After corticospinal tract damage, reticulospinal connections to motoneurons strengthen preferentially to flexor muscles. This could contribute to the disproportionately poor recovery of extensors often seen after spinal cord injury (SCI) and stroke. In this study, we paired electrical stimulation over the triceps muscle with auditory clicks, using a wearable device to deliver stimuli over a prolonged period of time. Healthy human volunteers wore the stimulation device for ∼6 h and a variety of electrophysiological assessments were used to measure changes in triceps motor output. In contrast to previous results in the biceps muscle, paired stimulation: (1) did not increase the StartReact effect; (2) did not decrease the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; (3) did not enhance muscle responses elicited by a TMS coil oriented to induce anterior-posterior current. In a second study, chronic cervical SCI survivors wore the stimulation device for ∼4 h every day for four weeks; this was compared with a four-week period without wearing the device. Functional and electrophysiological assessments were repeated at week 0, week 4, and week 8. No significant changes were observed in electrophysiological assessments after paired stimulation. Functional measurements such as maximal force and variability and speed of trajectories made during a planar reaching task also remained unchanged. Our results suggest that the triceps muscle shows less potential for plasticity than biceps; pairing clicks with muscle stimulation does not seem beneficial in enhancing triceps recovery after SCI. A wearable device which pairs auditory clicks with electrical stimulation over a muscle was previously shown to strengthen putative reticulospinal connections to the biceps brachii muscle. Here, we tested whether this device could also strengthen connections to the triceps muscle, both in healthy volunteers and in people with spinal cord injury (SCI). Surprisingly, there was no evidence of an effect. This suggests that connections to triceps differ from those to biceps in their ability to undergo plastic changes. This may underlie the poor recovery of triceps compared with biceps typically seen after spinal cord injury.Damage to the corticospinal tract through spinal cord injury (SCI) often results in decreased voluntary control of muscles below the level of injury, or even full paralysis. The recovery of any remaining function following SCI is associated with plastic changes and reorganization of neural pathways.While extensive axonal regeneration in the CNS is absent, even the most severe SCIs often spare regions of white matter  and survAlternatively, other descending pathways may provide a route for motor command transmission. Monkeys show a remarkable recovery after CST lesions , b and rIn the absence of a rubrospinal tract, humans may have to rely on medial brainstem pathways, including the reticulospinal tract (RST), after damage to the CST. While the CST has become the dominant pathway in primates, reticulospinal connections to motoneurons strengthen after CST lesions, partially restoring lost synaptic drive , 2018. INoninvasive methods to modulate the RST in humans are limited, but exploiting the fact that reticulospinal neurons receive extensive afferent input  and audiElbow extensors show notoriously limited recovery compared with elbow flexor muscles in individuals with cervical SCI . This asThe imbalanced recovery might be because of the differential control of flexor and extensor motoneurons by corticospinal and reticulospinal pathways . Indeed,Our previous work using the wearable device to modulate motor output , most liIn total, 11 healthy volunteers  participated in the study. Four subjects took part in two experiments. If participants took part in several stimulation paradigms, each session was separated by at least 7 d. All subjects gave written informed consent to the experimental procedures, which was approved by the appropriate ethics committee. The study was performed in accordance with the guidelines established in the Declaration of Helsinki, except that the study was not preregistered in a database.The single-day study in healthy subjects followed the same paradigm as our previous work targeting the biceps muscle .This reqFor this study, conducted over 1 d, the following assessments were used at baseline and after wearing the device: StartReact, loud sound with MEP, MEPs with different coil orientations . Assessments used in this study are summarized in Seven subjects wore the earpiece in the contralateral ear and 8 subjects wore the earpiece in the ipsilateral ear (relative to the stimulated right triceps).Subjects needed to fit the following inclusion criteria to be eligible for the study: at least 18 years of age; chronic (more than one year) cervical (C2–C7) injury; detectable electromyography (EMG) activity in triceps; without upper limb fracture or subluxation/dislocation of joints within last six months; be able to follow study instructions; willing to provide written informed consent .This study was designed as an interventional randomized crossover trial. The trial was registered in the ISRCTN registry (ISRCTN15025040). After completing the baseline session (week 0) which included all assessments . Participants were free to choose the stimulated side, to maximize the benefit to them from any potential improvement.An adverse event (AE) was defined as any untoward medical event, including abnormal laboratory values, occurring during the use of the study device, but not necessarily causally related to it. Events with onset before start of study device use were not considered as adverse events unless there was an increase in severity and/or frequency following use of the study device. No AEs were reported during the study.EMG was recorded through surface electrodes  secured on the skin over the belly of the triceps, biceps, and deltoid muscle.For the 1-d study in healthy subjects, the electrodes over the right triceps muscle were used for both EMG recording and for wearable stimulation, so they were kept in place for the whole day, ensuring consistency between the morning and evening sessions. For the SCI study, electrodes had to be repositioned for each session.EMG signals were amplified and filtered  with a bioamplifier , digitized at a sampling rate of 5 kHz  and stored on a computer for off-line analysis. Where necessary for a given assessment , the level of triceps EMG activity was displayed continuously on a computer screen via series of colored bars, allowing subjects to maintain a constant isometric contraction. Physiologic measurements were acquired at 10–20% of MVC across conditions. The exact level of MVC varied across participants, but was kept constant for all assessments of each participant.2 magnetic stimulator (Magstim) with a monophasic current waveform. We determined the optimal position for eliciting a motor evoked potential (MEP) in the triceps muscle (hotspot) by moving the coil tangential to the scalp, at an angle of 45° to the midline, with the handle pointing laterally and posteriorly, in small steps along the arm representation of M1. The hotspot was defined as the region where the largest MEP in the triceps muscle could be evoked  was defined as the stimulator intensity sufficient to elicit a visible MEP in at least five out of 10 consecutive stimuli, in the triceps contralateral to the stimulus with an active contraction of 10–20% maximal voluntary contraction (MVC).A Polaris Vicra camera  tracked both coil and head position, allowing the site of stimulation to be marked using the Brainsight neuronavigation system (Rogue Research Inc.). This ensured a stable coil location throughout the experiment, and allowed us to return to the same site in all sessions.StartReact was examined using a previously reported paradigm , which mSubjects were seated with the arm flexed at the elbow by 90° and secured in an arm restraint.A green light-emitting diode (LED) was located ∼1 m in front of the subject. Subjects were instructed to push against the restraint (elbow extension) as quickly as possible after the LED illuminated. EMG was recorded from both the triceps and biceps muscles, and reaction time measured as the time from cue to onset of the EMG burst. Three types of trial were randomly interleaved : LED illumination alone (VRT), LED paired with a quiet sound , LED paired with a loud sound . Subjects were initially presented with five consecutive loud sounds, without performing the task, to allow familiarization and to habituate the overt startle reflex.Data were analyzed trial-by-trial using a custom MATLAB program which identified the reaction time as the point where the rectified EMG exceeded the mean ± 7 SD of the baseline measured 0–200 ms before the stimulus. Every trial was inspected visually, and erroneous activity onset times  were manually corrected. This yielded a reaction time distribution for each condition.A paradigm similar to previous studies  was usedBy holding a figure-of-eight TMS coil in different orientations, activation can be biased toward different indirect (I) waves . With thMEPs in the triceps muscle were measured from the contralateral hemisphere in the two different coil orientations. As for the measurements of MEPs described above, the figure-of-eight coil was first held to induce a posterior-anterior (PA) current in the brain. The optimal scalp position was located with this orientation, and marked in the Brainsight neuronavigation software. This site was then used for stimulation to induce an anterior-posterior (AP) current in the brain, by rotating the coil so that the handle faced anterior and medial, as the current direction does not significantly influence the position of the hotspot . Within The level of triceps EMG activity was displayed continuously on a computer screen via a series of colored bars. Twenty MEPs were recorded  while subjects maintained a constant isometric contraction of 10−20% MVC by pushing against the arm restraint.Subjects were asked to perform three brief (3 s) maximal contractions by pushing or pulling against the arm restraint, for elbow extension or elbow flexion respectively. Each contraction was separated by 60 s. Force was measured with a dynamometer built into the arm restraint.Participants sat at a custom-built table  with theThe targets consisted of a start position at the center and 8 targets of equal angular range around the central target, each with 1-cm radius. The targets were arranged at a distance 10 cm radially from the center start position. One target at a time would light up green. The target turned red as soon as the cursor reached the target area. Participants had to hold the cursor inside the target for 800–1209.6 ms, before the center target would light up green and participants returned to start position. Targets appeared in a pseudo-randomized order.Arm position was tracked using a Polhemus Liberty motion tracking system (Polhemus) with a sensor built into the support sled.Despite the arm support, two participants were unable to perform the required reaching movement and analysis is based on the remaining 13 participants.Targets for participants who chose to use their left arm for the study were mirrored across the midline, so comparable muscle groups were used for each target across subjects.Trajectories of SCI participants were compared with data from 18 healthy volunteers performing the same task with their right arm .The Capabilities of Upper Extremity (CUE) Questionnaire measures upper extremity functional limitations in individuals with tetraplegia . It is aThe wearable device was similar to that used in our previous work . It compeq when delivered at 0.66 Hz, and 71 dB LAeq when delivered at 1.32 Hz; assuming device usage for at least 8 h. This is well below the recommended safe limit for noise exposure of 85 dB LAeq given by the United Kingdom’s Control of Noise at Work Regulations . For the SCI study, the earpiece was always placed contralateral to the stimulated triceps muscle.Stimuli were delivered with an intertrial interval of 1250–1750 ms (chosen at random from a uniform distribution); the delay between electrical stimulation and auditory click was 10 ms. This interstimulus interval was chosen so that the afferent volley should arrive at the brainstem just before RST cell activation by the click.The device logged to flash memory how many stimuli were given each time it was switched on, allowing the experimenter to check how often it had been used at the end of the four-week usage period.Data were analyzed using custom scripts written in the MATLAB environment . Statistical tests were performed using MATLAB and IBM SPSS Statistics for Windows, version 24 (IBM Corp.).EMG traces were full-wave rectified and then averaged. MEP amplitude was measured as the area under the curve of this average.Where MEPs were conditioned by loud sound, the amplitude of the conditioned MEP was expressed as a percentage of the unconditioned MEP.The StartReact effect was measured as the difference between the mean VART and VSRT.t test was performed to compare the normalized conditioned MEP amplitude against 100%, to evaluate the effect of conditioning at baseline.For the assessment which conditioned MEPs with loud sound, a one sample t tests were used to compare the measurements of each session to the measurements at baseline.For each experiment, individual paired t tests.For the SCI study, the session preceding device usage was taken as the “before”  and the session immediately after wearing the device was taken as the “after”  for the “device” condition. The same principle was used for the “no device” condition; with the “before” session being week 4 for group A and week 0 for group B and the “after” session being week 8 for group A and week 4 for group B. Differences between before and after sessions were compared with paired d was used to measure effect size.Where necessary, the procedure introduced by 2) was calculated using functional principal component analysis (PCA), a generalization of traditional PCA .To assess the overall movement quality during planar reaching, Mahalanobis distance squared  and target (Targets 1–8) on speed, distance, and MDC2 differences (after-before). Speed, distance, and MDC2 at baseline (week 0 for both groups A and B) were also assessed with a repeated measures ANOVA with factor target (Targets 1–8).Additionally, two-way repeated measures ANOVAs were performed with factors target (Targets 1–8) and condition  on speed, distance, and MDCp < 0.05. Descriptive statistics are presented as mean ± SD.The significance level was set at Binomial tests were performed to determine whether the number of subjects showing a certain change were more than expected by chance based on a binomial distribution.N = 15.p = 0.628 contralateral, p = 0.732 ipsilateral, p = 0.538 combined; There was no significant difference in StartReact effect after wearable device stimulation (t test p < 0.001) at baseline (p = 0.059). When the groups were combined, MEPs were significantly suppressed at baseline (p < 0.001) as expected from the literature  of subjects showing a certain direction of change for any of the assessments . Based on the average stimulus frequency, this is equivalent to 268,800 paired stimuli. p = 0.133, none p = 0.435; p = 0.177; p = 0.418, none p = 0.507; p = 0.604, none p = 0.617; p = 0.825, extension p = 0.471; p = 0.568, none p = 0.354; p = 0.630, none p = 0.419; The total score achieved in the CUE questionnaire did not change between sessions  and did not differ between conditions .F = 8.648, p < 0.001, η2 = 0.419; distance F = 14.170, p < 0.001, η2 = 0.541; target for both measures after four weeks of using the device  = 8.074, p < 0.001, η2 = 0.402; distance F = 16.092, p < 0.001, η2 = 0.573) and four weeks of not using the device  = 8.205, p < 0.001, η2 = 0.406; distance F = 17.644, p < 0.001, η2 = 0.595), but no effect of time  = 3.759, p = 0.076, η2 = 0.239; speed “none” F = 0.101, p = 0.756, η2 = 0.008; distance “device” F = 0.439, p = 0.520, η2 = 0.035; distance “none” F = 17.644, p < 0.001, η2 = 0.595) or their interaction  = 0.627, p = 0.733, η2 = 0.050; speed “none” F = 0.808, p = 0.583, η2 = 0.063; distance “device” F = 0.395, p = 0.903, η2 = 0.032; distance “none” F = 0.333, p = 0.937, η2 = 0.027).Group analysis of trajectories during the planar reaching task are shown in F = 0.743, p = 0.406, η2 = 0.058; distance F = 0.070, p = 0.797, η2 = 0.006), target  = 0.547, p = 0.7961, η2 = 0.044; distance F = 0.462, p = 0.859, η2 = 0.037), or their interaction  = 0.751, p = 0.629, η2 = 0.059; distance F = 0.340, p = 0.933, η2 = 0.028).Comparing the differences between sessions Ab,Bb rev2; N = 18). A mixed ANOVA with repeated measure target (1–8) and between-subject factor group  was used to analyze trajectories at baseline (2(27) = 239.232, p < 0.001) and therefore a Greenhouse–Geisser correction was used. Overall quality of trajectories from SCI participants differed significantly from healthy trajectories at baseline, with a main effect of group  = 15.686, p < 0.001, η2 = 0.351), target  = 3.518, p = 0.043, η2 = 0.108) and their interaction  = 3.518, p = 0.0431, η2 = 0.108).Trajectories were also evaluated using functional principal component analysis to compute Mahalanobis distance squared MDC2; C comparebaseline Ca. MauchF = 3.329, p = 0.093, η2 = 0.217; none F = 2.005, p = 0.182, η2 = 0.143), target  = 1.779, p = 0.102, η2 = 0.129; none F = 2.138, p = 0.048, η2 = 0.151), or their interaction  = 0.651, p = 0.713, η2 = 0.051; none F = 1.009, p = 0.431, η2 = 0.078) on MDC2 across sessions. Similar to maximal speed and distance to straight line, there was no effect of condition  = 0.091, p = 0.768, η2 = 0.008), target  = 1.803, p = 0.097, η2 = 0.131), or their interaction  = 0.521, p = 0.817, η2 = 0.042) on MDC2 when looking at the differences between sessions  and target 4 , although target four was not significant after correction for multiple comparisons.Significantly more subjects than expected by chance showed a decrease in MDCUnlike our previous results with the device targeting the biceps muscle , pairingA study by Increased amplitude in MEPs elicited by AP currents, increased StartReact effect and reduction in MEP suppression following loud auditory stimuli were previously all observed in the biceps muscle after wearable device stimulation for 6 h ; all of Because the overt startle reflex is known to involve the reticulospinal tract , severalThe cortical suppression of MEPs following LAS most likely results from stimulation of the reticular formation by the loud sound , and actTMS can preferentially recruit different descending waves in humans by changing the direction of the current induced in the brain . PA-direNone of these measures showed any significant changes for the triceps muscle after paired stimulation in healthy volunteers or after prolonged wearable device usage in chronic cervical SCI. In addition to our electrophysiological measurements, we also had a range of functional measurements to assess motor function before and after wearable device stimulation in participants with chronic cervical SCI. For one, we assessed maximal force produced before and after wearing the device B,C, althIn addition to strength, an important aspect of motor control is skilled muscle use; this is harder to assess as most movements have significant antigravity strength requirements. In order to separate motor control of the upper limb from strength, we used a planar reaching task similar to previous studies in stroke . This taIn our previous study, auditory clicks were always delivered contralaterally to the target muscle. However, it has been shown that galvanic-evoked vestibulocollic reflexes project contralaterally to flexors and ipsilaterally to extensors . AuditorAlthough reticulospinal neurons may respond better to plasticity protocols than corticospinal neurons , there iThis might be because flexor and extensor muscles receive differential control from corticospinal and reticulospinal pathways. Through corticospinal connections, flexors might receive larger monosynaptic facilitation and extensors stronger disynaptic inhibition in both monkeys  and humaAfter contralateral CST lesion in monkey, there was no evidence of novel connections from ipsilateral corticospinal fibers that would make any significant contribution to recovery . In contImportantly, there is no evidence of increased spasticity in stroke survivors using the wearable device . There wAll of the above evidence suggests that reticulospinal inputs compensate for the loss of corticospinal axons, but may do so preferentially in flexors, which could explain the asymmetrical recovery of biceps and triceps muscles observed in people after SCI . The faiCompliance was variable between SCI participants , with onThe CUE questionnaire is designed to measure upper extremity functional limitations in individuals with tetraplegia. However, 12 out of 32 questions focus on hand and finger function, hardly something expected to change after our plasticity protocol targeting the triceps.Furthermore, we recruited participants with both complete and incomplete cervical SCI. Even when voluntary movement is completely absent on clinical evaluation, neurophysiological methods using surface electromyography are sometimes able to identify and quantify evidence of preserved translesional conduction in chronic clinically complete SCI subjects , 2011. HThe heterogeneity of the participants was mostly because of the lack of injury-specific inclusion criteria (see Methods), as anyone with a cervical injury was allowed to participate. There was also very little clinical baseline data available, further contributing to the diverse nature of the participants. Future more extensive studies could use, for example, the ASIA scale to stratify participants and possibly improve the chance to detect an effect.


The purpose of this study was to compare the dosimetric characteristics of five different treatment planning techniques for locally advanced non‐small cell lung cancer (LA‐NSCLC) with sequential plan changes.A total of 13 stage III NSCLC patients were enrolled in this study. These patients had both computed tomography (CT) images for initial and boost treatment plans. The latter CT images were taken if tumor shrinkage was observed after 2 weeks of treatment. The prescription dose was 60 Gy/30 Fr . Five techniques  were recalculated for all patients. The accumulated doses between initial and boost plans were compared among all treatment techniques.20Gy) were 21.05 ± 10.56%, 20.86 ± 6.45, 19.50 ± 7.38%, 19.98 ± 10.04%, and 17.74 ± 7.86%. There was significant improvement about CI and V20Gy for hybrid compared with F‐3DCRT (p < 0.05).The conformity indexes (CI) of the planning target volume (PTV) of the five planning techniques were 0.34 ± 0.10, 0.57 ± 0.10, 0.86 ± 0.08, 0.61 ± 0.12, and 0.83 ± 0.11 for F‐3DCRT, I‐3DCRT, VMAT, bVMAT, and hybrid, respectively. In the same manner, lung volumes receiving >20 Gy (VThe IMRT/VMAT hybrid technique for LA‐NSCLC patients improved target CI and reduced lung doses. Furthermore, if IMRT was not available initially, starting with 3DCRT might be beneficial as demonstrated in the bVMAT procedure of this study. The study examined five planning techniques for advanced lung cancer, evaluating dosimetric traits with plan changes and extensions. It found plan changes useful for target alterations, but a single re‐planning in offline‐adaptive radiotherapy might not minimize lung dose adequately. The IMRT/VMAT hybrid showed enhanced conformity and lower lung doses, and starting with 3DCRT is recommended if IMRT is not available initially. For example, intensity‐modulated radiotherapy (IMRT),Therefore, the purpose of this study was to compare the dosimetric characteristics of five different treatment planning techniques for LA‐NSCLC with sequential plan changes.This study was approved by the Institutional Review Board (IRB) of the University of Yamanashi (no.: 2271). A total of 13 patients who underwent CRT for LA‐NSCLC between January 2016 and January 2020 at our hospital were included in the study, with different CT scans for the initial plan (pre 40 Gy) and boost plan (post 40 Gy). CT images were obtained using the Abches respiratory management device .Treatment plans were recalculated for this study. We employed five different treatment planning methods Figure . For allAfter the initial (40 Gy/20 Fr) and boost (20 Gy/10 Fr) plans were created for each CT image, deformable dose accumulation was performed on the boost CT image to create a summed dose distribution. Synergy with an agility gantry head (Elekta AB) was used for radiation therapy and the RayStation version 10A (RaySearch Laboratories) was used for the treatment planning. The X‐ray energy was 6 MV, the dose calculation algorithm was a collapsed cone convolution, and the grid size was 2 mm. Hybrid intensity‐ and structure‐based deformable image registration were used for deformable dose accumulation.The five treatment planning methods follow.The initial plan was formulated using two anterior–posterior (AP) irradiation directions, whereas the boost plan utilized two to four irradiation directions with an added oblique entrance to spare the spinal cord. A representative beam arrangement is illustrated in Figure In this method, beam alignment was performed using the 3DCRT optimization function in RayStation. We set six beams at 60‐degree intervals around the gantry to optimize the gantry angle, collimator angle, irradiation field shape, and monitor unit (MU) values. Because noncoplanar beams were not utilized, the couch angle remained fixed. The initial and boost plans were implemented using the same methodology. A representative beam arrangement can be seen in Figure 1–2 partial arc VMAT was performed. The same geometry was applied to both the initial and boost plans. A representative beam arrangement is shown in Figure For the initial plan, the F‐3DCRT with AP irradiation created in (a) was used. For the boost plan, the VMAT created in (c) was used. A typical beam arrangement is shown in Figure The beams were configured using two fixed IMRT (AP irradiation) combined with 1–2 partial arc VMAT. The same geometry was maintained for both the initial and boosted plans. These plans were crafted using the co‐optimization function of RayStation. A representative beam arrangement is shown in Figure 98%, D2%, Dmean, and conformity index [CI]), lung , spinal cord Dmax, heart Dmean, and esophageal Dmean were calculated. CI was calculated using the following formula:TVRI was the target volume covered by the reference isodose, 𝑇𝑉 was the target volume, and VRI was the volume of the reference isodose. The reference isodose was 40 Gy for initial plan and 20 Gy for boost plan. In addition, total MU values were investigated to assess the complexity of treatment planning and the impact of low‐dose exposure. All statistical analyses were performed using the JMP Pro 17.0 (SAS institute) with a Wilcoxon text and a p‐value <0.05 was considered statistically different.In this study, dosimetric comparison was performed by summing the dose distributions of the initial and boost doses. For each dose, the PTV (Dp < 0.05). PTV volume was 397.65 ± 384.51 cc for the initial and 287.29 ± 238.96 cc for boost plans (p < 0.05). Normal lung volume was 3889.07 ± 620.43 cc for the initial and 3882.59 ± 647.36 cc for boost plans (p = 0.946).Patient characteristics are shown in Table A comparison of representative dose distributions is shown in Figure p‐values for the different irradiation methods. The CI for VMAT and hybrid was >0.8. In particular, the VMAT technique showed better results for the PTV dose indices of D98% and D2%. However, there were no significant differences among the different irradiation techniques with respect to Dmean. Further, lung V20Gy was lower with the VMAT technique, especially hybrid, which showed a significant reduction compared to F‐3DCRT (p < 0.05); MLD was also better with hybrid than with the other irradiation techniques (p < 0.05). In contrast, the VMAT and hybrid groups showed higher V5Gy values. For the spinal cord, all techniques complied with the constraint of 50 Gy or less. Furthermore, no significant differences were observed between the irradiation techniques with regard to heart Dmean and esophageal Dmean. The MU values tended to be higher for techniques that used VMAT, especially for the hybrid.Table p‐values comparing initial plan extensions and sequential plan changes. For the heart, modifications in I‐3DCRT and VMAT led to a significant dose reduction (p < 0.05), while the hybrid resulted in a significant dose increase. For the lung dose index, there was no significant improvement observed between treatment strategies with or without plan changes. In addition, for CI, the initial plan extension on the boost CT image was poorer than on the initial CT image, especially in high‐precision irradiation methods like VMAT and hybrid. This indicates that the initial plan did not adapt to tumor changes.As part of an additional experiment, we compared dose indices between the extension of the initial plan for all fractions and sequential plan changes across the three plans  on both the initial and boost CT images. Table Although treatment planning for LA‐NSCNC traditionally utilized 3DCRT, the effectiveness of techniques involving IMRT and VMAT has been demonstrated frequently.The CI for all techniques using VMAT was better than that obtained using 3DCRT. This is likely because VMAT irradiates from multiple directions, resulting in a higher dose uniformity than 3DCRT. The similarity in CI between hybrid and VMAT is in agreement with previous reports.20Gy showed a decreasing trend with the use of VMAT, whereas it was better with the use of hybrid  in comparison with previous reports ,5Gy increased significantly with the use of VMAT compared with 3DCRT, similar to that observed in previous reports.In context of the normal lung dose, V20Gy while improving the target CI compared with conventional F‐3DCRT. However, setting dose constraints, confirming the irradiation field, and determining other geometrical parameters are necessary for appropriate use. Regarding the change in treatment plan from F‐3DCRT to VMAT , a significant improvement in dose distribution  was confirmed compared to continuing with F‐3DCRT, and a reduction in the spinal cord dose was also possible, as well as a reduction in lung V5Gy. This suggests that if IMRT is not ready by the start of the initial planning, treatment may be initiated with 3DCRT. In addition, focusing on the heart, the MHD was similar between IMRT and 3DCRT in the present study, in agreement with the findings from previous studies.As for I‐3DCRT, it was possible to reduce the lung VThe hybrid technique demonstrated favorable dose characteristics; however, its high MU value is a notable concern. A shorter irradiation time is preferable when considering respiratory motion management such as breath‐hold, and a lower MU value is required to minimize low‐dose exposure.This study had some limitations. First, this study was conducted at a single institution using a single treatment planner. Second, our study used a relatively small number of coplanar beams; therefore, studies on noncoplanar beams or increase in number of beams has not been conducted. Third, the optimal planning method may differ depending on the shape and location of the tumor. In this study, the number of cases was small, and each site was not examined separately. Therefore, further studies focusing on the tumor location are required. Fourth, the evaluation based on the boost CT might be subject to significant uncertainties related to lung volume changes and the deformable dose accumulation between the initial CT and the boost CT. Due to the limited number of cases in this study, a more detailed investigation of this influence is necessary.20Gy and V5Gy, but it should be noted that the MU value was higher. 3DCRT not only reduced exposure in the low‐dose region of the lungs but also may be used if IMRT is not ready by the start of initial planning.In conclusion, this study compared the dosimetric characteristics of five different treatment planning techniques for LA‐NSCLC with sequential plan changes. The ART might be a useful tool for target shape changes, while offline‐ART with just one replanning might not provide sufficient reduction in lung dose throughout the treatment duration. The target CI was improved by using VMAT‐based techniques. In particular, the hybrid technique reduced the lung VAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, M.S and H.O.; Resources, M.S, T.K., K.M., S.A., T.A., M.M., N.S., H.S., U.K., H.N, and H.O.; Methodology, M.S.; Formal Analysis, M.S, and H.O.; Writing – Original Draft Preparation, M.S and H.O.; Writing – Review & Editing, M.S, T.K., K.M., S.A., T.A., M.M., N.S., H.S., U.K., H.N, and H.O.There is no conflict of interest with regard to this manuscript.


The pathological results after surgery were used to assess the degree of pathological response. The scan parameters of 18F‐FDG PET/CT and their changes before and after NICT were compared with the pathological response.The clinical data of 54 patients with ESCC who underwent two cycles of NICT followed by surgery were retrospectively analyzed. NICT consisted of PD‐1 blockade therapy combined with chemotherapy. Among the 54 patients, 10 (18.5%) achieved complete pathological response (pCR) and 21 (38.9%) achieved major pathological response (MPR). The post‐NICT scan parameters and their changes were significantly associated with the pathological response. In addition, the values of the changes in the scanned parameters before and after treatment can further predict the pathological response of the patient.18F‐FDG PET/CT is a useful tool to evaluate the efficacy of NICT and predict pathological response in patients with ESCC. The post‐NICT scan parameters and their changes can help identify patients who are likely to achieve pCR or MPR. 18F‐FDG PET/CT scans were used before and after NICT to measure the changes in tumor metabolism and viability, and compared with the pathological response after surgery.18F‐FDG PET/CT scan parameters and their changes were found to be significantly associated with the pathological response, and could help identify patients who achieved complete or major pathological response.The efficacy of neoadjuvant immunochemotherapy (NICT) with PD‐1 blocked and chemotherapy was evaluated in 54 patients with esophageal squamous cell carcinnoma (ESCC) who underwent surgery after two cycles of NICT.  Previous studies have demonstrated the superiority of neoadjuvant chemoradiotherapy for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC).18F‐fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is a common technique for radiological staging of advanced ESCC18F‐FDG PET/CT parameters can accurately predict pCR after neoadjuvant immunochemotherapy in resectable ESCC.18F‐FDG PET/CT parameters in assessing the pathological response of ESCC.This real‐world study collected data from patients who underwent neoadjuvant immunochemotherapy and esophagectomy and investigated the role of This was a single center prospective real‐world study, approved by the Ethics Committee of the Sixth Medical Center of PLA General Hospital. The study included patients with esophageal squamous cell carcinoma who underwent neoadjuvant immunochemotherapy and esophagectomy at the Department of Thoracic Surgery, the sixth Medical Center of the Chinese PLA General Hospital, from January 2020 to December 2022. The patients underwent PET/CT examinations according to their clinical treatment assessment and provided informed consent for all treatments and examinations. We selected the pathological response after surgery as our primary endpoint, and evaluated it according to the Mandard tumor regression grade (TRG) system. All patients continued treatment and follow‐up after the experimental observation endpoint.The inclusion criteria were: age between 18 and 80 years; histologically or cytologically confirmed esophageal squamous carcinoma; and no prior radiotherapy, chemotherapy, or surgery for the tumor. The exclusion criteria were: prior immunotherapy or known allergy to monoclonal or chemotherapeutic agents; history of other critical illnesses such as multiorgan failure, widespread infection, shock, stroke, or any vascular embolic event within 6 months before enrollment; severe malnutrition; or other primary malignancies. Patients who did not receive a PET/CT scan 1 week before surgery were also excluded from the analysis.The patients received two cycles of neoadjuvant immunochemotherapy (NICT) before surgery, tailored to their individual conditions. The NICT consisted of intravenous lobaplatin (40 mg) and paclitaxel (400 mg) on day 1, and intravenous PD‐1 monoclonal antibody (200 mg) on day 2. The PD‐1 monoclonal antibodies used were sintilimab, camrelizumab, or tislelizumab. The NICT was repeated on day 15, and surgery was performed 2 weeks after the second cycle. The surgical procedure was esophagectomy with lymph node dissection.18F‐FDG as the tracer (provided by China Atomic High Tech). The patients fasted for 6 h before the scan and had their blood glucose levels checked (4.5–6.5 mmol/L). They received an intravenous injection of 18F‐FDG (185–370 MBq) based on their body mass and rested for about an hour before the scan. The scan covered the region from the cranial apex to the mid‐femur, starting with a fluoroscopic acquisition, followed by a CT scan , and then a 3D emission acquisition . The CT data were used for attenuation correction and reconstructed using ordered subsets expectation maximization (OSEM). The fused images were processed with GE AW workstation software.The patients underwent PET/CT imaging using a GE Discovery ST16 scanner with max), mean standardized uptake value (SUVmean), MTV, and TLG of the lesions at different sites. The SUVmax of the blood pool at the aortic arch (10 mm diameter) without including the vessel wall was measured, and the ratio of the SUVmax of the lesion to the SUVmax of the blood pool was calculated as SUVTBR. The changes in these parameters before and after treatment are expressed as percentages; for example, ΔSUVmax % = (Scan 1 SUVmax – Scan 2 SUVmax)/Scan 1 SUVmax × 100%.Two experienced nuclear medicine physicians visually assessed the PET/CT images to determine the extent and morphology of the lesions and the areas of increased FDG uptake. The PET/CT scans of patients before neoadjuvant immunochemotherapy (scan 1) and before surgery (scan 2) were recorded and compared. Semi‐quantitative analysis was performed using volumetrics to measure the maximum standardized uptake value  staining. The specimens were independently analyzed by two senior pathologists. The patients were classified into four groups based on the tumor regression score (TRS) according to the Mandard scoring system: pCR , non‐pCR , MPR , and non‐MPR .We recorded the duration of treatment for each patient, and created a swimmer plot based on their imaging, pathological, and pathological response data using Microsoft Excel. A swimmer plot is a graphical tool that can display the temporal dynamics of individual patients in a clinical trial. The plot can visually show the distribution and association of imaging and pathological results among patients.t‐test, Welch's t‐test, or Wilcoxon test depending on whether the data met the normal distribution and chi‐square test assumptions. For categorical variables, if the condition of 5 > theoretical frequency ≥1 and total sample size ≥40 was satisfied, the continuous corrected chi‐square test (Yates' correction) was used for comparison between groups. The patients were divided into pCR and non‐pCR groups, and MPR and non‐MPR groups based on postoperative pathological findings. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of each metabolic parameter index. The area under the ROC curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy with their 95% confidence intervals (95% CI) were calculated. The critical values for ROC curve analysis were calculated based on the Youden index. The differences in ROC curves were tested by DeLong's test. All data analyses were performed using R software (version 4.2.1) and the corresponding R package.The data were collected according to the actual condition of the patients and summarized by frequency and proportion for categorical variables. For numerical variables, descriptive statistics are reported as mean ± standard deviation or median (interquartile range), depending on whether the data followed a normal distribution, which was tested by the Shapiro–Wilk normality test. The homogeneity of variance was tested by Levene's test (based on mean). The comparison between two groups was performed by max, SUVmean, and SUVTBR were significantly lower in the pCR group than in the non‐pCR group (p < 0.05), and also lower in the MPR group than in the non‐MPR group (p < 0.05). Moreover, the changes in metabolic parameters from scan 1 to scan 2 (Δmetabolic parameters) differed significantly between the groups, except for ΔMTV. ΔSUVmax, ΔSUVmean, ΔSUVTBR, and ΔTLG were significantly lower in the pCR group than in the non‐pCR group (p < 0.05) and also lower in the MPR group than in the non‐MPR group (p < 0.05).This study enrolled 63 patients with esophageal squamous cell carcinoma between January 2020 and December 2022 and excluded nine patients who had prior treatment or did not undergo PET/CT before surgery. The final sample comprised 54 patients who received two cycles of neoadjuvant immunochemotherapy followed by esophagectomy Figure . Tables In addition, we created a swimmer plot based on the treatment status of 54 patients and found that the tumor regression status measured by PET/CT examination was consistent with the tumor regression status reported by pathological analysis Figure . The swit‐tests. Tables p‐values of the metabolic parameters by group. No significant differences in scan 1 parameters were found between the groups (p > 0.05). However, in scan 2, the pCR group had significantly lower SUVmax, SUVmean, and SUVTBR than the non‐pCR group (p < 0.05), and the MPR group had significantly lower SUVmax, SUVmean, and SUVTBR than the non‐MPR group (p < 0.05). The changes in metabolic parameters from scan 1 to scan 2 (Δmetabolic parameters) were also calculated and showed that ΔSUVmax, ΔSUVmean, ΔSUVTBR, and ΔTLG were significantly lower in the pCR group than in the non‐pCR group (p < 0.05), and also lower in the MPR group than in the non‐MPR group (p < 0.05). The only exception was ΔMTV, which did not differ significantly between the groups (p > 0.05).The metabolic parameters of PET/CT scans before (scan 1) and after (scan 2) neoadjuvant treatment were compared between different pathological response groups using TBR (AUC = 0.760) showed a significant ability to discriminate between pCR and non‐pCR patients , SUVmean (AUC = 0.891), and SUVTBR (AUC = 0.870) were all significant predictors of pCR. Among them, SUVmean had the highest AUC value  with a cutoff value of 2.188, resulting in a PPV of (9/54) 47.3% and a NPV of (34/54) 97.1% (Table max (AUC = 0.840), ΔSUVmean (AUC = 0.913), and ΔSUVTBR (AUC = 0.893) were all significant predictors of pCR.To examine the predictive value of metabolic parameters for pCR, ROC analysis was performed using scan 1 and scan 2 parameters Table . In scans Figure . In scan1% Table . No sign1% Table . ΔSUVmaxTBR (AUC = 0.768) was a significant predictor of MPR , SUVmean (AUC = 0.720), and SUVTBR (AUC = 0.745) were all significant predictors of MPR , ΔSUVmean (AUC = 0.947), ΔSUVTBR (AUC = 0.965), and ΔTLG (AUC = 0.846) were all significant predictors of MPR  with a cutoff value of 0.572, resulting in a PPV of (12/31) 85.7% and a NPV of (17/31) 100%. The ROC curves of these parameters were significantly different from each other using DeLong's test. Figure The ROC analysis for identifying MPR yielded similar results to those for identifying pCR Table . In scanR Figure . In scanR Figure . Among tR Figure . ΔSUVTBR18F‐FDG PET/CT for the pathological response of ESCC following neoadjuvant immunochemotherapy. In contrast to Wang et al., this study employed multiple PD‐1 inhibitors, which enhanced its validity. The study retrospectively analyzed 54 patients and examined the association between 18F‐FDG PET/CT and pathological response, with the aim of identifying patients with pCR, MPR, and non‐MPR after neoadjuvant immunochemotherapy. The results indicated that SUVmax, SUVmean in scan 2 and ΔSUVmax, ΔSUVmean, ΔSUVTBR had high predictive accuracy for the pCR and MPR of ESCC.This study investigated the prognostic significance of max , SUVmean  in scan 2, and ΔSUVmax , ΔSUVmean , and ΔSUVTBR  had a significant association with pCR with sensitivity of 90%, 90%,100%, 100%, 100%, specificity of 81.8%, 77.3%, 72.0%, 80.0%, 80.0%, and PPV of 52.9%, 47.4%,46.2%, 54.5% 54.5%, respectively. These results confirmed that 18F‐FDG PET/CT is a reliable method to evaluate pathological response after NICT. The role of SUVmax was inconsistent in previous studies. Some studies reported that SUVmax of 18F‐FDG PET/CT was not a strong predictor of pathological response of ESCC after NCRT due to esophagitis.max after nCRT.max and SUVmean were adequate predictors of pCR after NICT (AUC 0.848),mean, Hu et al. found that SUVmean was significantly higher in nonresponders than in responders. Receiver operating characteristics curve analysis identified SUVmean  as significant predictors of the response to concurrent chemoradiotherapy.TBR might have better predictive performance in ESCC after NICT. To the best of our knowledge, only the study by Wang et al. investigated SUVTBR in ESCC. In their study, SUVTBR (AUC 0.860) was better than ΔSUVTBR (AUC 0.668). However, our study showed that ΔSUVTBR (AUC 0.893) was better than SUVTBR (AUC 0.870) because of higher specificity (80% vs. 68.2%). The above differences between the study by Wang et al. and our study might be due to three aspects.This study showed that SUV18F‐FDG PET/CT in predicting the major pathological response to NICT of resectable ESCC. In this study, we further evaluated the predictive performance of 18F‐FDG PET/CT in ESCC patients. ΔSUVmax , ΔSUVmean  and ΔSUVTBR  were associated with MPR with sensitivity of 100%, 91.7%, 100%, specificity of 84.2%, 89.5%, 89.5% and PPV of 80.0%, 84.6%, 85.7%, respectively. Unlike the first half of this study, metabolic parameters of scan 2 had poor predictive performance in assessing MPR.NICT has brought remarkable changes to ESCC treatment for its impressive pCR and MPR rate and tolerable adverse effect rate.max on pre‐ or post‐treatment 18F‐FDG PET/CT, as well as a (relative) change in SUVmax, were analyzed. However, SUVmax or reduction of SUVmax had poor predictive performance in ESCC patients.mean and TLG after IC (scan 2) were related to MPR in ESCC patients who received NCRT.max, MTV, and TLG played a role in identifying MPR, but the AUC of ROC in predicting MPR was 0.70 (95% CI: 0.65–0.92) for ΔSUVmax, and 0.73 (95% CI: 0.58–0.88) for both MTV and TLG.18F‐FDG PET/CT in ESCC patients who received NICT.Previous studies have examined the association between PET/CT and major pathological response.18F‐FDG PET/CT for predicting pCR in resectable ESCC after NICT.18F‐FDG PET/CT is also a good predictor of MPR as shown in this study. Future clinical trials are needed to determine SUV threshold and cutoff value for pCR and MPR assessment.Identifying pCR and MPR is a clinical challenge. For patients with pCR, active surveillance may be sufficient. For patients with MPR, they may achieve pCR after another 1–2 cycles of NICT. Whether surgery is necessary for patients with pCR should be confirmed by further randomized controlled trials. However, it is crucial to find an accurate assessment of residual disease after NICT. A previous study and our study demonstrated the excellent performance of 18F‐FDG PET/CT for lymphatic metastasis in future research.Furthermore, we noticed that our analysis results were not entirely consistent with some previously published articles.18F‐FDG PET/CT is an excellent tool to predict pCR and MPR after NICT in patients with locally advanced ESCC. Future studies are still required to investigate the detailed SUV threshold and cutoff value of 18F‐FDG PET/CT. Additionally, studies with longer follow‐up time will elucidate the role of 18F‐FDG PET/CT in predicting the overall survival of ESCC after NICT. We also expect that more high‐quality and high‐sensitivity PET imaging probes and methods will provide more accurate and comprehensive diagnosis and evaluation for ESCC patients in the future.In summary, this study showed that SW, SD and JL: designed the study, analyzed experimental data and drafted the manuscript. SX: participated in the experiment and manuscript preparation. ZY: analyzed experimental data. TG and YL: conceived the study, evaluated the data, and prepared the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by Innovation Cultivation Fund of the Sixth Medical Center of PLA General Hospital (no. CXPY202003).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Heart failure (HF) is a common cause of morbidity and mortality, related to a broad range of sociodemographic, lifestyle, cardiometabolic, and comorbidity risk factors, which may differ according to the presence of atherosclerotic cardiovascular disease (ASCVD). We assessed the association between incident HF with baseline status across these domains, overall and separated according to ASCVD status.We included 5758 participants from the Baker Biobank cohort without HF at baseline enrolled between January 2000 and December 2011. The primary endpoint was incident HF, defined as hospital admission or HF‐related death, determined through linkage with state‐wide administrative databases (median follow‐up 12.2 years). Regression models were fitted adjusted for sociodemographic variables, alcohol intake, smoking status, measures of adiposity, cardiometabolic profile measures, and individual comorbidities. During 65 987 person‐years , incident HF occurred among 784 participants (13.6%) overall. Rates of incident HF were higher among patients with ASCVD  compared with those without ASCVD . Incident HF was associated with age, socio‐economic status, alcohol intake, smoking status, body mass index (BMI), waist circumference, waist–hip ratio, systolic blood pressure (SBP), and low‐ and high‐density lipoprotein cholesterol (LDL‐C and HDL‐C), with non‐linear relationships observed for age, alcohol intake, BMI, waist circumference, waist–hip ratio, SBP, LDL‐C, and HDL‐C. Risk factors for incident HF were largely consistent regardless of ASCVD status, although diabetes status had a greater association with incident HF among patients without ASCVD.Incident HF is associated with a broad range of baseline sociodemographic, lifestyle, cardiometabolic, and comorbidity factors, which are mostly consistent regardless of ASCVD status. These data could be useful in efforts towards developing risk prediction models that can be used in patients with ASCVD. Despite improvements in treatment strategies and mortality rates for heart failure (HF), prevalence remains high, and some studies suggest a rising incidence among younger adults in the United States.Some studies have suggested that risk factors for incident HF may differ dependent on prior myocardial infarction status. However, existing prediction models for incident HF are largely targeted at individuals without any concomitant cardiovascular disease (CVD)The present study sought to determine the relationship between a broad range of baseline sociodemographic, lifestyle, cardiometabolic, and comorbidity factors using longitudinal data from the Baker Biobank study overall and according to ASCVD status. Moreover, we aimed to appropriately account for the competing risk of non‐HF‐related death and assess for the presence of non‐linear relationships, which are increasingly recognized in the medical literature and are inconsistently accounted for in prior HF risk factor studies.This study was approved by the Alfred Human Research Ethics Committee (EC 357/09), and approval for data linkage was provided by the Australian Institute of Health and Welfare Ethics Committee (EC/2009/4/51). All patients gave written, informed consent to participate in the study. The reporting of this study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.The Baker Biobank is a CVD database in Australia that collected data on 6531 individuals aged 18–69 years between January 2000 and December 2011. Participants were recruited from hospital and health check clinics and included those with established CVD or with at least one risk factor for CVD (including obesity).Given that the purpose of the present study was to examine factors associated with development of incident HF, patients with a previous history of HF were excluded from the analysis. Patients not matched to the VAED or NDI datasets and therefore without any follow‐up data were also excluded.2), waist measurements (cm), and waist–hip ratios were determined by registered nurses and/or trained study personnel according to standard procedures and definitions.Baseline medical history, including comorbidities and medication history, was determined from patient self‐report and medical records at the time of the initial Baker Biobank consultation. Socio‐economic status was determined using the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), derived from 2016 Australian Bureau of Statistics national census data. A percentile ranging from 0 (lowest) to 100 (highest) is calculated according to residential postcode based on household income, education level, unemployment rate, internet availability, and home and vehicle ownership. Alcohol intake  and smoking status  were determined by participant self‐report. Baseline body mass index , high‐density lipoprotein cholesterol (HDL‐C), triglycerides, and fasting glucose were measured immediately following baseline blood sampling as previously described.TablePatients were grouped according to ASCVD status defined as self‐reported myocardial infarction, coronary artery disease, previous coronary artery bypass graft surgery, previous coronary stenting, stroke, or peripheral vascular disease at baseline. Patients who had a linked admission for a diagnosis relating to ASCVD prior to an admission for HF were also included in the ASCVD group  admission to hospital with HF recorded as a primary or non‐primary VAED diagnosis at discharge or (ii) death with HF recorded as a primary or non‐primary cause. HF hospitalization diagnosis in VAED and cause of death were defined according to International Classification of Diseases 10 Australian Modification (ICD‐10‐AM) with specific codes detailed in Supporting Information, TableMissing data  by comparing nested models with and without the variable of interest. P‐values for non‐linearity (P‐non‐linear) were calculated by comparing nested models with spline terms vs. nested models with linear terms. P‐values for interaction (P‐interaction) according to ASCVD status were calculated by comparing nested models with and without multiplicative interaction terms between ASCVD and the variable of interest.We performed several secondary analyses using Cox regression models. In these models, non‐HF‐related death was censored rather than included as a competing risk to facilitate the assessment of non‐linear effects and interactions according to ASCVD status. Models were adjusted for the same parameters as in the primary analysis. Continuous variables  were fitted as restricted cubic splines with three to five knots selected according to the number of knots minimizing the Akaike information criteria. The median value for the variable of interest was used as the reference point for plots of restricted cubic spline curves. Likelihood ratio tests were used to calculate Finally, we performed a sensitivity analysis repeating the primary analysis using a complete case approach to account for missing data rather than multiple imputation to assess the robustness of the primary results.rms, ggplot2, ggsurvfit, tidycmprsk, hmisc, mice, and survival packages.All analyses were conducted using R Version 4.2.2 using the In total, 6531 participants were included in the Baker Biobank. Participants without follow‐up data (71 people) and those with a history of HF (702 people) and those without follow‐up data were excluded, leaving 5758 participants in the analysis. Over a median follow‐up of 12.6 years [interquartile range (IQR) 8.1–15.1 years], representing 65 987 person‐years of follow‐up, incident HF occurred in 784 (13.6%) participants.Table Of the cohort, 1929 participants (33.5%) had a history of ASCVD, while 3829 participants (66.5%) did not. Rates of incident HF during follow‐up were 32.4% (624 participants) in the ASCVD group and 4.2% (160 participants) in the non‐ASCVD group Table 1.TableMedian age at enrolment was 59 years (IQR 47–69 years), and 38% were women. Participants who developed incident HF were older at enrolment (median 70 vs. 57 years) and more commonly male (66% vs. 61%). Differences in baseline characteristics between patients with ASCVD and those without ASCVD according to incident HF status are shown in Figure In adjusted Fine–Gray sub‐distribution hazard models, older age, lower socio‐economic status, current or previous smoking status, valvular heart disease, chronic kidney disease, diabetes mellitus, hypertension, stroke, myocardial infarction, coronary artery disease, and coronary bypass grafts were independently associated with risk of incident HF, while alcohol intake was inversely associated with incident HF risk Figure 1.Figure Minor differences in risk factors were present according to ASCVD status Figure 2. SpeciFigure In the primary analysis, greater waist–hip ratio and waist circumference were associated with higher risk of incident HF, and greater LDL‐C was inversely associated with incident HF risk Figure 3. AssocFigureP‐non‐linear < 0.05). Lower socio‐economic status was associated with increased risk below the median IRSAD percentile (87th percentile) and reduced risk above the median. Zero alcohol intake appeared to be associated with greater incident HF risk, while mild–moderate intake was associated with reduced risk.Secondary analyses assessing overall associations and non‐linearity for continuous sociodemographic and cardiometabolic variables using Cox regression models and restricted cubic splines are shown in P‐non‐linear < 0.05). For BMI, incident HF risk was greater above the median (27 kg/m2) but not reduced below the median, while for waist circumference, risk increased in a more proportional manner. SBP appeared to be inversely associated with HF risk, with higher risk among patients with lower baseline blood pressure. Risk of incident HF was higher for patients with lower baseline values for LDL‐C and HDL‐C.BMI, waist circumference, waist–hip ratio, SBP, LDL‐C, and HDL‐C were each associated with incident HF risk in adjusted Cox models, while DBP, fasting glucose, and triglycerides were not. Evidence for non‐linear associations was present for BMI, waist–hip ratio, SBP, and HDL‐C  or as separate ASCVD‐specific models.The influence of sociodemographic and lifestyle factors on HF development has been widely assessed.Most measures of cardiometabolic profile were associated with incident HF risk. Multiple studies have identified a relationship between measures of obesity and body fat and incident HF risk, but the non‐linearity of this relationship is not well established.The limited differences in risk factor significance between patients with ASCVD and those without ASCVD were somewhat surprising and contrast previous data regarding patients with and without a history of myocardial infarction. Among people hospitalized with HF, 56% have a comorbid diagnosis of ischaemic heart disease,This study has several limitations. The Baker Biobank is not fully representative of the wider Australian population. For example, a greater number of participants had high socio‐economic status according to postcode‐derived IRSAD percentile compared with the general population. Some lifestyle variables, such as exercise quantity and dietary factors, were not available in the dataset, hence limiting the assessment of lifestyle measures to alcohol quantity and smoking status. The study also relied on associations for individual measures at baseline only and data were not collected on changes in these factors across serial visits.In this prospective cohort study of middle‐aged and older adults free from HF at baseline, incident HF was associated with a broad range of baseline sociodemographic, lifestyle, cardiometabolic, and comorbidity factors, including age, socio‐economic status, smoking status, alcohol intake, BMI, waist circumference, SBP, and cholesterol profile. Risk factors were largely comparable between patients with ASCVD and those without ASCVD, although diabetes status had a greater association with incident HF among patients without ASCVD. These findings highlight the broad range of factors that should be considered in developing improved population‐ and individual‐level preventative strategies for incident HF and could be useful in efforts towards developing risk prediction models that can be used in patients with ASCVD.L.D. is supported by National Health and Medical Research Council of Australia (NHMRC) and National Heart Foundation (NHF) postgraduate scholarships. D.K. and D.S. are supported by NHF and NHMRC grants. M.J.C. receives an endowed fellowship in the Cardiology Centre of Excellence from Filippo and Maria Casella.The study was supported by a programme grant from the National Health and Medical Research Council.Table S1. International Classification of Disease 10 definitions for admissions relating to atherosclerotic cardiovascular disease.Table S2. International Classification of Disease 10 definitions for heart failure incidence.Table S3. Rates of missing baseline data in the Baker Biobank dataset.Figure S1. Sensitivity analysis using complete case approach for Figure 1.Figure S2. Sensitivity analysis using complete case approach for Figure 2.Figure S3. Sensitivity analysis using complete case approach for Figure 3.Methods S1. R code used for analyses.Click here for additional data file.


Squamous cell carcinoma (SCC) is a relatively common and heterogenous malignancy of different organs, such as the skin, esophagus, and lungs. Although most cases experience good survival with surgical methods, management of advanced types of the disease remains challenging. Several modalities, including different chemotherapy regimens and immunotherapies, have been investigated in this matter, among which Monoclonal antibodies (Mabs) are one of the most promising ones. Since the development of Mabs, they have been widely used to treat different diseases. Mabs have shown significant efficacy with high specificity along with acceptable safety, which makes them a favorable option in cancer therapy. In this article, we aimed to review the different aspects of using Mabs in SCC therapy.We found that treating with different Mabs has shown excellent efficacy accompanied by acceptable safety in treating SCC of different organs. Therefore, Mabs are considered great options in the treatment of SCC, especially in advanced cases. Overall, two highly potent types of Mabs in SCC therapy are anti‐EGFR Mabs and checkpoint inhibitors, especially Cetuximab, Nimotuzumab, and PD‐1 inhibitors. Bevacizumab is also a promising option as adjuvant therapy to other modalities.Although some Mabs have shown promising outcomes in SCC therapy, their application as a part of cancer treatment depends on further investigations regarding cost‐effectiveness and predictors of response. FDA has approved several Mabs in SCC therapies, and Mabs may have a crucial role in this era in the near future, especially in treating head and neck and esophageal SCC and metastatic lung cancer. We extracted articles related to Mab and SCC treatment up to June 2022. Medical Subject Headings (MeSH) terms were included. We obtained the full texts of relevant articles, and the relevant articles in the reference lists were also searched manually Figure .3The immune system's ability to recognize foreign cells enables the body to defend against cancerous cells.Enhancing knowledge about the mentioned mechanisms has provided several potential occasions to target tumor pathogenesis. The growth factor receptors activate along with the tumor progression. Mabs may decrease tumor activities by inactivating the binding of the ligands to these receptors or by blocking signaling. This mechanism can ultimately lead to cell death induction or increased sensitivity of tumor cells to therapeutic drugs.Consequently, Mabs provided unbelievable oncological purposes in several approaches.Using Mabs alone or in combination with other methods showed encouraging outcomes in controlling SCC.44.1in vitro and in vivo. EGFR gene amplification and EGFR tyrosine kinase domain mutation were shown to happen in patients with carcinoma. Appealingly both of these EGFR genetic changes are frequently responsive to EGFR targeting agents.Studies have proven the role of EGFR in the pathogenesis and progression of various cancers. Such as colorectal carcinoma and pancreatic carcinoma. The overexpression of EGFR and EGF‐like peptides is common in human carcinomas, and evidence has shown that these proteins promote cell transformation 4.1.1Cetuximab (Erbitux2), a high‐affinity recombinant Immunoglobulin G1 (IgG1), inhibits ligand binding and promotes EGFR interiorization and downregulation.The overactivation and high expression of EGFR in almost all HNSCC cases (over 90%) have been reported.Controversial findings on cetuximab efficiency and toxicity have been reported.In a non‐randomized, phase II clinical trial by Sacco et al., 33 patients with R/MHNSCC were treated with Pembrolizumab and Cetuximab regimens. The patients were at least 18 years old with no previous history of immunotherapy. Given to median follow‐up duration = 7.3 months (3.9–10.9), overall response rate was 45% .the most common adverse effect was oral mucositis, and no death occurred.n = 30) in comparison to a dual combination of Cetuximab with Avelumab  in patients with aSCAC . Overall response rate were 10%  versus 17% , respectively. Disease control rate were 50%  versus 57% . At a median follow‐up of 26.7 months (IQR 26.5%–26.9%), median PFS were 2 months  versus 3.9 months . median OS were 13.9 months  versus 7.8 . The results emphasized the promising role of dual therapy of EGFR and PD‐L1 inhibitors in the future.In another phase II randomized clinical trial, Lonardi et al. evaluated the efficacy of Avelumab alone  therapy, and nivolumab therapy were all used to treat him.Even though he had attained long‐term survival (>3 years), tumor growth was noticed shortly after starting nivolumab treatment. Nakao et al. opted to use cisplatin with gemcitabine in conjunction with necitumumab (every 3 weeks on days 1 and 8) therapy because his performance status was 1 at the end of nivolumab therapy as a fifth‐line therapy, and he was in good overall condition. After one session of treatment, the tumor shrank significantly in comparison to the baseline partial response (2).4.1.6In clinical trials, the epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) showed anti‐cancer effectiveness against malignancies such as non‐small cell lung cancer and HNSCC. Factors that may predict response to gefitinib have been discovered through research on non‐small cell lung cancer. The molecular markers that may predict response to gefitinib in HNSCC patients are poorly understood. Erjala et al. investigated putative connections between the gefitinib responsiveness and molecular markers of the EGFR/ErbB receptor family signaling pathway. Clonogenic survival experiments were used to establish the IC50 of gefitinib sensitivity. Western and real‐time reverse transcription‐PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels, as well as phosphorylation study of pEGFR, pErbB2, pErbB3, pAkt, and pErk, were used to characterize ErbB signaling. cDNA sequencing and real‐time PCR were used to assess EGFR kinase domain sequences and EGFR gene copy numbers, respectively. Finally, the gefitinib response was compared to the anti‐EGFR antibody cetuximab (Erbitux). They found that In HNSCC, EGFR amplification may predict gefitinib susceptibility. Other members of the EGFR/ErbB receptor family may have a role in gefitinib resistance. ErbB2 and ErbB3 may be prognostic markers and therapeutic targets in treating HNSCC with gefitinib in combination therapy. According to their findings, in HNSCC, EGFR amplification may predict sensitivity and increase ErbB2/ErbB3 signaling resistance to the EGFR TKI gefitinib.In HNSCC, the majority of targeted treatments have focused on inhibiting EGFR. Combining EGFR inhibitors with medications that target other members of the ErbB family, such as pertuzumab, may provide further benefit to HNSCC targeted therapy. The findings suggest that analyzing ErbB receptor signaling characteristics may provide predictive information and that simultaneous targeting of EGFR and other ErbB family members may reduce HNSCC cell proliferation Table .4.2Studies have shown that the HER2 protein is highly expressed in most esophageal SCC. Human epidermal growth factor receptor 2 (HER2)/neu amplification or overexpression has also been an independent prognostic factor in Esophageal SCC (ESCC) patients. It was also noted that patients with HER2/neu amplification or overexpression might benefit from using Mabs as adjuvant therapy.4.2.1HER2 is a tyrosine‐kinase protein.Therefore, using gefitinib and trastuzumab together would be a valuable and promising approach in HNSCC.4.3The role of IGF‐1R, IGF‐1, and IGF‐2 signaling in the development, maintenance, and progression of cancers is well established.4.3.1Cixutumumab is a fully human Mab targeting IGF‐1R, which is involved in cancer development. Few studies on the efficiency of cixutumumab monotherapy and its combination with other methods demonstrated that this regimen shows no reliable restrictive effect on R/M HNSCC.4.4HGF/Met signaling is associated with oncogenesis and tumor progression in different malignancies, and it induces aggressive cellular invasiveness, which is related to tumor metastasis.4.4.1Onartuzumab is a humanized and monovalent Mab that targets MET receptors and inhibits the signaling of hepatocyte growth factor (HGF).4.4.2Ficlatuzumab is a potent humanized IgG1 Mab that binds the hepatocyte growth factor (HGF inhibitor), preventing the activation of the c‐Met pathway. It restricts HNSCC by restraining the proliferation and relocation of cancer cells and suppressing activation; therefore, based on this theory, Kumar et al. evaluated the impact of this novel Mab and concluded that ficlatuzumab viably mitigates stromal impacts on HNSCC progression.4.5VEGF expression has been correlated to tumor invasion, venous and lymphatic invasion, lymph node metastasis, and tumor stage in ESCC. Therefore, it may be involved in the progression of esophageal carcinoma via its angiogenesis and lymphangiogenesis effects.4.5.1Bevacizumab, a humanized IgG1 Mab, functions as an anti‐VEGF recombinant Mab with the affinity to bind all VEGF‐A isoforms.Besides, A middle‐eastern study proved bevacizumab as a promising treatment for HNSCC due to its negative effects on VEGF secretion.In addition, a combination of bevacizumab with cisplatin and radiation therapy improved the 2‐year OS and PFS with a few adverse events, such as a significant increase in myelosuppression and leukopenia.In a phase II study, adding bevacizumab to pemetrexed in patients with HNSCC enhanced median OS to 11.3 months and treatment rate to 30%; however, toxic outcomes of bevacizumab application included significant bleeding in 15%, neutropenia in 10%, and infection in 12.5% of the patients and one death due to sepsis.Twelve patients with Vulvar Squamous Cell Cancer (VSCC) were recommended targeted therapy and received one or more of bevacizumab, erlotinib, or pembrolizumab. The duration of therapy was 7 months. 10–15 mg/kg of bevacizumab was given intravenously every 3 weeks. The outcomes were CR: 22.2%, SD: 33%, and also TRAEs were seen in 75% of patients.4.6It has been reported that membranous HER3 expression is significantly related to poor prognosis in HNSCC patients. Thereby, it may be used as a potential target for immunotherapy.4.6.1Duligotuzumab is a human IgG1 dual HER3/EGFR binding Mab for overcoming drug resistance due to the extensive crosstalk between ErbB/HER receptors. It has also been reported that membranous HER3 expression is significantly related to poor prognosis in HNSCC patients. Thereby, it may be used as a potential target for immunotherapy.4.6.2For higher efficiency in cancer therapy, scientists aimed to design antibodies that can simultaneously affect more than one receptor.4.7CD44 is a transmembrane glycoprotein. Overexpression of CD44v6 shows poor prognosis in colorectal cancer, as patients with many CD44v6‐positive cells in their tumors are generally diagnosed at late stages. Anti‐CD44 therapy has good efficacies for a variety of cancers.4.7.1Bivatuzumab mertansine (BIWI 1) is a new CD44v6‐targeting humanized Mab with the toxin mertansine.5Immune checkpoints that are in interaction with their ligands, inhibit T cell activation pathways that are responsible for physiological immune responses to certain antigens. Various malignancies have high levels of immune checkpoints, and their ligand in the tumor microenvironment, which leads to blockage of the induction of appropriate anti‐cancer immune responses. Several immune checkpoint inhibitors have been developed, examined, and approved for treating various malignancies.5.1PD‐1 is predominantly expressed in T cells. Its interaction with PD‐L1 and PD‐L2 indicated in antigen‐presenting cells (APCs) and tumors sends a negative signal to T cells, which can cause T‐cell exhaustion.5.1.1PD‐1, a cytotoxic T‐cell response inhibitor molecule, contributes to skin cancer development.Nivolumab is a human IgG4 Mab that blocks the interaction between the PD‐1 receptor and PD‐L1 and PD‐L2 via binding to the PD‐1 receptor, leading to inhibition of T cell cytokine production and proliferation. A phase III study compared the effect of nivolumab and chemotherapy on unresectable recurrent or advanced ESCC. It demonstrated that nivolumab significantly improved the OS and had an acceptable safety profile.In a study conducted by Yamakawa et al., 143 patients were treated with nivolumab. 27.3% of patients showed overall response and the disease was controlled in 46.2% of them. The overall survival of the patients was 11.2 months and the progression‐free survival rate was 2.7 months.Matsubara et al. conducted a study to predict the efficacy of Nivolumab on esophageal SCC by combined positive score (CPS) and tumor proportion score (TPS). The mean progression‐free survival  and objective response rate  of patients with CPS ≥10, 1–10, and <1 had a downward trend, respectively.5.1.2In multiple tumor forms, pembrolizumab, a highly selective humanized IgG4 Mab to PD‐1 receptor, has demonstrated robust antitumor effects and a tolerable safety profile and is currently validated for one or even more progressive tumors treatment in more than 60 countries worldwide.Phase Ib KEYNOTE‐012 research showed that treating R/MHNSCC cases with particular pembrolizumab regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks) shows the highest survival rate and safety.Ferrarotto et al. evaluated the effects of pembrolizumab in 19 patients with advanced, refractory CSCC. The patients had a long‐term follow‐up of 44.1 months. The results indicated pembrolizumab to be effective and safe in this population; However, two patients (10%) experienced remarkable treatment‐associated side effects.One research paper evaluated 628 Asian patients with advanced or metastatic ESCC to compare the therapeutic effects of pembrolizumab with chemotherapy. There were 314 patients in each treatment group. The Pembrolizumab group demonstrated survival advantages over patients who were treated with chemotherapy. Additionally, Fewer treatment‐related complications emerged in the pembrolizumab‐treated patients, which confirmed the safety superiority of pembrolizumab over chemotherapy.In another study, a regimen including pembrolizumab and cetuximab was administered to 33 patients with metastatic or recurrent HNSCC. This combination resulted in promising clinical advantages with a 6‐month ORR of 45%, which exceeded the previously published ORR of monotherapy with each antibody. Of note, 15% of the patients experienced severe adverse effects. The most common grade 3 or higher side effect was oral mucositis in 9% of the patients. Five patients stopped the treatment due to side effects.One phase II study included 159 patients with locally advanced or metastatic/recurrent CSCC from 59 centers. Every 3 weeks, the patients have treated with pembrolizumab 200 mg intravenously, repeated for the utmost 35 cycles. The immediate, potent anti‐tumor effects of pembrolizumab and its manageable toxicity, portrayed pembrolizumab as a promising treatment option in these patients.In an attempt to profile the biomarker aspects of pembrolizumab therapy, Haddad et al. investigated the correlations between certain biomarkers and clinical outcomes of pembrolizumab therapy in 192 patients with metastatic/recurrent HNSCC. Among the quantified biomarkers, tumor mutational burden (TMB), PD‐L1, and 18‐gene T‐cell‐inflamed gene expression seemed to have the potential as predictive biomarkers of patients’ response to pembrolizumab.However, combining the treatment of pembrolizumab with Acalabrutinib failed to increase the efficacy of pembrolizumab monotherapy. The related toxicity of this combination was another obstacle that seemed to hinder the feasibility of this treatment.Cohen et al. applied pembrolizumab with intralesional SD‐101 in a population of recurrent/metastatic HNSCC patients. The treatment combination prompted the objective response, especially in patients who were human papillomavirus positive. The results could be due to enhanced inflammation and activity of effector immune cells inside the tumor.In a recent phase II study, the combined therapy of pembrolizumab with afatinib was tested. Additionally, a biomarker quantification was also performed. Twenty‐nine patients with recurrent or metastatic HNSCC whose disease was refractory post platinum therapy were included. The conclusion suggested that afatinib may enhance pembrolizumab efficacy with improved ORR. Also, antigen presentation and cytotoxicity induced by natural killer cells (NK cells), indicated upregulation in the tumor tissue. Nonetheless, treatment toxicity of grade ≥3 was reported in 37.9% of the cases, which can be an issue of concern in applying this combination.p = .91), progression‐free survival (p = .47), and overall survival (p = .49) of the two groups. But the toxicity in pembrolizumab treatment was lower than cetuximab.A study performed by Tao et al., to compare the effect of pembrolizumab and cetuximab in the treatment of locally advanced SCC of the head and neck. Seventy five percent of patients had metastases. There was no significant difference between the locoregional control rate  (ESCC). In patients with ESCC, they were unable to show that adjuvant durvalumab enhanced survival following neoadjuvant CCRT. However, post‐CCRT PD‐L1 expression may predict survival in patients who get adjuvant durvalumab following neoadjuvant CCRT, although it needs to be shown. The use of adjuvant durvalumab was generally safe in this research, with events equivalent to those seen in prior durvalumab monotherapy studies. Only three individuals had to stop taking the study medicine permanently due to side effects, most of which were minor. In conclusion, the current placebo‐controlled, double‐blind, randomized phase II study failed to fulfill the primary goal, likely due to the small sample size and the control arm's outperformance. They did, however, gain important information for future study design. First, after neoadjuvant CCRT and surgery, adjuvant durvalumab therapy appears to be safe. Second, patients who receive adjuvant PD‐1/PD‐L1 inhibitors may benefit from knowing their post‐CCRT PD‐L1 status. Third, because patients with ypCR have a favorable prognosis and are less likely to benefit from adjuvant durvalumab, future studies studying adjuvant immunotherapy should be cautious when enrolling this population. They are cautiously optimistic that the efficacy of adjuvant ICIs, such as durvalumab, in patients with esophageal cancer will be confirmed in larger investigations.On the other hand, multiple clinical trials evaluate durvalumab, a programmed cell death ligand‐1 (PD‐L1)‐blocking monoclonal antibody, for treating HNSCC. Arends et al. looked at circulating proteins at the start of the study to see if there were any relevant biomarkers and to figure out what pathways were linked to durvalumab's clinical outcomes. For 158 durvalumab‐treated HNSCC patients in the phase II HAWK and CONDOR trials as a discovery dataset and 209 durvalumab‐treated HNSCC patients in the phase III EAGLE study as a validation dataset, 66 serum proteins were evaluated using multiplex immunoassays before therapy. Higher baseline concentrations of interleukin‐6 (IL‐6), C‐reactive protein, S100 calcium‐binding protein A12, and angiopoietin‐2 (ANGPT2) were associated with shorter overall survival (OS) after durvalumab treatment (p.05), in comparison higher concentrations of osteocalcin were associated with longer OS after durvalumab treatment (p.05). After correcting for baseline clinical variables, all five proteins remained strongly linked with OS, with consistent results across clinical efficacy endpoints based on univariate correlation analysis. The EAGLE trial's validation dataset validated the independent associations of IL‐6 and osteocalcin with OS and preserved directional patterns for the other biomarkers discovered in the discovery dataset. Their findings show that immunosuppressive proteins play a key role in HNSCC resistance to durvalumab treatment. There was a positive link between osteocalcin and clinical outcomes, which needs further examination. In conclusion, in durvalumab‐treated patients with HNSCC, circulating IL‐6 and osteocalcin concentrations at baseline have been demonstrated to be independently linked with clinical outcomes, with trends of additional effects for ANGPT2 in three clinical studies. In clinical trials of ICI monotherapy and combination therapy, measurement of these biomarkers before and after treatment should be the priority.5.1.4Avelumab is a fully human IgG1 lambda Mab against PD‐L1 that has shown a ADCC activity.Guigay et al. examined the effect of avelumab, an anti‐programmed death ligand 1 antibody, in metastatic or refractory head and neck squamous cell carcinoma (R/M SCCHN). Patients were aged ≥18 years and had previously received platinum‐based chemotherapy. Within 6 months of treatment, some were ineligible for platinum‐based chemotherapy, and some had refractory SCCHN. A dosage of 10 mg/kg every 2 weeks of avelumab was given to patients. The efficacy and safety of avelumab were reported and had a low rate of grade ≥3 TRAEs in R/M SCCHN and heavily pretreated patients.5.1.5Cemiplimab, a high‐affinity IgG4 Mab, blocks the PD‐1/PD‐L1 pathway.Migden et al. reported a response of 50% in a phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic CSCC with 26 patients and 47% in a pivotal phase 2 study of cemiplimab for a cohort of patients with metastatic disease with 59 patients.In a study made by Rischin et al.,In a phase I trial, Babiker et al. studied 15 patients who received combined therapy of cemiplimab, cyclophosphamide, radiation therapy (RT), and granulocyte‐macrophage colony‐stimulating factor1 (GM‐CSF). Mostly seen TEAEs were fatigue, constipation, asthenia, dyspnea, maculopapular rash, and pneumonia. Only two patients faced grade ≥3 TEAE (pneumonia). The efficacy of this combination therapy was not above other PD‐1 inhibitor monotherapies in R/M SCCHN.Treatment with Cemiplimab‐rwlc (CEMI) in metastatic or locally advanced CSCC has demonstrated its efficacy. Eighteen patients were evaluated in a study, and 3 mg/kg every 2 weeks or 350 mg every 3 weeks infusions of CEMI were given to the patients. Median follow‐up was 8 months, ORR was 67%, CR was 33%, PR was 33%, and DCR was 72%. Thirty three percent of adverse events with grades 2, 3, and 5 were observed in six patients.A study was conducted by Bailly‐Caille et al. on advanced cutaneous SCC, in which the therapeutic effect of Cemiplimab alone and in combination with radiotherapy was investigated. In this study, the observed objective response rate was 47.6 in Cemiplimab consumption versus 41.6 in combined treatment. The simultaneous use of radiotherapy and Cemiplimab (3 months) caused a faster clinical‐radiological response than the use of Cemiplimab alone (5.5 months).In a study by Ríos‐Viñuela et al., 13 patients with advanced cutaneous SCC were treated with Cemiplimab. 23% of patients showed complete response and 38% partial response to treatment. 80% of patients with partial response experienced disease progression during follow‐up. 46% of patients showed mild side effects.A phase 2 study was conducted by Gross et al. to investigate the effect of neoadjuvant therapy of cemiplimab in cutaneous SCC. 51% of patients showed a complete pathological response and 13% of them showed a major pathological response, that is, less than 10% of tumor cells remaining. Also, objective response was reported in 68% of patients.5.2CTLA‐4, expressed on T cells, interacts with CD80/CD86, limiting T‐cell activation and leading to anergy.5.2.1The combination of chemotherapy as the first line therapy with ipilimumab, a human IgG1 kappa antibody to CTLA4, has not resulted in significant changes in survivalAltogether, more studies are required to find new methods and to consider the side effects of ipilimumab, to prove safer approaches.5.2.2Tremelimumab is a fully human IgG2 Mab that targets cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) and exhibits antitumoral effects by blocking the CTLA‐4 pathway.Phase II research investigated the efficiency of tremelimumab as monotherapy. There were about 244 patients in each group. One group received durvalumab as monotherapy (group 1), the second group received both tremelimumab and durvalumab as combined therapy, and the third group was standard of care (SoC). The results showed no marked differences in OS between durvalumab monotherapy or combined use of durvalumab and tremelimumab versus SoC. However, survival rates increased in 12–24 months, and response rates showed that durvalumab was a beneficial therapeutic agent.6A key mechanism of tumor resistance to immune cells is mediated by the expression of peptide‐loaded HLA class I molecule (HLA‐E) in tumor cells, which suppresses NK cell activity via ligation of the NKG2A.6.1Monalizumab is the first‐in‐class humanized IgG4 Mab targeting NKG2A, which enhances NK cell activity against various tumor cells and rescues CD8+ T cell function. It also stimulates NK cell activity against antibody‐coated target cells.7Using cMab U36 labeled with 211Astatine showed reliable results in treating rats with HNSCC; on the other hand, combining this radioimmunotherapy with cetuximab revealed better results in controlling carcinoma and drew attention to interactions between CD44v6 and epidermal growth factor receptor (EGFR).8Various Mabs, working through various mechanisms, have been studied in treating the SCC of different organs, and different results have been found. The main groups of Mabs in SCC therapy are Mabs targeting EGFR, HER2, HGF, and VEGF, alongside checkpoint inhibitors  and tumor targeting Mabs. Here, we discuss some of the most crucial roles of Mabs in SCC therapy according to what was mentioned earlier in the study, by Mab, and by organ:8.1Most HNSCCs express high levels of EGFR.Another anti‐EGFR Mab, nimotuzumab has been proven to induce promising results in SCC of different organs, including the head and neck, lung, and esophagus. It may be considered a first‐line treatment in these patients.8.2Trastuzumab, an anti‐HER2 Mab, can induce ADCC in ESCCs with high HER2 expression, especially in combination with cetuximab.Ficlatuzumab, an anti‐HGF Mab, can promote cytotoxicity in combination with cetuximab in refractory HNSCC. Nonetheless, it surely needs more investigation to evaluate its effectiveness and toxicity in clinical trials.8.3Positive outcomes in treating SCCs with PD‐1 inhibitors have been illustrated, probably due to the high expression of PD‐L1 in ESCC, CSCC, and HNSCCs.Avelumab, combined with cetuximab, has been observed to be an efficient treatment for advanced‐stage HNSCC patients who are unsuitable for treatment with cisplatin.Ipilimumab and tremelimumab, CTLA4 inhibitors, have shown controversial results in treating SCC. Although ipilimumab, in combination with nivolumab, has shown potential efficacy both in lung SCC and as second‐line therapy in HPV‐related HNSCC,8.4Bevacizumab has higher efficiency as well as similar toxicities when compared to chemotherapy and radiotherapy. It is also a good option in combination with other modalities in advanced HNSCC therapy, even as first‐line treatment.8.5Mabs have been widely used and studied in the treatment of HNSCC. Due to the fruitful results of using Mabs in clinical settings, they are considered to have a key role in this era, especially in the advanced stages of the disease. Mabs are considered excellent options in locally advanced, recurrent, and metastatic HNSCCs. The most potent Mabs in HNSCC are EGFR antagonists and checkpoint inhibitors, especially PD‐L1 antagonists.8.6Outstanding results of treating ESCC with Mabs have encouraged their wide use for this cancer. PD‐1 inhibitors, especially nivolumab, have exhibited favorable efficacy in ESCC.8.7CSCC has also shown promising responses to Mabs, especially checkpoint inhibitors.8.8Several Mabs, including nimotuzumab, bevacizumab, ipilimumab, necitumumab, and pembrolizumab have shown acceptable efficacy in treating Lung SCC as a type of non‐small cell lung cancer.9Altogether, treatments with different Mabs have shown excellent efficacy along with acceptable safety in the SCC of different organs. Therefore, Mabs are considered excellent options in treating SCC, especially for the advanced stages of the disease. Overall, two highly potent types of Mabs in SCC therapy are anti‐EGFR Mabs and checkpoint inhibitors, especially cetuximab, nimotuzumab, and PD‐1 inhibitors. Cetuximab can also be used not just as first‐line treatment in R/MHNSCC, but additionally as a second and third treatment due to its strong response rate. Bevacizumab is another beneficial option to be added to other modalities; it can indirectly decrease cell proliferation and enhance apoptosis By reducing the nutrient supply to the tumor. Furthermore, when taken with standard anticancer medicines, bevacizumab is likely to have additional antitumor effects. It was also discovered that patients with recurrent squamous‐cell carcinoma of the head and neck who received zalutumumab had longer progression‐free survival. Nivolumab has also emerged as a remarkable therapeutic option with an acceptable toxicity profile in patients with R/M HNSCC who have had postplatinum therapy. Although some Mabs have shown promising outcomes in SCC therapy, their application as a part of cancer treatment depends on further investigations on their cost‐effectiveness and predictors of response. Additionally, phase 4 trials and studies, comparing different Mabs to identify their advantages and disadvantages and choosing the best choice in each clinical setting are required. Due to significant efficacy, several Mabs are considered valuable choices in different lines of the treatment of SCC of different organs. However, some concerns still exist. Some Mabs still need more investigations in terms of safety, underlying mechanisms of action, and the extent to which they enhance treatment response. Cetuximab is a widely studied Mab that had shown severe adverse effects in first trials. However, recent studies in the present decade improved its safety by setting different combined therapies and more exact regimens.On the other hand, some Mabs, such as bevacizumab, trastuzumab, and pembrolizumab, revealed very slight adverse effects in mono‐ and multi‐therapies. Combining these safe Mabs with more efficient but less safe ones would develop more promising regimens to adjust the adverse effects of Mab‐therapies and achieve the best antitumor treatments in the future. The high price is another obstacle to the wide use of Mabs, particularly in developing countries. The development of safe new effective methods of Mab production, Mabs to new biomarkers, and dual‐targeting Mabs may propose Mabs as a promising treatment of SCC of different organs in the future.Amirhossein Tamimi: Investigation (lead); methodology ; resources ; visualization ; writing – original draft (lead); writing – review and editing (supporting). Atena Tamimi: Investigation (supporting); methodology ; resources ; visualization ; writing – original draft (supporting); writing – review and editing (supporting). Fatemeh Sorkheh: Conceptualization (supporting); investigation (supporting); methodology ; resources ; visualization ; writing – original draft (supporting); writing – review and editing (supporting). Saba Mardekatani Asl: Conceptualization (supporting); investigation ; resources ; visualization ; writing – original draft (supporting); writing – review and editing (supporting). Arezoo Ghafari: Conceptualization ; investigation (supporting); visualization ; writing – original draft (supporting); writing – review and editing (supporting). Arian Ghannadi Karimi: Conceptualization (supporting); investigation (supporting); resources (supporting); visualization ; writing – original draft (supporting); writing – review and editing (supporting). Gisou Erabi: Conceptualization (supporting); investigation ; visualization ; writing – original draft (supporting); writing – review and editing (supporting). hossein pourmontaseri: Conceptualization ; project administration (supporting); supervision (supporting); visualization ; writing – original draft ; writing – review and editing (supporting). Niloofar Deravi: Conceptualization (lead); investigation (supporting); methodology ; project administration (lead); supervision (lead); writing – original draft (supporting); writing – review and editing (lead).The authors declare no conflict of interest.