bluuebunny/crossref_metadata_2025 huggingface dataset:
What Can Be Done to Solve the Unmet Clinical Need of Hepatocellular Carcinoma Patients following Lenvatinib Failure?
Authors: Hiraoka Atsushi , Kumada Takashi , Tada Toshifumi , Kariyama Kazuya , Tani Joji , Fukunishi Shinya , Atsukawa Masanori , Hirooka Masashi , Tsuji Kunihiko , Ishikawa Toru , Takaguchi Koichi , Itobayashi Ei , Tajiri Kazuto , Shimada Noritomo , Shibata Hiroshi , Ochi Hironori , Kawata Kazuhito , Yasuda Satoshi , Toyoda Hidenori , Ohama Hideko , Nouso Kazuhiro , Tsutsui Akemi , Nagano Takuya , Itokawa Norio , Hayama Korenobu , Arai Taeang , Imai Michitaka , Koizumi Yohei , Nakamura Shinichiro , Joko Kouji , Michitaka Kojiro , Hiasa Yoichi , Kudo Masatoshi ,   RELPEC Study Group and HCC 48 Group
Published: March 2021

Background/Aim: An effective postprogression treatment of lenvatinib (LEN) against unresectable hepatocellular carcinoma (u-HCC) has not been established. We aimed to elucidate the clinical role of continuing LEN beyond progression of disease (PD). Methods: From March 2018 to October 2020, 99 u-HCC patients, in whom PD was confirmed (male:female = 78:21, median age 72 years, Child-Pugh A = 99, Barcelona Clinic Liver Cancer stage A:B:C = 2:43:54, LEN as first-line = 55), were enrolled (stopped LEN at PD [A group], n = 26; continued LEN beyond PD [B group], n = 73). Radiological response was evaluated with RECIST 1.1. Clinical features and prognostic factors for overall survival (OS) were retrospectively investigated using inverse probability weighting (IPW) calculated by propensity score. Results: Median time to progression, best response, and modified albumin-bilirubin grade (mALBI) at both baseline and PD did not show significant difference between the groups. Postprogression treatment in the A group was best supportive care in 17, sorafenib in 4, regorafenib in 3, ramucirumab in 1, and hepatic arterial infusion chemotherapy in 1. After adjusting with IPW, the B group showed better prognosis in regard to OS after PD and OS after introducing LEN than the A group (10.8/19.6 vs. 5.8/11.2 months, p < 0.001, respectively). In IPW-adjusted Cox hazard multivariate analysis, significant prognostic factors for OS after PD were mALBI 2b/3 at PD (HR 1.983, p = 0.021), decline of Eastern Cooperative Oncology Group performance status (ECOG PS) from baseline at PD (HR 3.180, p < 0.001), elevated alpha-fetoprotein (≥100 ng/mL) at introducing LEN (HR 2.511, p = 0.004), appearance of new extrahepatic metastasis (HR 2.396, p = 0.006), positive for hand-foot skin reaction (HFSR) before PD (any grade) (HR 0.292, p < 0.001), and continuing LEN beyond PD (HR 0.297, p < 0.001). Conclusion: When ECOG PS and hepatic reserve function permit, continuing LEN treatment beyond PD, especially in u-HCC patients showed HFSR during LEN treatment, might be a good therapeutic option, at least until a more effective drug as a postprogression treatment after LEN failure is developed.
Proteogenomic Insights into the Physiology of Marine, Sulfate-Reducing, Filamentous Desulfonema limicola and Desulfonema magnum
Authors: Schnaars Vanessa , Wöhlbrand Lars , Scheve Sabine , Hinrichs Christina , Reinhardt Richard , Rabus Ralf
Published: March 2021

The genus Desulfonema belongs to the deltaproteobacterial family Desulfobacteraceae and comprises marine, sulfate-reducing bacteria that form filaments and move by gliding. This study reports on the complete, manually annotated genomes of Dn. limicola 5ac10T (6.91 Mbp; 6,207 CDS) and Dn. magnum 4be13T (8.03 Mbp; 9,970 CDS), integrated with substrate-specific proteome profiles (8 vs. 11). The richness in mobile genetic elements is shared with other Desulfobacteraceae members, corroborating horizontal gene transfer as major driver in shaping the genomes of this family. The catabolic networks of Dn. limicola and Dn. magnum have the following general characteristics: 98 versus 145 genes assigned (having genomic shares of 1.7 vs. 2.2%), 92.5 versus 89.7% proteomic coverage, and scattered gene clusters for substrate degradation and energy metabolism. The Dn. magnum typifying capacity for aromatic compound degradation (e.g., p-cresol, 3-phenylpropionate) requires 48 genes organized in operon-like structures (87.7% proteomic coverage; no homologs in Dn. limicola). The protein complements for aliphatic compound degradation, central pathways, and energy metabolism are highly similar between both genomes and were identified to a large extent (69–96%). The differential protein profiles revealed a high degree of substrate-specificity for peripheral reaction sequences (forming central intermediates), agreeing with the high number of sensory/regulatory proteins predicted for both strains. By contrast, central pathways and modules of the energy metabolism were constitutively formed under the tested substrate conditions. In accord with their natural habitats that are subject to fluctuating changes of physicochemical parameters, both Desulfonema strains are well equipped to cope with various stress conditions. Next to superoxide dismutase and catalase also desulfoferredoxin and rubredoxin oxidoreductase are formed to counter exposure to molecular oxygen. A variety of proteases and chaperones were detected that function in maintaining cellular homeostasis upon heat or cold shock. Furthermore, glycine betaine/proline betaine transport systems can respond to hyperosmotic stress. Gliding movement probably relies on twitching motility via type-IV pili or adventurous motility. Taken together, this proteogenomic study demonstrates the adaptability of Dn. limicola and Dn. magnum to its dynamic habitats by means of flexible catabolism and extensive stress response capacities.
Time-Varying mHAP-III Is the Most Accurate Predictor of Survival in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization
Authors: Campani Claudia , Vitale Alessandro , Dragoni Gabriele , Arena Umberto , Laffi Giacomo , Cillo Umberto , Giannini Edoardo G. , Tovoli Francesco , Rapaccini Gian Ludovico , Di Marco Maria , Caturelli Eugenio , Zoli Marco , Sacco Rodolfo , Cabibbo Giuseppe , Mega Andrea , Guarino Maria , Gasbarrini Antonio , Svegliati-Baroni Gianluca , Foschi Francesco Giuseppe , Biasini Elisabetta , Masotto Alberto , Nardone Gerardo , Raimondo Giovanni , Azzaroli Francesco , Vidili Gianpaolo , Brunetto Maurizia Rossana , Farinati Fabio , Trevisani Franco , Marra Fabio ,   ITA.LI.CA Group
Published: March 2021

Introduction: The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods: An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. Results: The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10–1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. Conclusion: An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.
Diffuse Cystic Metastases in the Lung after Nivolumab Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report
Authors: Muto Satoshi , Ozaki Yuki , Inoue Takuya , Okabe Naoyuki , Matsumura Yuki , Hasegawa Takeo , Shio Yutaka , Suzuki Hiroyuki
Published: March 2021

Although diffuse cysts in the lung can be found in many diseases, they are uncommon in metastatic lung adenocarcinoma. They are even more unusual after the administration of immune checkpoint inhibitors. A case of lung adenocarcinoma that developed diffuse cysts in the lungs during treatment with nivolumab is reported. The patient was a 60-year-old woman with postoperative recurrent lung adenocarcinoma in mediastinal lymph nodes and pleural dissemination. After first-line treatment with cisplatin, pemetrexed, and bevacizumab, computed tomography (CT) showed disease progression. Treatment was then switched to nivolumab. After 5 courses of nivolumab, CT showed multiple ground-glass nodules in her lungs. After 4 more courses of nivolumab, the ground-glass nodules increased in size, and cystic air spaces appeared in their centers. The patient did not have any symptoms. Laboratory tests showed no evidence of infection or nivolumab-induced pneumonitis. Sialyl Lewis X-i antigen increased, and positron emission tomography showed abnormal uptake of 18F-fluorodeoxyglucose in these lesions. Considering this evidence, the cystic lesions were diagnosed as multiple lung metastases. Various differential diagnoses should be considered when diffuse cystic lesions are found in the lungs after the administration of immune checkpoint inhibitors.
The Alkaline Phosphatase Flare Phenomenon: A Transient Substantial Increase in Alkaline Phosphatase Concentration in a Prostate Cancer Patient after Starting GnRH Agonist Treatment
Authors: Merlo Pierina , Rochlitz Christoph , Osthoff Michael
Published: March 2021

A 78-year-old man with metastatic prostate cancer was referred to the hospital 5 weeks after the initiation of systemic therapy with goserelin (GnRH agonist) because of a significant increase in alkaline phosphatase (ALP) concentration despite clinical improvement. Further workup revealed a decrease in prostate-specific antigen levels and a lack of radiological signs of disease progression. Subsequently, the ALP dropped spontaneously. This case report is an example for an early ALP flare after initiation of endocrine therapy in patients with bone metastasis which is consistent with a treatment response. Clinicians should be familiar with the ALP flare phenomenon in this setting, which does not reflect disease progression or treatment failure, in order to prevent unnecessary investigations, hospital admissions, or even erroneous termination of successful therapy.
Vertebral Metastasis Treated by Vertebroplasty, a Cause of Respiratory Failure: Case Report and Literature Review
Authors: Chevallier Mathieu , Chevallier-Lugon Chloé , Friedlaender Alex , Addeo Alfredo
Published: March 2021

Bone is a frequent site of metastases in advanced cancers including lung, breast, prostate, kidney, or myeloma. Lesions are commonly located on the spine. Neoplastic invasion of the vertebral body can result in painful vertebral fractures, leading to disability and substantial morbidity. Percutaneous vertebroplasty is a minimally invasive surgical procedure used to treat spinal fractures due to osteolytic tumors. It could result in pain reduction or resolution in 80–90% of patients with fractures, and it improves stability. Although considered safe, vertebroplasty has been associated over the years with life-threatening complications. We have reported the case of a 55-year-old patient with lung adenocarcinoma, who underwent vertebroplasty for a pathological neoplastic fracture of L2. The procedure was complicated by a leak of cement into the systemic venous circulation, characterized by an 11-cm filament in the right heart chambers and multiple pulmonary emboli. To our knowledge, only one similar case was previously reported, involving an intracardiac cement filament longer than 10 cm. The data are scant, hence the importance of collecting and reporting possible complications about what is perceived as a rather safe procedure. The case highlights the need for a robust postprocedure imaging plan to detect complications, which can impact patients’ morbidity and survival.
Intrafamilial Phenotypic Variability Associated with the I1739V Mutation in the SCN9A Gene
Authors: Peddareddygari Leema Reddy , Grewal Raji P.
Published: March 2021

The SCN9A gene encodes a voltage gated sodium channel Nav1.7 in which mutations can result in a wide variety of phenotypes ranging from congenital insensitivity to pain to small fiber neuropathy. We report the genotype phenotype analysis in a family carrying a specific mutation, I1739V, in the SCN9A gene. Neurophysiological studies have documented the gain of function impact of this mutation on this sodium channel. Interestingly, there is significant interfamilial phenotypic variability in individuals carrying this mutation. In our family, a father daughter combination had identical genotypes analyzing the SCN9A gene and multiple other genes known to cause neuropathy. Both of them carry the I1739V mutation but exhibit significant phenotypic variability with complaints of decreased sensitivity to discomfort in the father while the daughter has the clinical and laboratory features consistent with a small fiber neuropathy. We hypothesize that there are modifiers of the I1739V mutation that could involve intronic or exonic gene variants which contribute to this intrafamilial phenotypic variability. Our study has implications for genetic counseling, personalized medicine and the development of drugs to treat neuropathic pain.
Successful Treatment with Lorlatinib after the Development of Alectinib-Induced Liver Damage in ALK-Positive Non-Small-Cell Lung Cancer: A Case Report
Authors: Makimoto Go , Kawakado Keita , Nakanishi Masamoto , Tamura Tomoki , Kuyama Shoichi
Published: March 2021

Alectinib is a key drug for treating anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Alectinib-induced hepatotoxicity is less common than that through other ALK inhibitors, such as crizotinib or ceritinib. Herein, we describe a case of ALK-positive adenocarcinoma successfully treated with lorlatinib after developing alectinib-induced hepatotoxicity. A 57-year-old Japanese man received alectinib as first-line therapy for ALK-positive NSCLC. After 79 days, alectinib was discontinued because of hepatotoxicity and later restarted at 150 mg/day, inducing hepatotoxicity again after 64 days. Switching to lorlatinib treatment (continued for >4 months) caused no severe adverse effects. Hence, lorlatinib may be useful for patients experiencing alectinib-induced hepatotoxicity.
A Case of Renal Pelvic Cancer with a Complete Duplication of the Renal Pelvis and Ureter
Authors: Nirei Takuma , Tabei Tadashi , Ito Hiroki , Kobayashi Kazuki
Published: March 2021

This paper describes a case of renal pelvic cancer with a complete duplication of the renal pelvis and ureter, which is substantially rare. A 76-year-old man was referred to the hospital because of gross hematuria for 2 years. A tumor was detected in the upper right kidney using enhanced computed tomography and magnetic resonance imaging scan, and the downstream ureter was suspected to open into the prostate. Retrograde ureteroscopy via the ectopic ureter orifice showed a hemorrhagic papillary tumor consistent with imaging findings. Laparoscopic radical nephroureterectomy was performed and the prostate was preserved because the tumor was only in the renal pelvis. Histopathological examination showed the tumor as a high-grade urothelial carcinoma. There was no sign of recurrence at one and a half years after operation. Ureteroscopy was effective in detecting an upper urinary tract tumor, even via ectopic ureter orifice, and preserving the prostate was possible.
The Emerging Role of Quantification of Imaging for Assessing the Severity and Disease Activity of Emphysema, Airway Disease, and Interstitial Lung Disease
Authors: Goldin Jonathan Gerald
Published: March 2021

There has been an explosion of use for quantitative image analysis in the setting of lung disease due to advances in acquisition protocols and postprocessing technology, including machine and deep learning. Despite the plethora of published papers, it is important to understand which approach has clinical validation and can be used in clinical practice. This paper provides an introduction to quantitative image analysis techniques being used in the investigation of lung disease and focusses on the techniques that have a reasonable clinical validation for being used in clinical trials and patient care.
Hyponatremia and Acute Kidney Injury as a Consequence of Malnutrition: A Case Report
Authors: Nielsen Astrid Just , Mose Frank Holden
Published: March 2021

This case presents how malnutrition due to underlying psychiatric disease can cause severe, chronic hyponatremia and acute kidney injury. A 31-year-old man was admitted due to fatigue. Blood tests displayed hyponatremia of 101 mmol/L and acute kidney injury. The patient had restricted himself to a uniform diet mainly consisting of rice boiled without salt. Isotone and hypertonic sodium chloride were used to secure a controlled rise in the sodium level. Despite fluid therapy, a delayed response in improvement in renal function was seen. After discharge, the patient started a balanced diet and the sodium level was almost normalized. Renal function eventually recovered. Long-term malnutrition may affect the tubular function of the kidney. Severe hyponatremia, other electrolyte disturbances, and protein and vitamin deficiency can be factors that interact in this pathogenesis. Resuming a normal diet may allow the kidney’s function to return to normal despite malnutrition during months.
Periprocedural Peritonitis Prophylaxis: A Summary of the Microbiology and the Role of Systemic Antimicrobials
Authors: Hsueh Leon , Hu Susie L. , Shah Ankur D.
Published: March 2021

Background: Peritonitis is a leading complication of peritoneal dialysis (PD). One strategy that the International Society for Peritoneal Dialysis (ISPD) has used to help mitigate the morbidity and mortality associated with peritonitis is through prevention, including antibiotic prophylaxis utilization in high-risk situations. The aim of this study is to summarize our current understanding of postprocedural peritonitis and discuss the existing data behind periprocedural antibiotic prophylaxis, focusing primarily on PD catheter insertion, dental procedures, colonoscopies, upper endoscopies with gastrostomy, and gynecologic procedures. Summary: The ISPD currently recommends intravenous antibiotics prior to PD catheter insertion, colonoscopies, and invasive gynecologic procedures, though prophylaxis has only demonstrated benefit in a prospective, randomized control setting for PD catheter insertion. However, multiple retrospective studies exist that support the use of antibiotic prophylaxis for the other 2 procedures. No specific antibiotic regimen has been established as most optimal to prevent peritonitis for any of the 3 procedures. Antibiotic coverage should include the Enterobacteriaceae family, as well as Gram-positive organisms commonly found on the skin flora for PD catheter insertion, anaerobes for colonoscopies, and common organisms from the urogenital flora in gynecologic procedures. Additionally, the ISPD currently recommends oral amoxicillin prior to dental procedures. There is currently no ISPD recommendation to provide antibiotic prophylaxis prior to an upper endoscopy with or without gastrostomy, though this is a potential area for research. Key Messages: PD patients are at high risk for developing peritonitis after typical procedures. Antibiotic prophylaxis is a potential strategy that the ISPD utilizes to prevent these infections. However, further research needs to be done to determine the optimal antibiotic regimen.
Rare Etiology of Odynophagia in a Female Adolescent
Authors: Koutsoumourakis Anastasios , Gagalis Asterios , Fotoulaki Maria , Stafylidou Maria
Published: March 2021

Herpes esophagitis (HE) is a rare condition in immunocompetent adolescents. However, it commonly occurs as a primary infection in younger individuals. Herein, we report a 16-year-old female patient who had a history of fever for 5 days, odynophagia, and orolabial herpes infection for 7 days. Clusters of painful vesicles on an erythematous base on the lips, gingiva, and palate were observed on physical examination. Further, esophagogastroduodenoscopy revealed diffuse linear ulcerations in the distal esophagus. The patient then received the following treatment: intravenous (I.V.) acyclovir 5 mg/kg three times a day, I.V. omeprazole 40 mg two times a day, and acyclovir 5% cream four times a day. After 8 days of admission, the patient was discharged. A follow-up esophagogastroduodenoscopy was performed 7 weeks after discharge, and the results revealed that the esophageal mucosa had a normal appearance. The effect of antiviral treatment against HE remains unknown in these patients. Nevertheless, it is believed to accelerate the healing process in individuals with esophageal mucosal barrier damage. To the best of our knowledge, this case of a female adolescent with an intact immune system is the sixth case of herpes simplex esophagitis to be reported in the literature.
A Gastric Intramucosal Mixed Adenocarcinoma-Neuroendocrine Tumor
Authors: Sano Yoshifumi , Saito Shoichi , Kawachi Hiroshi , Tsutsumi Jun , Fujisaki Junko
Published: March 2021

Gastric mixed adenocarcinoma-neuroendocrine tumor (NET) is a rare composite tumor, and a limited number of studies have reported on it. A 77-year-old man was admitted to our hospital because of acute cholecystitis. He underwent a cholecystectomy. Esophagogastroduodenoscopy during his admission revealed a slightly elevated tumor, and biopsy demonstrated a well-differentiated tubular adenocarcinoma. The tumor was resected completely by endoscopic submucosal dissection. Histological findings showed that it measured 9 mm in diameter, was located within the mucosa, and consisted of well-differentiated tubular adenocarcinoma and a NET G1. The NET was covered with adenocarcinoma and both components exhibited histological continuity. The NET and a part of the adenocarcinoma component showed a positive reaction for chromogranin A and synaptophysin. Neither enterochromaffin-like cell hyperplasia nor endocrine cell micronest surrounded the tumor. The diagnosis was gastric mixed adenocarcinoma-NET. The histological continuity between the two components can be likened to the same histogenesis.
Evaluation of Astigmatism-Correcting Efficiency and Rotational Stability after Cataract Surgery with a Double-Loop Haptic Toric Intraocular Lens: A 1-Year Follow-Up
Authors: Nováček Ladislav Viktor , Němcová Marie , Tyx Kateřina , Lahodová Kristýna , Rejmont Leoš , Rozsíval Pavel , Studený Pavel
Published: March 2021

Objectives: The aim of this study was to assess the clinical outcomes, predictability of results, efficiency of astigmatism correction, and rotational stability of the Bi-Flex 677TAY (Medicontur Medical Engineering Ltd., Zsámbék, Hungary) monofocal toric intraocular lens (IOL) designed for cataract patients with astigmatism. Methods: The IOLs were implanted either mono- or binocularly, following routine cataract surgery. Visual and refractive outcomes, as well as off-axis rotation were assessed throughout a 1-year follow-up period. All clinical data for this work were collected retrospectively. Vector analysis based on the Alpins method was performed to assess the efficiency of astigmatism correction. Results: No complications or adverse events occurred during surgery or the follow-up period. IOL implantation brought 88% of eyes into the ±0.50 D, and 100% into the ± 1.00 D range compared to the target spherical equivalent refraction, emmetropia. Astigmatism correction brought similar results: 94% of eyes had a residual cylindrical error of not higher than ±0.50 D, and 97% were within ±1.00 D. Vector analysis resulted in a correction index of 0.96 and a difference vector of 0.17. Both refractive and visual outcomes showed long-term stability. During the 12-month follow-up period, no eyes had a rotation of >5°. Absolute rotation after 1 year was 1.42 ± 1.89° (median = 0°), while signed rotation was 1.06 ± 2.12° (median = 0°). Conclusion: The Bi-Flex 677TAY monofocal toric IOL, designed by Medicontur Medical Engineering Ltd., represents an efficient and safe solution for cataract patients with astigmatism. Clinical and refractive outcomes are predictable, and rotational stability ensures long-term visual comfort.
Hydronephrosis Caused by Metastatic Breast Cancer
Authors: Sugimoto Hitoshi , Oda Goshi , Yokoyama Minato , Hayashi Kumiko , Yoshino Maho , Ogawa Ayumi , Hosoya Tokuko , Nakagawa Tsuyoshi , Uetake Hiroyuki
Published: March 2021

Breast cancer metastasizes mainly to organs such as bone, lung, and liver, whereas metastases to the peritoneum and urinary tract are rare. Metastasis to the peritoneum or urinary tract may result in renal dysfunction, infection, and painful hydronephrosis. In our hospital, 1,409 breast cancer surgeries were performed between January 2004 and December 2015, and 7 cases of hydronephrosis associated with recurrence were observed. The median age of patients was 69 years (57–79 years). The median time from surgery to diagnosis of hydronephrosis was 47 months (20–70 months). Histology was invasive ductal carcinoma (IDC) in 6 cases and invasive lobular carcinoma (ILC) in 1 case. There were 6 bilateral cases and 1 unilateral case of hydronephrosis. The causes were retroperitoneal metastasis in 5 cases and lymph node metastasis in 2 cases. The hydronephrosis was untreated in 2 cases, and treated with a ureteral stent in 2 cases, nephrostomy in 1 case, and nephrostomy due to ureteral stent failure in 2 cases. The median survival from the onset of hydronephrosis was 12 months (3–57 months). Although the probability of hydronephrosis in breast cancer recurrence was not high, care must be taken to avoid renal dysfunction, infection, or pain, which may require treatment.
Combination of Crizotinib and Osimertinib in T790M+ EGFR-Mutant Non-Small Cell Lung Cancer with Emerging MET Amplification Post-Osimertinib Progression in a 10-Year Survivor: A Case Report
Authors: Blasi Miriam , Kazdal Daniel , Thomas Michael , Christopoulos Petros , Kriegsmann Mark , Brandt Regine , Volckmar Anna-Lena , Kirchner Martina , Heußel Claus Peter , Stenzinger Albrecht , Kuon Jonas
Published: March 2021

Tyrosine kinase inhibitors (TKIs) represent the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The duration of the response is, however, limited in time owing to the development of resistance mechanisms to both first- and second-generation agents such as MET oncogene amplification. This report describes the successful results obtained with the combination of the third-generation TKI osimertinib with the multitargeted TKI and MET inhibitor crizotinib in a patient with EGFR-mutant NSCLC with emerging MET amplification with a tolerable toxicity profile.
Refractory Bullous Pemphigoid in a Patient with Metastatic Lung Adenocarcinoma Treated with Pembrolizumab
Authors: Cardona Andrés F. , Ruiz-Patiño Alejandro , Zatarain-Barron Zyanya Lucia , Ariza Santiago , Ricaurte Luisa , Rolfo Christian , Arrieta Oscar
Published: March 2021

We present the case of a 73-year-old male patient with a history of tobacco use who presented with a central nervous system mass that was confirmed to be a lung adenocarcinoma metastasis. High PD-L1 expression as well as negativity to other targetable drivers led to initiation of pembrolizumab monotherapy and ablative stereotactic radiation therapy on oligo­residual disease, achieving a complete response after 2 years of therapy. Following discontinuation of systemic treatment, the patient developed widespread desquamative plaques. A skin biopsy revealed subepidermal blistering and eosinophilic infiltration in conjunction with C3 and IgG depositions on the basement membrane, detected by immunofluorescence. A diagnosis of bullous pemphigoid was obtained, and systemic corticosteroids were administered with lesion progression. Infliximab was also administered without meaningful clinical improvement. Metronomic cyclophosphamide achieved a complete resolution of skin lesions and up to this day the patient continues with tumor control and is free of dermatological findings. In conclusion, bullous pemphigoid is a very rare dermatological adverse effect related with pembrolizumab treatment. Only two cases, including this one, have been reported, especially with this medication for the treatment of non-small cell lung cancer. With more reported cases, management strategies can be optimized even in the steroid refractory setting.
Unusual Synchronous Association of Solid Tumors with Hematological Malignancies in Multiple Primary Cancers: Case Series and Literature Review
Authors: Al-Gahmi Aboelkhair , Alhuthali Mohammed , Alrehaili Mohammad , Baltow Badee , Tashkandi Emad
Published: March 2021

The incidence of synchronous multiple primary malignancies (MPMs), which include both solid and hematological malignancy, is considered very rare. In addition, the involvement of sites such as brain, thyroid, and breast are among the least reported in such complex conditions. Here we report five different types of solid tumors including glioblastoma multiforme, thyroid papillary carcinoma, breast invasive ductal carcinoma, colon cancer, and gastric adenocarcinoma that were associated with synchronous five different hematological malignancies in the form of T-cell lymphoblastic non-Hodgkin lymphoma (NHL), nodal marginal zone NHL, diffuse large B-cell NHL, Hodgkin lymphoma, and gastric mucosa-associated lymphoid tissue marginal zone NHL, respectively. The diagnosis of MPMs can be challenging, and there is no standard treatment for such difficult primary malignancies. However, the management of these conditions should be individualized using tumor board discussion and ensuring multidisciplinary coordinated care, besides considering treatment of the more aggressive malignancy before that with the less malignant potential.
A Substantial Response from Adding Palbociclib to Endocrine Therapy in Brain Metastasis from Hormone Receptor-Positive, HER2-Negative Breast Cancer: Case Reports
Authors: Abusanad Atlal , Al Hashem Hashem
Published: March 2021

Brain metastasis (BM) from breast cancer has poor prognosis despite new advances and multi-modality treatments. No current data is guiding the use of palbociclib in the management of hormone receptor (HR)-positive breast cancer patients with BM as these patients were excluded systematically from all phase 3 trials. Here, we report an evident clinical response from combining palbociclib with endocrine therapy in HR-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer with BM.
Frontal Hypoperfusion and the Effectiveness of Perampanel in Long-Lived Patient with Lafora Disease
Authors: Obara Koji , Abe Erika , Toyoshima Itaru
Published: March 2021

We report a long-lived patient with Lafora disease (LD). A 34-year-old woman experienced onset of seizures at the age of 11 years. She was bedridden in her early twenties due to frequent generalized tonic-clonic seizures, myoclonus, and progressive mental deterioration. Her seizures occurred all the time despite administration of multiple anticonvulsants at high doses. At the age of 31, she started perampanel, which resulted in reduction of anticonvulsants after her visible myoclonus and convulsions disappeared. Brain magnetic resonance imaging showed marked cerebral and cerebellar atrophy, and single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed significant hypoperfusion of the frontal lobe and cerebellum. We identified a W219R homozygous mutation in exon 1 of the NHLRC1 gene. Because perampanel may not only control seizures but also prevent mental deterioration in LD, we propose that perampanel should be administered from the early stage of LD.
The Association of Tumor-Infiltrating Lymphocytes and Programmed Cell Death 1 Expression with the Incidence of Distant Metastasis in Triple-Negative Breast Cancer Subjects in Sanglah General Hospital, Bali, Indonesia
Authors: Sudarsa I Wayan , Gunawan I Putu Ari , Manuaba Ida Bagus Tjakra Wibawa
Published: March 2021

The triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a high rate of distant metastasis. The tumor immunity microenvironment plays an important role, including tumor-infiltrating lymphocytes (TIL) and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1), in promoting TNBC aggressiveness. This study aimed to determine the association of TIL and PD-L1 expression with the incidence of distant metastasis in TNBC. This study is a cross-sectional study involving TNBC subjects at Sanglah General Hospital, Denpasar, conducted in 2019. The parameters analyzed were the expression of TIL, PD-L1, and the incidence of distant metastasis. The expression of TIL was analyzed histopathologically while PD-L1 was measured with Ventana PD-L1 kit test. Subject characteristics were obtained from medical records. Data were collected and analyzed by SPSS 22.0. As many as 31 subjects with TNBC were included in this study, with 51.6% subjects with distant metastasis. The majority of subjects with distant metastasis had low TIL and low tumoral PD-L1 but high PD-L1 stromal in TIL. From statistical analysis, only PD-L1 stromal in TIL expression was associated significantly with distant metastasis (p = 0.043). In conclusion, there was a significant association between PD-L1 stromal in TIL and the incidence of distant metastasis in TNBC.
Limb Ischemia due to Extensive Arterial Thrombosis in the Absence of Venous Occlusion as an Unusual Complication of Critical Illness from COVID-19
Authors: Nowroozpoor Armin , Bank Matthew A. , Jafari Daniel
Published: March 2021

There is increasing evidence of a link between the coronavirus disease 2019 (COVID-19) and venous and arterial thrombotic events. Here, we report a 60-year-old male patient with severe COVID-19 who developed extensive arterial thromboses and limb ischemia despite being on therapeutic-dose anticoagulation. While the exact mechanism for such events is unknown, our report highlights the importance of maintaining a high degree of suspicion in critically ill patients. Further research should focus on the mechanistic pathways along with the optimal anticoagulation and/or antithrombotic strategy.
Co-Occurrence Conundrum: Brain Metastases from Lung Adenocarcinoma, Radiation Necrosis, and Gliosarcoma
Authors: Qian David C. , Weinberg Brent D. , Neill Stewart G. , Goodman Abigail L. , Olson Jeffrey J. , Voloschin Alfredo D. , Ramalingam Suresh S. , Shu Hui-Kuo G.
Published: March 2021

Non-small cell lung cancer (NSCLC) commonly presents with metastasis to the brain. When brain metastases are treated with stereotactic radiosurgery (SRS), longitudinal imaging to monitor treatment response may identify radiation necrosis, metastasis progression, and/or another primary brain malignancy. A 60-year-old female with metastatic NSCLC involving the brain underwent treatment with systemic therapy and SRS. While some brain metastases resolved, two remaining sites evolved to resemble radiation necrosis on magnetic resonance imaging and spectroscopy. One of those sites was later confirmed to be radiation necrosis after receding with steroids and bevacizumab. The other lesion continued to enlarge and was then surgically resected, pathologically proven to be a gliosarcoma. When scan findings diverge among multiple treated disease sites, imaging should be cautiously interpreted in conjunction with clinical information as well as early surgical consultation for biopsy consideration, especially when there is suspicion of unusual or superimposed pathologies.
Self-Reported Cognitive Decline Based on the Ascertain Dementia 8 Questionnaire May Be Effective for Detecting Mild Cognitive Impairment and Dementia in the Community: The Wakuya Project
Authors: Kasai Mari , Sugawara Tomohiro , Takada Junko , Kumai Keiichi , Nakamura Kei , Meguro Kenichi
Published: March 2021

Introduction: To assess cognitive impairment, self-awareness is an important issue. The Ascertain Dementia 8 questionnaire (AD8) is a brief observation checklist for detecting mild cognitive impairment (MCI) and dementia. After analyzing the reliability and validity of a self-reported Japanese version of the AD8 (AD8-J), we compared self- and informant-reported versions of the AD8-J. Methods: A total of 93 community residents aged 75 years or older living in Wakuya, Northern Japan, agreed to participate in this study; 35 were rated as Clinical Dementia Rating (CDR) 0 (healthy), 46 as CDR 0.5 (defined herein as MCI), and 12 as CDR 1 or above (dementia, confirmed by the DSM-IV). We examined the reliability and validity using a receiver operating characteristic (ROC) curve. We analyzed the differences between self-reported and informant-reported AD8-J using a repeated measures ANOVA. Results: The self-reported AD8-J showed a satisfactory reliability (i.e., Cronbach coefficient, α = 0.71; Guttman split half method coefficient = 0.60). For CDR 0 vs. CDR 0.5 or above, the area under the ROC curve was 0.74 and the cutoff score was 1/2, with a sensitivity of 70.7% and a specificity of 65.7%. Analysis of the subscores of AD8 suggested that, from the early stage of dementia, the subjects showed a subjective decline in memory and interest in hobbies/activities, as well as problems with judgment. Conclusion: It is suggested that the self-reported AD8-J was effective in detecting MCI and dementia. We could use it for detecting MCI and dementia, including in those living alone, in the primary health checkup.
Evaluation, Acceptance, and Qualification of Digital Measures: From Proof of Concept to Endpoint
Authors: Goldsack Jennifer C. , Dowling Ariel V. , Samuelson David , Patrick-Lake Bray , Clay Ieuan
Published: March 2021

To support the successful adoption of digital measures into internal decision making and evidence generation for medical product development, we present a unified lexicon to aid communication throughout this process, and highlight key concepts including the critical role of participant engagement in development of digital measures. We detail the steps of bringing a successful proof of concept to scale, focusing on key decisions in the development of a new digital measure: asking the right question, optimized approaches to evaluating new measures, and whether and how to pursue qualification or acceptance. Building on the V3 framework for establishing verification and analytical and clinical validation, we discuss strategic and practical considerations for collecting this evidence, illustrated with concrete examples of trailblazing digital measures in the field.
Mildly Elevated Pulmonary Arterial Pressure Is Associated With a High Risk of Progression to Pulmonary Hypertension and Increased Mortality: A Systematic Review and Meta‐Analysis
Authors: Xue Lin , Yang Yicheng , Sun Bo , Liu Bingyang , Zeng Qixian , Xiong Changming
Published: March 2021

Background

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (PAP) ≥25 mm Hg measured by right heart catheterization. However, the upper limit of a normal mean PAP is 20 mm Hg. There is a gap between the upper limit of normal and the threshold for diagnosing PH. Therefore, we aimed to investigate whether individuals with a mildly elevated PAP, defined as 20 mm Hg < mean PAP <25 mm Hg, are at an increased risk of progression to PH or mortality than those with a normal PAP.

Methods and Results

We reviewed studies evaluating the risk of progression to PH and/or mortality in individuals with a mildly elevated PAP versus those with a normal PAP. The mean PAP value of each participant was confirmed by right heart catheterization. We reviewed 1213 studies and 8 fulfilled our inclusion criteria. Our results indicated that individuals with a mildly elevated PAP were 1.81 to 2.45 times more likely to progress to PH than individuals with a normal PAP. There was a statistically significant difference in mortality between the mildly elevated PAP and normal PAP groups (hazard ratio, 2.48; 95% CI, 1.69–3.64). We also pooled survival probabilities in each arm to obtain a summary survival curve for each group, and the pooled survival rates in the mildly elevated PAP group were numerically lower than those in the normal PAP group.

Conclusions

Our study revealed that individuals with a mildly elevated PAP were at an increased risk of progression to PH and mortality than those with a normal PAP.
Atrial Fibrillation Is Associated With Mortality in Intermediate Surgical Risk Patients With Severe Aortic Stenosis: Analyses From the PARTNER 2A and PARTNER S3i Trials
Authors: Brener Michael I. , George Isaac , Kosmidou Ioanna , Nazif Tamim , Zhang Zixuan , Dizon Jose M. , Garan Hasan , Malaisrie S. Chris , Makkar Raj , Mack Michael , Szeto Wilson Y. , Fearon William F. , Thourani Vinod H. , Leon Martin B. , Kodali Susheel , Biviano Angelo B.
Published: March 2021

Background

The impact of atrial fibrillation (AF) in intermediate surgical risk patients with severe aortic stenosis who undergo either transcatheter or surgical aortic valve replacement (AVR) is not well established.

Methods and Results

Data were assessed in 2663 patients from the PARTNER (Placement of Aortic Transcatheter Valve) 2A or S3i trials. Analyses grouped patients into 3 categories according to their baseline and discharge rhythms (ie, sinus rhythm [SR]/SR, SR/AF, or AF/AF). Among patients with transcatheter AVR (n=1867), 79.2% had SR/SR, 17.6% had AF/AF, and 3.2% had SR/AF. Among patients with surgical AVR (n=796), 71.7% had SR/SR, 14.1% had AF/AF, and 14.2% had SR/AF. Patients with transcatheter AVR in AF at discharge had increased 2‐year mortality (SR/AF versus SR/SR; hazard ratio [HR], 2.73; 95% CI, 1.68–4.44;
P
<0.0001; AF/AF versus SR/SR; HR, 1.56; 95% CI, 1.16–2.09;
P
=0.003); patients with SR/AF also experienced increased 2‐year mortality relative to patients with AF/AF (HR, 1.77; 95% CI, 1.04–3.00;
P
=0.03). For patients with surgicalAVR, the presence of AF at discharge was also associated with increased 2‐year mortality (SR/AF versus SR/SR; HR, 1.93; 95% CI, 1.25–2.96;
P
=0.002; and AF/AF versus SR/SR; HR, 1.67; 95% CI, 1.06–2.63;
P
=0.027). Rehospitalization and persistent advanced heart failure symptoms were also more common among patients with transcatheter AVR and surgical AVR discharged in AF, and major bleeding was more common in the transcatheter AVR cohort.

Conclusions

The presence of AF at discharge in patients with intermediate surgical risk aortic stenosis was associated with worse outcomes—especially in patients with baseline SR—including increased all‐cause mortality at 2‐year follow‐up.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifiers: NCT01314313 and NCT03222128.
Characteristics of Populations Excluded From Clinical Trials Supporting Intensive Blood Pressure Control Guidelines
Authors: Anderson Timothy S. , Odden Michelle C. , Penko Joanne , Kazi Dhruv S. , Bellows Brandon K. , Bibbins‐Domingo Kirsten
Published: March 2021

Background

Only one third of patients recommended intensified treatment by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for high blood pressure would have been eligible for the clinical trials on which recommendations were largely based. We sought to identify characteristics of adults who would have been trial‐ineligible in order to inform clinical practice and research priorities.

Methods and Results

We examined the proportion of adults diagnosed with hypertension who met trial inclusion and exclusion criteria, stratified by age, diabetes mellitus status, and guideline recommendations in a cross‐sectional study of the National Health and Nutrition Examination Survey, 2013–2016. Of the 107.7 million adults (95% CI, 99.3–116.0 million) classified as having hypertension by the ACC/AHA guideline, 23.1% (95% CI, 20.8%–25.5%) were below the target blood pressure of 130/80 mm Hg, 22.2% (95% CI, 20.1%–24.4%) would be recommended nonpharmacologic treatment, and 54.6% (95% CI, 52.5%–56.7%) would be recommended additional pharmacotherapy. Only 20.6% (95% CI, 18.8%–22.4%) of adults with hypertension would be trial‐eligible. The majority of adults <50 years were excluded because of low cardiovascular risk and lack of access to primary care. The majority of adults aged ≥70 years were excluded because of multimorbidity and limited life expectancy. Reasons for trial exclusion were similar for patients with and without diabetes mellitus.

Conclusions

Intensive blood pressure treatment trials were not representative of many younger adults with low cardiovascular risk and older adults with multimorbidity who are now recommended more intensive blood pressure goals.
Criminalizing Migration
Authors: Hernández César Cuauhtémoc García
Published: March 2021

Beginning in the 1980s, the United States embarked on a decades-long restructuring of federal laws criminalizing migration and increasing the consequences for migrants engaging in criminal activity. Today, the results are clear: a law enforcement apparatus and immigration prison system propelled by a vast infrastructure of laws and policies. The presidency of Donald Trump augmented this trend and brought it to public attention. But lost in President Trump's unique flair is an ideological commitment shared by multiple presidential administrations and legislators from both major political parties to use the criminal justice system and imprisonment to sift migrants. Examining these ideological attachments reveals Trump-era policies to be the outer edge of decades-long trends rather than extreme and momentary deviations from the norm.
The Legal Status Divide among the Children of Immigrants
Authors: Gonzales Roberto G. , Ruszczyk Stephen P.
Published: March 2021

Over the past thirty-five years, federal immigration policy has brightened the boundaries of the category of undocumented status. For undocumented young people who move into adulthood, the predominance of immigration status to their everyday experiences and social position has been amplified. This process of trying to continue schooling, find work, and participate in public life has become synonymous with a process of learning to be “illegal.” This essay argues that despite known variations in undocumented youths by race, place, and educational history, undocumented status has become what Everett Hughes called a “master status.” The uniform set of immigration status-based exclusions overwhelms the impact of other statuses to create a socially significant divide. The rise, fall, and survival of the Deferred Action for Childhood Arrivals program, a policy offering qualified youths a temporary semilegal status, have underlined how closely access and rights hew to the contours of contemporary immigration policy.