periportal, and celiac regions. Moreover, multiple enlarged lymph nodes were seen in the mediastinum in bilateral paratracheal, prevascular, and subcarinal regions, and in left supraclavicular region. In addition, hepatomegaly with liver measuring 17.8 cm was present. However, no lesion was seen in liver parenchyma. There was mild left-sided pleural effusion (Figs. and ). There was no lesion in his brain suggestive of metastasis. His right testis was enlarged. Ultrasonography (USG) showed a hypoechoic nodule (Fig. ) in his right testis from which a fine-needle aspiration biopsy was done, which revealed metastatic adenocarcinoma (Fig. ).
In view of distant metastasis, we planned to give our patient neoadjuvant chemotherapy. However, within 2 weeks of surgery he developed progressive respiratory distress. A chest X-ray showed infiltrations and bilateral pleural effusion. He was intubated and was kept in our intensive care unit (ICU). However, his condition deteriorated and he developed multiple organ dysfunction syndrome (MODS) in the next few days. Eventually he died with multiple organ failure. An autopsy was not performed as per the wish of his family members. The entire course of illness from appearance of first symptom to death was only 2 months.


The patient is a 44-year-old immigrant male who presented to our institution with multiple masses in bilateral parotid glands, left greater than right. He had a history of neurocysticercosis, presumably owing to ingestion of uncooked pork in Mexico and had undergone a previous craniotomy with removal of the brain mass in Mexico. The patient had been vaccinated against tuberculosis, and subsequent work-up for systemic tuberculosis was negative. This new onset of bilateral parotid masses since his emigration to USA was presumed to represent cysticercosis lesions. A CT scan of the neck with i.v. contrast demonstrated bilateral parotid masses with a dominant, ring-enhancing, hypodense lesion in the left superficial parotid gland, which measured 3.0 × 2.9 cm (). A left superficial parotidectomy was performed, and upon pathological analysis, the peripherally enhancing lesion grossly appeared as a large yellowish fluid-filled cyst (). Micropathology revealed a squamous epithelium-lined cyst with lymphoepithelial complexes (brown islands) consistent with a lymphoepithelial cyst (). This raised the concern of HIV infection, which was confirmed with serological studies.


This patient was a 71-year-old male who presented with abdominal discomfort and was found to have significant splenomegaly upon physical exam, confirmed by imaging. He was diagnosed clinically with SMZL and underwent splenectomy to control his disease. We have not been able to determine whether he had peripheral blood lymphocytosis at that time of initial presentation.
Ten years after the initial diagnosis of lymphoma, he presented to our institution with weight loss and extensive anterior mediastinal, hilar, and retroperitoneal lymphadenopathy with an anterior mediastinal mass measuring 9.8 × 5.6 cm. Serum lactate dehydrogenase was elevated (281 U/L, reference range: 135–225 U/L). He was started on weekly rituximab with no response. In view of progressive symptoms, he was switched to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy at an outside institution. He presented to our institution after his first cycle of R-CHOP for additional recommendations. He felt dramatically better at that time. The clinical impression was that he had a large-cell transformation of his previously diagnosed low-grade SMZL.
Laboratory analysis showed a white blood cell count of 9.4 × 103 cells/μL, hemoglobin level of 12.2 g/dL, platelet count of 242 × 103/μL, and absolute lymphocyte count of 1.33 × 103/μL. Peripheral smear was morphologically unremarkable. Peripheral blood flow cytometry showed a minor monotypic B-cell population, CD5, CD10, and CD23 negative, comprising 0.7% of analyzed events, consistent with minimal peripheral blood involvement by his previously diagnosed lymphoma. He was referred for lymph node biopsy to clarify the diagnosis.
Excisional biopsy of the axillary lymph node showed extensive involvement by lymphoma composed of both small, cytologically atypical lymphoid cells with abundant cytoplasm admixed with more predominant intermediate to large-sized lymphoma cells with variably abundant cytoplasm, large nuclei, and prominent, centrally located nucleoli, consistent with prolymphocytes (Figures and ). The aggregates of prolymphocytes did not resemble proliferation centers seen in CLL/SLL as they were more discrete, monotonous, and expansile in nature. Transformed cells, defined as having intermediate to large-sized nuclei and central nucleoli, comprised more than 50% of all lymphoma cells. Sheets of large cells were not present; thus, designation as a large-cell transformation was not warranted [, ].
By immunohistochemistry, lymphoma cells were positive for CD20, CD5 (dim, subset), BCL2, and cyclin D1 (diffuse, positive in small lymphoma cells and those with prolymphocytic features), and negative for CD3, CD10, LEF1, and SOX11 (Figures –). EBER staining by in situ hybridization was negative. The KI67 proliferation index was estimated at 40%, and it highlighted the large transformed cells in particular. Based on these findings, the possibility of mantle cell lymphoma (MCL) was considered.
The previous material (splenectomy and bone marrow biopsy from 10 years before) was then reviewed at our institution, and the original interpretation of SMZL was indeed confirmed. In the splenic resection, the lymphoma cells were present in a micronodular pattern within white pulp, invaded red pulp, and were composed of small-sized lymphoma cells with monocytoid morphologic features, negative for CD5 and cyclin D1 (). Staging bone marrow biopsy performed at the time of initial splenectomy showed extensive involvement by low-grade lymphoma with an interstitial nodular and focally intrasinuoidal pattern (). Lymphoid cells in the aspirate smear were small and did not have features of large-cell or prolymphocytic transformation. Karyotype and FISH studies performed in the bone marrow were negative for t(11; 14)(CCND1-IgH).
Given the confirmation of the initially diagnosed SMZL, we performed FISH for t(11; 14)(CCND1-IgH) using IgH and CCND1 dual-labeled probes in the lymph node sample both at our institution as well as at an external reference lab, and both were negative for CCND1-IgH rearrangement (). An additional FISH test using a CCND1 break apart probe was also performed and failed to detect rearrangements involving CCND1. Additional copies of CCND1 were not present.
To assess the clonal relationship between the splenic and nodal neoplasms, PCR analysis for IgH rearrangement was performed in both samples. The same monoclonal IgH peaks (framework region (FR) 1: splenectomy: 342.24, lymph node: 342.38; FR2: splenectomy: 277.71, 285.58; lymph node: 277.69 and 285.36; FR3: splenectomy: 146.14, lymph node: 146.3, Figures and ) were identified in the original and current samples, supporting that the two lymphomas were clonally related. Next-generation sequencing (NGS) using the FoundationOne Heme comprehensive genomic profiling assay (Foundation Medicine, ) identified genomic alterations of NOTCH2, BRCA2, and SRSF2 but was negative for rearrangements involving CCND1 in both samples from the two different time points, further supporting that the lymphomas were clonally related and that despite the acquired strong expression of cyclin D1, the neoplasm lacked CCND1 gene rearrangement or mutation.
Taken together, these findings indicate that the lymphoma with prolymphocytic transformation involving the lymph node represented disease progression of the patient's original SMZL. The prolymphocytic histologic transformation was defined in this case by the presence of sheets of intermediate to large-sized lymphoma cells with prolymphocytic morphologic features and was associated with acquired partial CD5 and diffuse cyclin D1 expression in the absence of acquired t(11; 14) (CCND1-IgH).


This patient was a 53-year-old male without relevant past medical history who presented with one week of intermittent fevers, night sweats, weight loss, early satiety, cough, and exertional shortness of breath. Physical examination revealed diffuse small lymphadenopathy and massive splenomegaly. Imaging studies confirmed massive splenomegaly with the spleen measuring 31 cm in craniocaudal dimension with diffuse hypermetabolic activity, SUV 5.6, in keeping with lymphomatous involvement. There were also numerous subcapsular wedge-shaped areas of photopenia and hypodensities measuring up to 3.5 cm, which were suspected to be splenic infarcts ().
Laboratory analysis showed an elevated LDH of 421 U/L (normal range: 132–225 U/L), leukocytosis (white blood count: 210 × 109 cells/L), anemia, and thrombocytopenia. Peripheral blood smear confirmed lymphocytosis with many circulating lymphoma cells being small to intermediate in size with mature nuclear chromatin (). Approximately 50% of circulating lymphoma cells were large with abundant cytoplasm, more open and vesicular nuclear chromatin and prominent nucleoli, consistent with prolymphocytes (). Cells with villous or circumferential cytoplasmic projections were not seen. Flow cytometry immunophenotyping in peripheral blood showed that lymphoma cells were positive for CD20, CD19, CD79a, CD22, and CD23 with lambda surface light chain restriction and negative for TdT, CD34, CD10, and CD5. Initial diagnostic considerations included prolymphocytic transformation of atypical CD5 negative CLL, B-prolymphocytic leukemia (B-PLL), and leukemic MCL, noting that the immunophenotypic expression patterns of B-PLL and SMZL can be indistinguishable.
Bone marrow core biopsy showed diffuse infiltration by intermediate-sized cytologically atypical lymphoma cells, and aspirate smear showed that most lymphoma cells had prolymphocytic morphologic features in the bone marrow (Figures –). An intrasinusoidal pattern of involvement was difficult to appreciate due to the extensive degree of marrow involvement. Immunohistochemistry in the bone marrow core biopsy showed lymphoma cells were diffusely and strongly positive for cyclin D1 () and negative for CD5, LEF1, and SOX11. Chromosome analysis in bone marrow aspirate showed a normal karyotype 46, XY in 20 metaphases. FISH studies for t(11; 14) (CCND1-IgH) in the peripheral blood and bone marrow aspirate were negative but were positive for deletion 7q (33% of cells), deletion 17p (97% of cells), and deletion 13q (18% of cells). Next-generation sequencing using the FoundationOne Heme comprehensive genomic profiling assay identified a genomic alteration of TP53 and was negative for rearrangements or mutations involving CCND1 and other tested genomic alterations. Extra copies of CCND1 were not detected.
Based on the absence of t(11; 14)(CCND1-IgH) as detected by FISH, karyotype, and NGS, a diagnosis of MCL was excluded despite diffuse cyclin D1 expression. The presence of massive splenomegaly, the lymphoma cell morphology and immunophenotype, and presence of deletion 7q, support that this lymphoma is best classified as SMZL with prolymphocytic transformation and diffuse cyclin D1 expression. However, extreme leukocytosis, presenting with B symptoms and diffuse lymphadenopathy, as seen in this case, is unusual for SMZL; thus, we cannot exclude that this lymphoma is a B-PLL with diffuse cyclin D1 expression. The presence of deletions 13q and 17p, although not specific, are recurrent abnormalities seen in approximately 27% and 50% of B-PLL, respectively, and may support this classification [].
Because this patient did not have splenectomy, we also cannot completely exclude the possibility of splenic diffuse red pulp small B-cell lymphoma, although CCND3 mutations, which are recurrent in that lymphoma, were not identified, and the presentation was more aggressive than typically reported in diffuse red pulp small B-cell lymphoma.


A 50-year-old Chinese female with a history of right breast neoplasm was treated with repeat lumpectomy for 4 times during 8 years. Physical examination revealed a 2.0-cm palpable mass in the right breast at the original surgical site. The lesion was not associated with any edema or blister, and no skin discoloration or ulcer was found. Subsequent mammogram and ultrasound examination demonstrated a possible malignancy (BI-RADS-4B and BI-RADS-4C, respectively). Digital mammography and ultrasonography indicated that there were no other specific characteristics compared with breast cancer. A CT scan for brain, lung, liver, and bone were conducted to exclude metastasis.
The patient had a history of repeat lumpectomy, and the pathological analysis showed adenosis, phyllodes tumor, and fibrous tissue, accompanied by glass changes and highly differentiated AS. Therefore, mastectomy was suggested by our multidisciplinary team, and the patient underwent a right mastectomy with sentinel lymph node biopsy in January, 2018. The lesion was diagnosed as AS (Fig. A–D), which was immunohistochemically positive for endothelial markers CD31 (Fig. A), CD34 (Fig. B), ETS related gene (Fig. C), and FVIII-R-Ag (Fig. D). No other therapy was given postsurgery, and the patient had no recurrence after 3 months. This study was proved by the Ethical Committee of our hospital, and a written consent was obtained from the patient.


A 36-year-old, white-haired Korean man (Fig. . II-2: Proband) visited the ophthalmology department complaining of loss of vision in the inferior visual field of his right eye. His face was characterized by lateral displacement of the inner canthus of both eyes with a medial eyebrow and a high broad nasal bridge (Fig. ). His medical history was significant for paralysis of one arm after a cerebral infarction 13 years earlier and right-sided sensorineural hearing loss. His father (Fig. . I-1), who had had hearing impairment, died of a myocardial infarction in his 50s, and his brother (Fig. . II-1) had bilateral hearing loss and heterochromia iridis. His best corrected vision was 20/25 with myopic correction (− 2.50 diopters) on the right and 20/20 with myopic correction (− 3.50 diopters) on the left. His intraocular pressure was 15 mmHg in the right eye and 13 mmHg in the left eye. A hypochromic left iris (Fig. ) was observed on slit-lamp examination. Funduscopy showed an ischemic change at the posterior pole with sparing of the foveal center along with retinal hemorrhages and white patches along the superotemporal arcade (Fig. ). Optical coherence tomography revealed thickening and opacification of the retinal layers corresponding to the ischemic area (Fig. ). Both BRVO and BRAO were detected on fluorescein angiography (Fig. ). An intravitreal anti-vascular endothelial growth factor (Avastin®, bevacizumab) injection (1.25 mg in 0.05 mL) was administered in the right eye for macular edema. After 2 months, the patient’s macular edema was significantly improved and his visual acuity was maintained at 20/25.
Single nucleotide polymorphism analysis was performed by comparing a peripheral blood sample with the NM_181457 reference, and a PAX3 mutation was confirmed in exon 2 on chromosome 2q35 (Fig. ). An ACTCC deletion was noted at c.91–95, causing a frameshift of protein Thr31. A diagnosis of WS type 1 was made on the basis of this genetic mutation and the patient’s clinical features. Further biochemical workup revealed a raised serum homocysteine level (28.3 μmol/L). Antiphospholipid antibodies, including anticardiolipin and lupus anticoagulant, were also detected. Other blood coagulation factors were in the normal range or negative. The electrocardiogram showed no significant abnormality.


A 71-year-old African American female with a history of hypertension was diagnosed with stage IIa classical HL in 2003. She underwent four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) achieving a complete remission (CR). In 2016, she developed progressive bilateral patchy visual loss over 4 months prior to seeking medical attention. She was seen by an ophthalmologist (AKR) who diagnosed bilateral FBA (Figure ). Based on the ophthalmologic findings, patient was evaluated for HL relapse. She was otherwise asymptomatic and has gained 1.4 kg over the past year. Full blood count and chemistry profile were unchanged. Testing for other causes of FBA was negative, including fluorescent treponemal antigen absorption (FTA-ABS), T-spot, angiotensis-1-coverting enzyme, muramidase-lysozyme, Antineutrophil cytoplasmic antibodies (ANCA), and toxoplasma IgG and IgM antibodies. Testing from an ocular fluid sample for viral causes was deferred by the patient.
Computed tomography (CT) scan of the chest, abdomen, and pelvis showed a mildly prominent left supraclavicular lymph node as well as enlarged nodes at the right iliac chain and right iliac fossa. Positron emission tomography (PET) scan showed diffuse involvement of the left supraclavicular, bilateral iliac chain, and retroperitoneal lymph nodes with maximum standardized uptake values (SUV-max) of 10.7. There were right paracolic soft tissue tumor implants with SUV-max of 5.8, and metabolically active sclerotic lesions in the left iliac bone with SUV-max of 3.4. A right external iliac node biopsy confirmed classical HL with the same histological and immunohistochemical findings as the biopsy at presentation. Reed-Sternberg cells were positive by immunohistochemistry for CD15 and CD30, and negative for CD45, CD20, CD3, EBER, and AE1/AE3. Flow cytometry showed no immunophenotypic evidence of monoclonal B lymphocytes or immune-phenotypically abnormal T lymphocytes.
Patient started intravenous therapy for HL with brentuximab vedotin and intraocular injections of bevacizumab 1.25 mg/0.05 mL monthly for 4 months. After two cycles of brentuximab, the patient achieved a CR by PET/CT scan. Because of the long first remission, patient's age, and preference, it was decided to continue brentuximab and not proceed with autologous stem cell transplant. Her vision improved from 20/30 to 20/25 OD (right eye) and worsened from 20/50 to 20/65 OS (left eye) over the course of 6 months after the beginning of HL treatment. The lack of improvement in the left eye was secondary to a choroidal neovascular membrane which developed subfoveally. On follow-up imaging with fluorescein angiography her periphlebitis minimally improved in both eyes and she had resolution of her angiographic edema in the right eye, but no improvement in the left eye. (Figure ).


A 68-year-old woman presented to the Department of Oral and Maxillofacial Surgery at Nagoya Ekisai Hospital (Nagoya, Japan) with a chief complaint of malaise and a 7-month history of swelling of the left buccal mucosa. The patient had no congenital swelling of the left buccal mucosa at birth and no history of systemic disease or relevant family history. The patient had undergone maxillary molar restoration treatment 2 years earlier, after which she reported biting regularly on her buccal mucosa. On most occasions, the wound had healed within a week, so she had not sought medical treatment. An extraoral examination revealed no facial swelling or asymmetry. However, an intraoral examination revealed an area of diffuse swelling on the left buccal mucosa measuring about 15 mm × 30 mm and containing a papillary lesion with multiple red, blue, and clear pebble-like vesicles (Figure ). On palpation, the lesion was nontender and soft. The swelling had not expanded to the veins and was pulsatile. An orthopantomogram confirmed that the adjacent bone was intact. Magnetic resonance imaging revealed a soft tissue mass with a clearly distinguishable outline of the buccinator muscle (Figure ). The lesion was surgically excised under local anesthesia with a margin of 3 mm and a depth of 2 mm via the inside surface of the fascia of the buccinator muscle. The outcome was favorable. Pathologic examination of the specimen revealed expanded lymphatic vessels lined by thin endothelial cells and containing lymphatic fluid. A diagnosis of lymphatic malformation was confirmed on histopathology and immunohistochemical studies. Immunohistochemistry was negative for vascular markers such as CD31 and CD34, and the lymphatics stained specifically for D2-40 (podoplanin) (Figures , , ). On follow-up, the wound was found to have healed with no evidence of trismus or recurrence. The patient continued to be recurrence-free at her 2-year follow-up. Informed consent was obtained from the patient, and the procedures were in accordance with the Helsinki Declaration.


The patient was a 60-year-old man who was diagnosed with alcoholic liver cirrhosis and type 2 diabetes when he was 50 years old. His drinking history was 540–720 mL Japanese sake per day for 35 years, and his smoking history was 30 cigarettes per day for 30 years. His ascites increased in 2008 when he was 57 years old, and he repeatedly exhibited symptoms of hepatic encephalopathy. Due to the liver cirrhosis symptoms, the patient was treated with several medications including furosemide, spironolactone, lactulose, and total amino acid preparation. To prevent the complications of liver cirrhosis, coil embolization to a portal venous shunt was performed twice. The patient was admitted to our hospital in June 2012 because of slowly progressive renal impairment and nephrotic syndrome.
Upon admission, the patient's height and weight were 166 cm and 64 kg, respectively. His body temperature was 36.7°C and his blood pressure was 150/60 mmHg. His consciousness was clear. His abdomen was slightly expanded but exhibited no tenderness. The liver and spleen were not palpable. No rash or purpura was noted on the skin. Diabetic and/or hypertensive changes were not observed in the ocular fundus.
The laboratory findings on admission were hemoglobin level of 9.4 g/dL (normal range 13.5–17.6 g/dL), platelet count of 11x104/μL (normal range, 13.1–36.2x104/μL), prothrombin time measurement of 68% (normal range, 70–130%), total bilirubin level of 0.9 mg/dL (normal range, 0.3–1.2 mg/dL), NH3 level of 85 mg/dL (normal range, 30–80 mg/dL), blood urea nitrogen level of 41 mg/dL (normal range, 8–20 mg/dL), serum creatinine concentration of 1.77 mg/dL (normal range, 0.5–1.1 mg/dL), serum total protein level of 5.7 g/dL (normal range, 6.7–8.3 g/dL), serum albumin level of 2.1 g/dL (normal range, 3.5–5.2 g/dL), total cholesterol of 188 mg/dL (normal range, 120–219 mg/dL), and HbA1c of 5.8% (normal range, 4.3–5.8%). The serum levels of IgG were 1558 mg/dL (normal range, 870–1700 mg/dL), of IgA were 481 mg/dL (normal range, 110–410 mg/dL), of IgA1 were 398 mg/dL (normal range, 50–314 mg/dL), of IgA2 were 83 mg/dL (normal range, 10–156 mg/dL), and of IgM were 219 mg/dL (normal range, 35–220 mg/dL). The serum levels of free κ and λ light chains were 149.0 mg/L (normal range, 3.3–19.4 mg/L) and 106.0 mg/L (normal range, 5.7–26.3 mg/L). The serum free light chain ratio was within normal range. The serum level of complement factor C3 was 79 mg/dL (normal range, 65–135 mg/dL), of C4 was 17 mg/dL (normal range, 13–35 mg/dL), and of CH50 was 41.1 U/mL (normal range, 30–50 U/mL). All of the other serology findings including anti-nuclear antibody, hepatitis B virus surface antigen, hepatitis C virus antibody, anti-neutrophil cytoplasmic antibody, and anti-glomerular basement membrane antibody were negative. There was no M-spike on serum and urine protein electrophoresis. A serum test for a cryoglobulin precipitation was negative.
The urinary sediments showed many red blood cells in high power fields together with granular casts and dysmorphic red blood cells. The urinary protein excretion was 4.7 g/day. The 24-hour creatinine clearance was 45 mL/min. Computed tomography revealed liver deformity with moderate accumulation of ascites. The kidneys were normal in size and there were no signs of urinary tract obstruction.
The renal biopsy specimens contained a total 28 glomeruli, 12 of which were globally sclerotic. The degree of interstitial fibrosis/tubular atrophy was 50–60% of the total biopsy specimen identified. Moderate fibrous intimal hyperplasia was observed in the arcuate artery. Diffuse segmental double-contours of the glomerular basement membrane and mesangial cell hypercellularity were identified in nonsclerotic glomeruli, exhibiting a membranoproliferative glomerulonephritis-like pattern (). Some glomeruli showed moderate-to-severe endocapillary hypercellularity, accompanied by fibrocellular crescents (). Fluorescent immunostaining showed granular staining of IgA and C3, but not of IgG, IgM, or C1q, on glomerular capillaries and some mesangial areas (Figures –). Among the IgA subtypes, staining of IgA1 (GenWay Biotech, San Diego, CA, USA) was observed, but staining of IgA2 (GenWay Biotech) was not identified (Figures and ). With light chain immunostaining, only κ (SouthernBiotech, Birmingham, AL, USA) was identified and no λ staining (SouthernBiotech) was seen (Figures and ). On electron microscopy, the glomerular capillary walls showed double contours. Electron-dense deposits were found in the paramesangium and around the subendothelial space of the glomeruli (). No organized structure deposits were identified (). Based on these findings, this case was histologically diagnosed as diffuse membranoproliferative glomerulonephritis with monoclonal IgA1-κ deposits.
Because this case was accompanied by moderately advanced decompensated liver cirrhosis, there was a concern that the patient may have serious side effects due to aggressive treatment such as the administration of corticosteroids. Thus, supportive treatment based on medications such as RAS inhibitors/diuretics, in addition to dietary therapy including salt restriction/branched-chain amino acid administration, was selected. Although these treatments led to a modest decrease in the urinary protein excretion, the patient's renal dysfunction slowly progressed and finally resulted in end-stage renal failure and initiation of dialysis therapy.