Case of probable spontaneous regression of Merkel cell carcinoma combined with squamous cell carcinoma without surgical intervention

Merkel cell carcinoma (MCC) is a rare but more lethal cutaneous cancer than melanoma. However, spontaneous regression of a number of MCC has been reported, although the cause of this regression remains unclear. In most cases, MCC regresses after a surgical procedure, for example, biopsy. Herein, we report a case of Merkel cell polyomavirus‐negative MCC coincident with squamous cell carcinoma (SCC) that underwent true spontaneous regression without biopsy. One month after the patient's first visit, clinical examination revealed that the tumor had not grown, but its surface showed changes in texture and color. Histopathologically, the excised specimen was indicative of MCC coincident with SCC and showed extensive necrosis in the upper portion of the tumor, numerous caspase‐3‐positive apoptotic cells, an accumulation of CD68‐positive foam cells and vascular invasion. These findings suggested that the tumor had regressed. We hypothesize that extensive coagulative necrosis resulting from an insufficient local blood supply triggered the shedding of some products or components of MCC and SCC, which in turn induced antitumor immunity against both lesions.     

Merkel cell carcinoma associated with stable chronic hemodialysis: A report of two cases

Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous malignancy associated with the Merkel cell polyomavirus (MCPyV). Multiple studies have shown that the incidence of MCC is higher among immunocompromised individuals than among the general population. In fact, immunosuppressed individuals account for approximately 10% of the MCC patient population. In this report, we describe two cases of MCPyV‐related MCC in Japanese patients on hemodialysis. In both the cases, MCC was present on the face. Both cellular and humoral immunities have been shown to be decreased in uremic patients, and dialysis patients have a high risk of viral‐mediated cancers, including human papillomavirus‐associated cancers. Immune dysfunction related to uremia and dialysis may be associated with a high risk of developing MCC.     

Achieving simplified disease activity index remission in patients with active rheumatoid arthritis is associated with subsequent good functional and structural outcomes in a real-world clinical setting under a treat-to-target strategy

Objective: To verify predictive validity of simplified disease activity index (SDAI) remission for subsequent functional and structural outcomes in real-world clinical settings under a treat-to-target strategy (T2T).

Methods: In this multicenter, prospective cohort study, T2T was implemented in rheumatoid arthritis (RA) patients with moderate-to-high disease activity. SDAI or clinical disease activity index (CDAI) was assessed every 12 weeks, and treatment was adjusted to achieve clinical remission or low disease activity (LDA). Multivariate logistic regression models were used to examine the associations of SDAI remission (≤3.3) at week 24 with the health assessment questionnaire-disability index (HAQ-DI)?≤?0.5 or with the delta van der Heijde-modified total Sharp score (ΔvdH-mTSS)?Results: Of 318 patients enrolled, 271 completed the follow-up for 72 weeks and were subjects of the analyses. Factors [odds ratio (95% confidence interval)] significantly associated with the HAQ-DI ≤0.5 were SDAI remission at week 24 [2.99 (1.42–6.28), p?=?0.004], baseline HAQ-DI [0.28 (0.18–0.45), p?=?1.3?×?10^?7], and baseline vdH-mTSS [0.986 (0.976–0.996), p?=?0.009]. A factor associated with ΔvdH-mTSS?p?=?0.002].

Conclusion: Predictive validity of SDAI remission for good outcomes was verified in a T2T-implementing cohort in the current clinical settings.     

Comparison of endoscopic gastritis based on Kyoto classification between diffuse and intestinal gastric cancer

BACKGROUND Gastric cancers can be categorized into diffuse-and intestinal-type cancers based on the Lauren histopathological classification. These two subtypes show distinct differences in metastasis frequency, treatment application, and prognosis. Therefore, accurately assessing the Lauren classification before treatment is crucial. However, studies on the gastritis endoscopy-based Kyoto classification have recently shown that endoscopic diagnosis has improved.AIM To investigate patient characteristics including endoscopic gastritis associated with diffuse-and intestinal-type gastric cancers in Helicobacter pylori(H. pylori)-infected patients.METHODS Patients who underwent esophagogastroduodenoscopy at the Toyoshima Endoscopy Clinic were enrolled. The Kyoto classification included atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. The effects of age, sex, and Kyoto classification score on gastric cancer according to the Lauren classification were analyzed. We developed the Lauren predictive background score based on the coefficients of a logistic regression model using variables independently associated with the Lauren classification. Area under the receiver operative characteristic curve and diagnostic accuracy of this score were examined.RESULTS A total of 499 H. pylori-infected patients(49.6% males; average age: 54.9 years) were enrolled; 132 patients with gastric cancer(39 diffuse-and 93 intestinal-type cancers) and 367 cancer-free controls were eligible. Gastric cancer was independently associated with age ≥ 65 years, high atrophy score, high intestinal metaplasia score, and low nodularity score when compared to the control. Factors independently associated with intestinal-type cancer were age ≥ 65 years(coefficient: 1.98), male sex(coefficient: 1.02), high intestinal metaplasia score(coefficient: 0.68), and low enlarged folds score(coefficient:-1.31) when compared to diffuse-type cancer. The Lauren predictive background score was defined as the sum of +2(age ≥ 65 years), +1(male sex), +1(endoscopic intestinal metaplasia), and-1(endoscopic enlarged folds) points. Area under the receiver operative characteristic curve of the Lauren predictive background score was 0.828 for predicting intestinal-type cancer. With a cut-off value of +2, the sensitivity, specificity, and accuracy of the Lauren predictive background score were 81.7%, 71.8%, and 78.8%, respectively.CONCLUSION Patient backgrounds, such as age, sex, endoscopic intestinal metaplasia, and endoscopic enlarged folds are useful for predicting the Lauren type of gastric cancer.     

Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine‐refractory differentiated thyroid cancer

Lenvatinib significantly prolonged progression‐free survival (PFS) versus placebo in patients with radioiodine‐refractory differentiated thyroid cancer (RR‐DTC) in the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. This subanalysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT. Outcomes for Japanese patients (lenvatinib, n = 30; placebo, n = 10) were assessed in relationship to the SELECT population (lenvatinib, n = 261; placebo, n = 131). The primary endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Lenvatinib PFS benefit was shown in Japanese patients (median PFS: lenvatinib, 16.5 months; placebo, 3.7 months), although significance was not reached, presumably due to sample size (hazard ratio, 0.39; 95% confidence interval, 0.10–1.57; P = 0.067). Overall response rates were 63.3% and 0% for lenvatinib and placebo, respectively. No significant difference was found in overall survival. The lenvatinib safety profile was similar between the Japanese and overall SELECT population, except for higher incidences of hypertension (any grade: Japanese, 87%; overall, 68%; grade ≥3: Japanese, 80%; overall, 42%), palmar–plantar erythrodysesthesia syndrome (any grade: Japanese, 70%; overall, 32%; grade ≥3: Japanese, 3%; overall, 3%), and proteinuria (any grade: Japanese, 63%; overall, 31%; grade ≥3: Japanese, 20%; overall, 10%). Japanese patients had more dose reductions (Japanese, 90%; overall, 67.8%), but fewer discontinuations due to adverse events (Japanese, 3.3%; overall, 14.2%). There was no difference in lenvatinib exposure between the Japanese and overall SELECT populations after adjusting for body weight. In Japanese patients with radioiodine‐refractory differentiated thyroid cancer, lenvatinib showed similar clinical outcomes to the overall SELECT population. Some differences in adverse event frequencies and dose modifications were observed. Clinical trial registration no.: NCT01321554.     

Angiotensin II Dose-Dependently Stimulates Human Renal Proximal Tubule Transport by the Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate Pathway

Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT₁)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.Among the several regulatory systems for BP, the renin-angiotensin system (RAS) plays a key role. Angiotensin II (Ang II) can regulate BP by type 1 (AT₁) Ang II receptors in either the kidney or the extrarenal tissues. Using a kidney cross-transplantation strategy, Crowley et al.¹ revealed that AT_1A in the kidney is critical for the pathogenesis of Ang II-mediated hypertension and its cardiovascular complications. Crowley et al.¹ also showed that genetic abrogation AT_1A in renal proximal tubules (PTs) alone is sufficient to reduce BP and provide substantial protection against Ang II–induced hypertension in mice, suggesting that the stimulation of PT sodium transport by Ang II has a major impact on BP regulation.²Paradoxically, however, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by low (picomolar to nanomolar) concentrations of Ang II, whereas it is inhibited by high (nanomolar to micromolar) concentrations of Ang II.^3,4 Notably, the concentrations of Ang II within the kidney are known to be much higher than the concentrations in plasma, although the measurement of urinary Ang II may be less valuable.^5,6 Therefore, the inhibitory effect of high concentrations of Ang II could also have some physiologic relevance to the regulation of in vivo PT transport.⁵ Ang II regulates the major PT sodium transporters the apical Na⁺/H⁺ exchanger isoform 3 (NHE3), the basolateral Na⁺-HCO₃⁻ cotransporter (NBCe1), and the basolateral Na⁺/K⁺ ATPase in the biphasic manner.^7–12 Although controversial results had been reported of the receptor subtype(s) mediating the biphasic effects of Ang II,^13,14 the studies using isolated PTs obtained from AT_1A knockout (KO) mice have established that AT_1A mediates both the stimulatory and inhibitory effects of Ang II.^11,15 The stimulation by Ang II has been attributed to the activation of protein kinase C and/or the decrease in the intracellular cAMP concentration, resulting in the activation of extracellular signal-regulated kinase (ERK) pathway.^16–18 However, the inhibition by Ang II has been attributed to the activation of the phospholipase A₂/arachidonic acid/5,6-epoxyeicosatrienoic acid (EET) pathway and/or the nitric oxide (NO)/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway.^7,12,17,19 Although the biphasic regulation of PT transport by Ang II has been reported in several species, such as rats, mice, and rabbits,^3,4,15 whether Ang II has similar biphasic effects on human PT transport remains unknown. Moreover, the signaling mechanisms mediating the Ang II actions on human kidney have not been clarified at all.To clarify these issues, we examined the effects of Ang II on isolated human PTs obtained from nephrectomy surgery. Unexpectedly, our findings revealed that Ang II, unlike in the other species, dose-dependently stimulates human PT transport. The different modes of transport regulation by Ang II can be largely explained by the contrasting roles of the NO/cGMP pathway, which as a downstream mediator of Ang II signaling in PTs, is stimulatory in human subjects but inhibitory in the other species. The unopposed marked stimulation of PT transport by the high local concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Furthermore, the stimulatory effect of the NO/cGMP pathway on human PT transport may represent a previously unrecognized therapeutic target of hypertension.     

Recurrent,Spontaneous Esophageal Ruptures Associated With Antiphospholipid Antibody Syndrome: Report of a Case

A 52-year-old man was admitted to our hospital with a spontaneous esophageal rupture (Boerhaave syndrome) and was successfully treated. Eight years after the first incident, he was readmitted with a recurrent rupture. Recurrence of Boerhaave syndrome is extremely rare, with only 7 cases reported in the English literature. During treatment, the patient was also diagnosed with antiphospholipid syndrome (APS). Although APS is known to cause a variety of symptoms due to vascular thrombosis, recurrence of Boerhaave syndrome, coincident with APS, has never been reported. The pathogenesis of Boerhaave syndrome has not been clearly determined. This report serves to increase awareness of the risk of APS, which results in an increased risk of spontaneous rupture of the esophagus.Key words: Boerhaave syndrome, Esophageal rupture, Antiphospholipid syndromeSpontaneous rupture of the esophagus (Boerhaave syndrome) is a relatively rare entity among digestive tract emergencies.¹ Because Boerhaave syndrome has a high rate of mortality, few reports describe the late complications of the syndrome. Further, recurrence of the syndrome is extremely rare, with only 7 cases having been reported in the English literature.^2–7 In addition, the pathophysiologic mechanisms responsible for Boerhaave syndrome have not been clearly determined.Antiphospholipid syndrome (APS) is a type of autoimmune syndrome and is known to cause a variety of complications, which are primarily caused by vascular disorders. In the present report we describe a case of recurrent Boerhaave syndrome associated with APS, and we discuss the pathogenesis of spontaneous esophageal ruptures.