Retroperitoneal Liposarcoma With Leiomyosarcomatous Differentiation

We herein describe a 60-year-old Japanese man with a giant retroperitoneal liposarcoma undergoing leiomyosarcomatous differentiation. He was admitted to our hospital because of a 5-month history of dysphagia and abdominal distention. Abdominal computed tomography showed a giant tumor that occupied the entire retroperitoneal space. The majority of the mass was lipomatous and low density; both a heterogenous and solid mass were also present. A giant retroperitoneal liposarcoma was diagnosed, and tumor resection was performed. At surgery, the tumor was mostly isolated from the retroperitoneum and other organs. Histopathologically, the tumor comprised well-differentiated and dedifferentiated liposarcoma with heterologous differentiation of the leiomyosarcomatous components, which is a rare phenomenon in liposarcoma. The patient was alive 3 years after the first treatment, although he has had 3 local recurrences (approximately one recurrence yearly) and has been treated by repeated resection and radiotherapy.Key words: Retroperitoneum, Liposarcoma, Leiomyosarcomatous differentiationDedifferentiated liposarcoma (DL) is one of the most frequent sarcomas of the retroperitoneum. It is defined by the association of an atypical lipomatous tumor, namely, areas of well-differentiated liposarcoma (WDL), with a dedifferentiated component. WDL is composed of mature adipocytes and atypical stromal cells with an enlarged, hyperchromatic nucleus. Usually, the dedifferentiated part of the liposarcoma is composed of either a spindle/pleomorphic high-grade sarcoma or a mixoid/spindle cell low-grade sarcoma. The WDL component may be easily overlooked, and DL may thus be mistaken for another high-grade sarcoma. It has been reported in one study that approximately 5% of the dedifferentiated component showed heterologous differentiation, such as leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, and angiosarcoma.¹ A less common phenomenon is the occurrence of WDL with leiomyosarcomatous (LMS) differentiation.² Limited to the retroperitoneum, only 8 cases of liposarcoma with LMS components have been reported.^3–7 We herein report a case of retroperitoneal liposarcoma comprising WDL and DL, with LMS components, treated by surgical resection.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent ¹⁹²Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.     

Hyperthermia generated with ferucarbotran (Resovist®) in an alternating magnetic field enhances cisplatin-induced apoptosis of cultured human oral cancer cells

Hyperthermia is a promising anti-cancer treatment in which the tissue temperature is increased to 42–45 °C, and which is often used in combination with chemotherapy or radiation therapy. Our aim in the present work was to examine the feasibility of combination therapy for oral cancer with cisplatin and hyperthermia generated with ferucarbotran (Resovist^®; superparamagnetic iron oxide) in an alternating magnetic field (AMF). First, we established that administration of ferucarbotran at the approved dosage for magnetic resonance imaging provides an iron concentration sufficient to increase the temperature to 42.5 °C upon exposure to AMF. Then, we examined the effect of cisplatin combined with ferucarbotran/AMF-induced hyperthermia on cultured human oral cancer cells (HSC-3 and OSC-19). Cisplatin alone induced apoptosis of cancer cells in a dose-dependent manner, as is well known. However, the combination of cisplatin with ferucarbotran/AMF was significantly more effective than cisplatin alone. This result suggests that it might be possible to reduce the clinically effective dosage of cisplatin by administering it in combination with ferucarbotran/AMF-induced hyperthermia, thereby potentially reducing the incidence of serious cisplatin-related side effects. Further work seems justified to evaluate simultaneous thermo-chemotherapy as a new approach to anticancer therapy.     

Direct use of 1,3-dienes for the allylation of ketones via catalytic hydroindation

In this study, in situ catalytically generated allylic indium from 1,3 dienes and InCl₂H was developed for use in the allylation of ketones. This protocol resulted in the unprecedented establishment of a successive combining of quaternary C–C bonds, which could then be applied to many types of ketones. Other branched 1,3 dienes and vinyl cyclopropanes, could also be coupled with ketones in a reaction where CuH would not be applicable.

In this study, in situ catalytically generated allylic indium from 1,3 dienes and InCl₂H was developed for use in the allylation of ketones.

Homoallylic alcohols are useful building blocks in the synthesis of bioactive natural compounds and pharmaceuticals. For these syntheses, the preparation of tertiary compounds has remained challenging regardless of whether or not they are given asymmetrically.¹ The allylation of ketones with allylic reagents is a typical method for the preparation of these compounds (Scheme 1a).² This method, however, cannot avoid wasteful steps such as the transmetalation between Grignard reagents and B, Si or Sn sources and the reductive generation between allylic halides and low-valent metals. Although this method can be applied to highly stereocontrolled reactions, the wasteful steps are cumbersome and more practical reaction methods are required.Open in a separate windowScheme 1Synthesis of homoallylic alcohols from allylation reagents with ketones.For this process, 1,3-dienes are an important industrial feedstock that is produced on a massive scale via either the cracking of ethylenes or the transformation of biomass. Easily available dienes have recently replaced the conventional allylation of aldehydes with the aid of transition metal catalysts (Scheme 1b).³ After the first application using a Ti catalyst by Gendre and Moïse,⁴ Krische has expanded the field with the introduction of Ru-catalyzed stereocontrolled reactions.⁵ Other transition metals such as Ni,⁶ Ir,⁷ and Rh⁸ have contributed to improvements in coupling. A recent adoption of ketones as viable substrates was achieved by Liu and Buchwald via proficient Cu–H chemistry.⁹ The scope of possible substrates could be expanded even further,¹⁰ however, particularly with the use of 1,3-dienes and ketones that possess a variety of functional groups.Our group has explored the hydrostannylation¹¹ or indation¹² of unsaturated bonds in the preparation of reactive organostannanes or indiums that could be applied to further transformations, although stoichiometric amounts of Sn or In sources must be added to the reaction systems. Recently, a transition metal-free reductive coupling of 1,3-dienes,¹³ or their derivatives such as vinyl cyclopropanes,¹⁴ with aldehydes catalyzed by Bu₂SnXH has been developed, but the method would not allow the use of ketones due to the low reactivity of the reaction intermediate, allylic stannanes (Scheme 1c). On the other hand, our group has already developed a process for the hydroindation of 1,3-dienes with a stoichiometric amount of InX₂H to give allylic indiums followed by the allylation of ketones.^12b,12d Herein, we report the catalytic coupling of 1,3-dienes or vinyl cyclopropanes with ketones through the generation of allylic indiums via the hydroindation of 1,3-dienes with a catalytic amount of InX₂H (Scheme 1c).We initiated the optimization of the reaction conditions by combining 1,3-butadiene (1a) and acetophenone (2a) in a sealed test tube (13 The desired product 3aa was obtained in a 92% yield as a mixture of the diastereomers (entry 1). The yield was lowered either when no MeOH was used or when the reaction time was cut by half (entries 2 and 3). A screening of the silanes showed that MePhSiH₂ was the optimal hydride source (entries 4–7). We found that the reaction was finished in 3 h when the reaction temperature was raised to 60 °C (entry 8). Replacing the solvent with MeCN, Et₂O or toluene did not improve the reaction yield (entries 9–11). It was necessary to add NaOMe to the reaction system for a facile generation of InCl₂H (entry 12).¹⁶ It was important to add InCl₃ to the reaction (entry 13). A radical scavenger, TEMPO, suppressed the progress of the reaction, which implied that this reaction contains a radical process (entry 14). The reaction yield was decreased when the lower amount of the catalyst was employed (entry 15).Optimization of the reaction conditions^a

Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos)

Although the diagnostic and severity grading criteria on the 2013 Tokyo Guidelines (TG13) are used worldwide as the primary standard for management of acute cholangitis (AC), they need to be validated through implementation and assessment in actual clinical practice. Here, we conduct a systematic review of the literature to validate the TG13 diagnostic and severity grading criteria for AC and propose TG18 criteria. While there is little evidence evaluating the TG13 criteria, they were validated through a large‐scale case series study in Japan and Taiwan. Analyzing big data from this study confirmed that the diagnostic rate of AC based on the TG13 diagnostic criteria was higher than that based on the TG07 criteria, and that 30‐day mortality in patients with a higher severity based on the TG13 severity grading criteria was significantly higher. Furthermore, a comparison of patients treated with early or urgent biliary drainage versus patients not treated this way showed no difference in 30‐day mortality among patients with Grade I or Grade III AC, but significantly lower 30‐day mortality in patients with Grade II AC who were treated with early or urgent biliary drainage. This suggests that the TG13 severity grading criteria can be used to identify Grade II patients whose prognoses may be improved through biliary drainage. The TG13 severity grading criteria may therefore be useful as an indicator for biliary drainage as well as a predictive factor when assessing the patient's prognosis. The TG13 diagnostic and severity grading criteria for AC can provide results quickly, are minimally invasive for the patients, and are inexpensive. We recommend that the TG13 criteria be adopted in the TG18 guidelines and used as standard practice in the clinical setting. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47 . Related clinical questions and references are also included.     

Diagnosis of IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis(IgG4-SC)is often associated with autoimmune pancreatitis.However,the diffuse cholangiographic abnormalities observed in IgG4-SC may resemble those observed in primary sclerosing cholangitis(PSC),and the presence of segmental stenosis suggests cholangiocarcinoma(CC).IgG4-SC responds well to steroid therapy,whereas PSC is only effectively treated with liver transplantation and CC requires surgical intervention.Since IgG4-SC was first described,it has become a third distinct clinical entity of sclerosing cholangitis.The aim of this review was to introduce the diagnostic methods for IgG4-SC.IgG4-SC should be carefully diagnosed based on a combination of characteristic clinical,serological,morphological,and histopathological features after cholangiographic classification and targeting of a disease for differential diagnosis.When intrapancreatic stenosis is detected,pancreatic cancer or CC should be ruled out.If multiple intrahepatic stenoses are evident,PSC should be distinguished on the basis of cholangiographic findings and liver biopsy with IgG4 immunostaining.Associated inflammatory bowel disease is suggestive of PSC.If stenosis is demonstrated in the hepatic hilar region,CC should be discriminated by ultrasonography,intraductal ultrasonography,bile duct biopsy,and a higher cutoff serum IgG4 level of 182 mg/dL.     

Classification and Diagnostic Criteria for IgG4-Related Sclerosing Cholangitis

IgG4-related sclerosing cholangitis (IgG4-SC) can be classified into four types based on cholangiographic findings and regions of biliary stricture. This cholangiographic classification is useful to differentiate IgG4-SC from mimickers including cholangiocarcinoma, primary sclerosing cholangitis, and pancreatic cancer. Autoimmune pancreatitis (AIP) is a valuable clue for the diagnosis of IgG4-SC because the two are frequently found in association with each other. Two sets of diagnostic criteria for IgG4-SC have been proposed. In Japan, the clinical diagnostic criteria 2020 were recently developed. These clinical diagnostic criteria include narrowing of the intrahepatic and/or extrahepatic bile duct, thickening of the bile duct wall, serological findings, pathological findings, other organ involvement, and effectiveness of steroid therapy. When these criteria are applied, IgG4-SC is initially classified as associated or not associated with AIP, and cholangiographic classification is used for differential diagnosis. In most instances, IgG4-SC can be diagnosed on the basis of clinical diagnostic criteria. However, it is challenging to diagnose isolated IgG4-SC or IgG4-SC not associated with AIP. Here, we review the classification and diagnostic criteria for IgG4-SC, specifically focusing on the clinical diagnostic criteria 2020 and a large IgG4-SC case series from a nationwide survey in Japan.