Chemotherapy rechallenge in metastatic colon cancer: A case report and literature review

BACKGROUNDColorectal cancer (CRC) is the third leading cause of cancer-related death in males and females in the United States. Approximately, 20%-22% of patients have metastatic disease at the time of presentation, and 50%-60% will develop metastasis over the course of their disease. Despite advances in systemic therapies, there remains a paucity of effective third- and later-line therapies for patients with ongoing disease progression. However, rechallenging chemo-resistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer (mCRC).CASE SUMMARYA 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness. Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease. He underwent a colectomy with anastomosis. Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma (T4bN1bM1a). He received adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), but therapy was discontinued due to the development of atrial fibrillation. Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL, and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type. He was started on irinotecan with oxaliplatin (IROX), and bevacizumab (14 cycles), developed disease progression, was transitioned to FOLFOX and cetuximab, and then eventually three cycles of pembrolizumab. Following disease progression, he was rechallenged with IROX therapy, as he previously responded well to oxaliplatin-based therapy. The IROX rechallenge provided this patient with a ten-month survival benefit, decreased metastatic burden, and marked improvement in his clinical condition.CONCLUSIONRechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.     

Microclimate and development of pressure ulcers and superficial skin changes

This study aims to evaluate the microclimate and development of pressure ulcers and superficial skin changes. A prospective cohort study was conducted in an acute care ward in Indonesia. Risk factors for pressure ulcers and superficial skin changes were identified based on the Bergstrom Braden conceptual model. Microclimate data were collected every 3 days for 15 days while the development of pressure ulcers and superficial skin changes was observed every day. Pressure ulcers and superficial skin changes were developed in 20 of the 71 participants. Total mean difference in skin temperature was higher for patients with pressure ulcers and superficial skin changes (0·9 ± 0·6°C) compared with controls (0·6 ± 0·8°C) (P = 0·071). Binary logistic regression predictor values for pressure ulcers and superficial skin changes were 0·111 for type of sheet and 0·347 for Braden Scale results. In conclusion, difference in skin temperature seems to be a predictor for pressure ulcer development and superficial skin changes, while synthetic fibre sheets are able to maintain a beneficial microclimate.     

Burkholderia bacteria infectiously induce the proto-farming symbiosis of Dictyostelium amoebae and food bacteria

Symbiotic associations can allow an organism to acquire novel traits by accessing the genetic repertoire of its partner. In the Dictyostelium discoideum farming symbiosis, certain amoebas (termed “farmers”) stably associate with bacterial partners. Farmers can suffer a reproductive cost but also gain beneficial capabilities, such as carriage of bacterial food (proto-farming) and defense against competitors. Farming status previously has been attributed to amoeba genotype, but the role of bacterial partners in its induction has not been examined. Here, we explore the role of bacterial associates in the initiation, maintenance, and phenotypic effects of the farming symbiosis. We demonstrate that two clades of farmer-associated Burkholderia isolates colonize D. discoideum nonfarmers and infectiously endow them with farmer-like characteristics, indicating that Burkholderia symbionts are a major driver of the farming phenomenon. Under food-rich conditions, Burkholderia-colonized amoebas produce fewer spores than uncolonized counterparts, with the severity of this reduction being dependent on the Burkholderia colonizer. However, the induction of food carriage by Burkholderia colonization may be considered a conditionally adaptive trait because it can confer an advantage to the amoeba host when grown in food-limiting conditions. We observed Burkholderia inside and outside colonized D. discoideum spores after fruiting body formation; this observation, together with the ability of Burkholderia to colonize new amoebas, suggests a mixed mode of symbiont transmission. These results change our understanding of the D. discoideum farming symbiosis by establishing that the bacterial partner, Burkholderia, is an important causative agent of the farming phenomenon.Symbiotic interactions are ubiquitous in nature and can play a central role in the evolutionary trajectory of organisms. For instance, symbiosis can drive rapid lateral procurement of novel traits as interacting organisms gain access to the genetic capabilities of their partner (1, 2). The evolutionary power of symbiosis is apparent in the many major life forms that owe their very existence to past and present symbiotic partnerships (3, 4). A famous example is the emergence of eukaryotes through their ancestor’s acquisition of bacteria that subsequently evolved into organelles indispensable for energy generation (5). Although many classic examples of symbiosis are conspicuously mutualistic, the characteristics of other symbiotic associations can be complex, dynamic, and less definable. In some cases, symbionts have good or bad effects on their host that vary depending on genotypic and environmental details (6, 7). The length and transmission mode of symbiosis also can have strong effects on the selection and evolution of partner traits. Although older symbiotic associations are often obligate and stable, recent associations can be transient and protean (8). Additionally, vertical transmission may favor mutualistic interactions, whereas horizontal transmission can allow the emergence and spread of more pathogenic characteristics (9–11). However, as a whole, the fates of symbioses are often the result of a delicate balance between mutualism and pathogenesis, requiring pathogenic characteristics at the least to facilitate infection and beneficial properties to promote maintenance (12, 13). Indeed, many cases of mutualistic associations are thought to have evolved from ancient parasitic infections (14, 15). Examining nascent, malleable, or less definable forms of symbiosis may provide insight into the mechanisms that promote or corrode this balance and their subsequent evolutionary consequences.Amoeba–bacteria interactions make a promising system for gaining insight into diverse and dynamic symbiotic relationships. Amoebas interact with bacteria in multiple ways. Most apparently, they are predators of bacteria. However, other amoeba–bacteria interactions are less favorable for the amoebas. Some bacteria can evade amoeba phagocytosis and thereby diminish amoeba predatory prowess and food acquisition (16). Still worse, amoebas can fall victim to bacterial processes or exploitation, with some bacteria producing products detrimental to amoeba fitness or surviving phagocytosis to invade and multiply within amoeba cells (17, 18). There also are stable symbiotic interactions between amoebas and bacteria in which the origins, mechanisms, and impacts on both species are less defined. For instance, several bacterial endosymbionts inhabit amoebas, incurring variable and not always obvious consequences to the amoeba host (19–22). In addition, certain isolates of the soil-dwelling amoeba Dictyostelium discoideum persistently associate with bacteria, an association that has beneficial or detrimental outcomes depending on the environmental conditions (23–25). Amoebas can serve as environmental reservoirs for bacterial pathogens (26, 27) or as training facilities for the adaptation of bacteria to evade eukaryotic phagocytosis or to survive intracellularly after phagocytosis (17, 28). Although, for the eukaryotic host, some of these interactions may have decidedly unfortunate outcomes, such as the emergence of bacterial pathogenesis through intracellular adaptation, others may illuminate important evolutionary advances, such as the transition of bacterial endosymbionts into organelles that provide novel functionality. Thus, the diversity and persistence of amoeba–bacteria interactions may have several ecological and health-related consequences.The stable association between bacteria and some wild isolates of D. discoideum supplies a particularly interesting study system for elucidating symbiotic causes and consequences. D. discoideum is a soil-dwelling amoeba that transitions between solitary and social life stages (29). In the solitary stage, D. discoideum cells consume bacteria through phagocytosis and divide by binary fission. When food is exhausted, amoebas coaggregate, ultimately forming a multicellular structure called a “fruiting body.” As the fruiting body develops, ∼20% of the cells sacrifice themselves to form an erect stalk. The remaining cells ascend the stalk, forming a globular sorus at the top where they differentiate into sturdy spores (29). In the sorus, spores are positioned for dispersal into more favorable environments, presumably through contact and transport upon animals (30). Multiple wild isolates of the amoeba D. discoideum, but not all of them, have been found to be stably associated with several bacteria species (24). These amoebas persistently carry both edible and inedible bacteria with them through the social stage and are termed “farmers” because of their ability to reseed new environments with a food source (23, 24). Interestingly, farmer isolates produce fewer spores under optimal conditions than their non–bacteria-carrying counterparts; however, this cost is countered by farmers’ advantage in being able to replenish their food supply when dispersing to food-poor environments (24). Additionally, some of the bacterial isolates that farmers carry produce compounds detrimental to nonfarmer clones but not to their host farmer, giving the host farmer a competitive advantage in a mixed population (23, 25).The ease of D. discoideum manipulation coupled with the variability inherent in the farming symbiosis provide a promising platform for addressing questions concerning symbiosis between microbes and eukaryotes. For instance, are mutualistic associations and their resulting phenotypes driven by the host, by the bacteria, or by a very specific interaction between the two? How much coevolution is required to reach a beneficial outcome? In aphids and other insects, defensive symbionts can sweep through populations and be horizontally transferred to new hosts (31, 32). Even Buchnera, a vertically transferred obligate symbiont of aphids, still confers its benefits to new hosts after experimental infection (33). Taken together, this horizontal transfer suggests that little coevolution may be needed for the formation of novel symbiosis. However, in some plant–rhizobia or –mycorrhizal associations, the symbiont phenotype can vary substantially among hosts, and the outcome of the association is determined by the interaction of host and symbiont-derived factors (34–38). Similarly, a synergistic interplay between host and symbiont components mediates the initiation and persistence of the bobtail squid–Vibrio fischeri symbiosis (39–41). For the D. discoideum farming symbiosis, it previously had been assumed that farmers were genetically distinct from nonfarmers, suggesting the role of a host-specific factor in establishing the symbiosis (24). This study aims to characterize more thoroughly the partner dynamics within the D. discoideum farming symbiosis by specifically analyzing the role of bacterial associates in farming phenotypes.To determine the role bacterial partners play in farming, we first examined the diversity of bacterial passengers associated with our present collection of stable farmer clones. We confirmed that several different bacterial species can be isolated from farmer D. discoideum; however isolates belonging to the Burkholderia genus were ubiquitous among our tested farmers. These Burkholderia isolates fail to support amoeba growth when provided as the only food source and therefore are considered inedible. Because of their prevalence in our farmer clones and because Burkholderia species form symbiotic relationships with diverse organisms, we hypothesized that these Burkholderia isolates could be crucial for the symbiotic relationship with D. discoideum that results in the farming phenomenon (42). Therefore we asked whether nonfarmer D. discoideum could be colonized by farmer-associated Burkholderia isolates and whether colonization could induce secondary bacterial carriage. We established that the Burkholderia associated with D. discoideum fall into two distinct phylogenetic clades. We found that the tested Burkholderia isolates from each clade robustly colonized nonfarmer D. discoideum sori, with this colonization persisting through multiple rounds of D. discoideum spore dispersal, germination, and vegetative growth. Like their farmer counterparts, nonfarmers colonized with Burkholderia can carry bacterial food, allowing them to reseed new territories with food bacteria following spore dispersal. Inversely, removal of Burkholderia from wild farmers by antibiotic treatment results in the loss of detectable bacterial food carrying. These findings suggest that Burkholderia colonization drives secondary bacterial carriage (farming) in D. discoideum. In total, these results suggest that specific Burkholderia isolates stably colonize D. discoideum and induce a novel adaptive trait of ecological relevance, the carriage of bacterial food. Our initial evidence suggests that the consequences of Burkholderia carriage may differ according to symbiont and host genotypes. For instance, some Burkholderia isolates impose a higher cost to their hosts, and the extent of this cost appears to be more severe for newer hosts than for the original host. We also observe Burkholderia (and occasionally, our laboratory food bacterium, Klebsiella pneumoniae) inside colonized D. discoideum spores after fruiting body formation. This observation, together with Burkholderia’s ability to be horizontally transmitted to new hosts and to associate stably with old hosts, suggests a mixed mode of Burkholderia transmission. The less severe fitness costs exerted by Burkholderia colonization in the original hosts suggests that long-term vertical transmission may lead to compensatory host adaptation.     

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under high-glucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or d-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2–Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of d-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, d-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest d-glucarate as a potential therapeutic agent for the amelioration of DKD.     

Current status of lung cancer screening

Recent results have demonstrated a major reduction in lung cancer mortality through computed tomography screening and no benefit from chest radiograph (CXR) screening. This presents a huge potential for benefit but also poses challenges regarding management of details to minimize harm. Many unresolved questions remain that must be addressed to implement computed tomography screening for lung cancer in a thoughtful and responsible way.     

Microbiota That Affect Risk for Shigellosis in Children in Low-Income Countries

Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17–0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8–220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.–induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.     

The feasibility and accuracy of ultrasound assessment in the labor room

Objective: Vaginal examination is widely used to assess the progress of labor; however, it is subjective and poorly reproducible. We aim to assess the feasibility and accuracy of transabdominal and transperineal ultrasound compared to vaginal examination in the assessment of labor and its progress.

Methods: Women were recruited as they presented for assessment of labor to a tertiary inner city maternity service. Paired vaginal and ultrasound assessments were performed in 192 women at 24–42 weeks. Fetal head position was assessed by transabdominal ultrasound defined in relation to the occiput position transformed to a 12-hour clock face; fetal head station defined as head-perineum distance by transperineal ultrasound; cervical dilatation by anterior to posterior cervical rim measurement and caput succedaneum by skin-skull distance on transperineal ultrasound.

Results: Fetal head position was recorded in 99.7% (298/299) of US and 51.5% (154/299) on vaginal examination (p?¹). Bland–Altman analysis showed 95% limits of agreement, ?5.31 to 4.84 clock hours. Head station was recorded in 96.3% (308/320) on vaginal examination (VE) and 95.9% (307/320) on US (p?=?.79¹). Head station and head perineum distance were negatively correlated (Spearman’s r?=??.57, p?p?p?p?Conclusions: We describe comprehensive ultrasound assessments in the labor room that could be translated to the assessment of women in labor. Fetal head position is unreliably determined by vaginal examination and agrees poorly with US. Head perineum distance has a moderate correlation with fetal head station in relation to the ischial spines based on vaginal examination. Cervical dilatation is not reliably assessed by ultrasound except at dilatations of less than 4?cm. Caput is readily quantifiable by ultrasound and its presence is associated with lower fetal head station. Transabdominal and transperineal ultrasound is feasible in the labor room with an accuracy that is generally greater than vaginal examinations.