Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.
We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.
78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).
IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.

BACKGROUND: Xanthoma disseminatum (XD) is a rare form of non-Langerhans histiocytosis with extensive cutaneous involvement. There is a paucity of evidence-based recommendations for treatment decision-making. Previous case reports have established purine analogues, especially cladribine, as a hopeful first-line treatment option, but characterization of the clinical and pathological responses is lacking.
OBJECTIVE: To characterize the clinical and pathological responses to cladribine monotherapy based on serial examinations in XD patients.
METHODS: We retrospectively studied the clinical, pathological and laboratory data in a cohort of five XD patients who received intravenous cladribine monotherapy with serial examinations in our hospital. Compared with baseline characteristics, changes in clinical features and pathological patterns were identified and analysed. We also conducted a literature review of reported cases of cladribine treatment in XD patients.
RESULTS: Four male and one female patient were involved in the study. All patients demonstrated satisfactory clinical responses to cladribine monotherapy after 5 to 10 cycles. We observed a pathological shift in pattern from classic xanthogranuloma to transitional fibrohistiocytic infiltration during the treatment, and pathological responses heralded persistent clinical improvement. Other than afebrile neutropenia, no prominent adverse events were identified. Sustainable lesion clearance was achieved in all five patients during the follow-up period, ranging from 19 to 66 months.
CONCLUSIONS: Cladribine monotherapy is an effective and well-tolerated therapeutic option for XD patients. Pathological transformation is a signature of the clinical response and possibly unveils the underlying histiocyte biology of diseases in the xanthogranuloma family.

Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging.
We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up.
Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs.

Gemcitabine is a commonly used antimetabolite that has been effective in a broad spectrum of tumors so far. The main grade three and four known toxicity of this drug is myelosuppression. Cardiac adverse events have rarely been reported and gemcitabine-induced atrial-fibrillation (AF) has been described in only five previous cases so far. Here we report the 6th case of gemcitabine-related AF. A 68-year-old man diagnosed with metastatic nasopharyngeal cancer was referred to our oncology department. He started first line chemotherapy with gemcitabine and cisplatin. He presented poorly tolerated atrial fibrillation related to gemcitabine infusion that lasted for six days. The treatment was then withdrawn and the patient received best supportive care. We conclude that Medical oncologists and cardiologists should be aware of such toxicities of gemcitabine, especially in the elderly who seem to be at a higher risk of such adverse events and which may dictate discontinuation of the drug.

BACKGROUND: Capecitabine is an antimetabolite antineoplastic agent widely used in the treatment gastrointestinal cancers. The common frequently reported cutaneous adverse drug reaction associated with capecitabin are a palmar-plantar erythrodysesthesia syndrome, rash and hyperpigmentation. This case reports a capecitabine-induced palmar hypopigmentation.
METHODS: We report the case of a 74-years old patient with jejunum adenocarcinoma treated by capecitabine. The patient developed a pseudo-vitiligo after 2 cycles capecitabine and without history of cutaneous disorders. The skin lesions were characterized with skin hypopigmentation on both hands.Management and outcome: The hypopigmentation slowly recovered after capecitabine discontinuation.
CONCLUSIONS: This is the first described case of pseudo-vitiligo induced by capecitabine. This impressive but non-severe adverse effect should be known by oncologists and oncology pharmacists to reassure the patients in particular about the possible recovery after discontinuation of capecitabine.

Introduction: Italy, since the end of February 2020, is experiencing the corona virus disease 2019 (COVID-19) pandemic that may present as an acute respiratory infection. We report on COVID-19 pneumonia in the context of a complex case of Cushing\'s disease (CD). Case Report: A 67-year-old man with CD, who was admitted to our hospital, presented with signs and symptoms of adrenal insufficiency with persistent hypotension and glycemia toward the lower limits. We progressively withdrew almost all treatments for diabetes and CD (pasireotide and metyrapone), and i.v. hydrocortisone was necessary. A tendency to hyperkalemia was probably associated to enoxaparin. We summarized the many possible interactions between medications of Cushing\'s syndrome (CS) and COVID-19. Conclusion: Adrenal insufficiency might be a clinical challenge that needs a prompt treatment also in CS patients during COVID-19 infection. We should consider the possibility to titrate or temporary halt medical therapies of CS in the context of COVID-19 infection. Unexpected hyperkalemia in CS patients under treatment with heparin might be the signal of aldosterone suppression.

Background: Carney complex (CNC) is a rare multiple endocrine neoplasia syndrome with autosomal dominant inheritance. Affected individuals present with mucocutaneous lentigines/blue nevi, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors. Mutations in PRKAR1A have been identified as genetic cause of the disease. Here, we report on pregnancy, delivery and puerperium in a woman with genetically confirmed CNC and her newborn. Case: The 31 year-old gravida 5 para 1 with CNC was referred at 26 weeks of gestation. Adrenocorticotropin-independent hypercortisolism, hyperglycemia, hypertension, low serum potassium, and osteoporotic fractures were present. Treatment with metyrapone, a reversible 11-beta-hydroxylase inhibitor, was initiated. The maternal condition improved, and a 5 weeks\' pregnancy prolongation could be achieved. Elective repeat cesarean section was performed at 31 weeks of gestation for recurrent vaginal bleeding. The neonate developed transient hyponatremia necessitating hydrocortisone substitution for 2 weeks. Conclusion: In our case, treatment of CNC-associated hypercortisolism in pregnancy with metyrapone was effective. Maternal side effects did not occur. The newborn presented with transient hypocortisolism most likely due to transplacental drug effect. Our case illustrates that the treatment of rare diseases in pregnancy represents a challenge requiring interdisciplinary team work.

American visceral leishmaniasis (VL) is a vector-borne disease caused by Leishmania infantum (syn. chagasi) and transmitted by Lutzomyia longipalpis and Lutzomyia evansi phlebotomine sand flies. Dogs not only are the main host reservoirs of the parasite but also suffer the disease; therefore, canine VL (CVL) has assumed an important role in public health. In Colombia, human and CVL are restricted to two transmission foci: one in the north region (Caribbean coast) and other in the central south region (middle Magdalena River Valley). We present a CVL case involving a 2-year-old male dog with a history of lack of appetite, general weakness, and progressive loss of weight. A diagnosis of CVL was obtained using the direct parasitological examination in spleen and bone marrow samples stained with Giemsa and RT-qPCR. The infecting Leishmania species was identified as L. infantum by PCR-restriction fragment length polymorphism amplifying the Hsp70 gene from bone marrow and spleen samples and confirming by sequencing. The patient responded favorably to treatment with intramuscular meglumine antimoniate at a dose of 100 mg/kg daily for 8 weeks and oral allopurinol at a dose of 10 mg/kg every 12 hours until new indication. This is the first report of urban CVL in the city of Cali, Colombia, highlighting the need for surveillance and control programs in the municipalities of the department of Valle del Cauca, a region where VL has not been informed before. The findings also indicate the need to reinforce the surveillance programs in other rural and urban regions of the country where favorable eco-epidemiological conditions exist.

Adenine phosphoribosyl transferase (APRT) deficiency is a rare genetic form of kidney stones and/or kidney failure characterized by intratubular precipitation of 2,8 dihydroxyadenine crystals. Early diagnosis and prompt management can completely reverse the kidney injury.
44 year old Indian male, renal transplant recipient got admitted with acute graft dysfunction. Graft biopsy showed light brown refractile intratubular crystals with surrounding giant cell reaction, consistent with APRT deficiency. Patient improved after receiving allopurinol and hydration.
APRT forms a reversible cause of crystalline nephropathy. High index of suspicion is required for the correct diagnosis as timely diagnosis has therapeutic implications.

Adenine phosphoribosyltransferase (APRT) deficiency (OMIM #614723) is a rare autosomal recessive defect in the purine salvage pathway that causes excessive production of 2,8-dihydroxyadenine, leading to nephrolithiasis and chronic kidney disease (CKD). This case report describes the natural history of CKD in untreated APRT deficiency. We describe a novel APRT mutation (chr16:88877985 G / C; c.195 C>/G; p.His54Asp) presenting with CKD without nephrolithiasis. The patient initially required dialysis, but kidney function improved with allopurinol. We reviewed APRT deficiency reported in the literature to determine the loss of kidney function in individuals with untreated APRT deficiency and its relationship to nephrolithiasis. We identified 95 individuals in whom kidney function was assessed prior to treatment. There was a bimodal distribution of kidney failure. AKI occurred frequently in childhood due to obstructing nephrolithiasis or crystalline nephropathy and was usually reversible. CKD developed after age 20 in all patients irrespective of nephrolithiasis history, with 36/42 patients > 40 years of age having at least stage 3 CKD, and 24/42 having an eGFR > 10 mL/min/1.73m2 or being on dialysis. There were 13 adults without nephrolithiasis and 50 adults with nephrolithiasis. The mean age of end-stage renal diesease (ESRD) was 50.52 ± 13.9 for those without nephrolithiasis and 43.4 ± 15.8 years for those with nephrolithiasis (p = 0.24). APRT deficiency is associated with slowly progressive CKD that occurs independently of nephrolithiasis. Diagnosis should be considered in all individuals with chronic tubulointerstitial kidney disease, with or without the presence of nephrolithiasis. In our patient, allopurinol 300 mg/day resulted in improvement of kidney function.
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